Purple Canaries

Joyce Gould with Jill Gould

Acute Porphyria “Missed Diagnosis” Patients Speak Out

ACUTE PORPHYRIA PATIENT/CAREGIVER DISCUSSION PAPER

An Open Letter/Response to Corresponding Authors: Jean-Charles Deybach, MD, PhD and Robert J. Desnick, PhD, MD

From:   Joyce Gould, mother, caregiver and author of “Purple Canary” on behalf of black-listed, “a.p. missed diagnosis” acute porphyria patients/caregivers

Re:       “International Porphyria Molecular Diagnostic Collaborative [IPMDC]: an evidence-based database of verified pathogenic and benign variants for the porphyrias.”

Copy to: Brenden Chen, MD, PhD; Sharon Whatley, FRCPath; Michael Badminton, MBChB, PhD; Aasane K. Aarsand MD, PhD; Karl E. Anderson, MD; D. Montgomery Bissell, MD, Herbert L.Bonkovsky, MD, PhD; Maria D. Cappellini, MD; Ylva Floderus, PhD; Edith C.H. Friesema, PhD; Laurent Gouya, PhD; Pauline Harper, MD, PhD; Raili Kauppinen, MD PhD; Yonina Loskove, BA; Pavel Martásek MD, PhD; John D. Phillips, PhD; Hervé Puy, MD, PhD Severre Sandberg, MD, PhD; Caroline Schmitt, PharmaD, PhD; Jordi To-Figuereas, PhD; Yedidyah Weiss, BA; Makiko Yasuda, MD, PhD.

And:   Recipients identified by “missed diagnosed” patient/caregiver community

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I want to thank you all for the “gift” (the above referenced journal article) that appeared May 12 (Mother’s Day) on my computer for this “Special Article” provided a “Special Opportunity” for me to address your group as one. This response is, essentially, a lengthy whistleblowing effort to explain why IPDWC’s plan to present the above referenced document at the ICPP as “proof” that the International Collaboration’s acute porphyria genomic/genetic diagnostic protocol is seriously flawed.

For the past several years, I have been involved with and represent via this letter a coalition of desperately ill yet determined patients/caregivers located throughout the US and in various countries outside the US. We’d been forewarned that a paper with this topic was in the works and now that it’s arrived, our response follows.

Together, we seek answers that have been elusive for far too long concerning our and/or our loved ones’ acute porphyria. In spite of naysaying experts (some of whom have taken great pains to silence us) who refuse to acknowledge that these patients’ porphyrias exist, we persist—in a determined, macabre maypole-esque march. Each of us holds his/her contribution, an information, experience or research “ribbon” that with each start and stop step is woven into a complex pattern reminiscent of the intricate acute porphyria(s) that impact our lives.

The “missed diagnosed” patient/caregiver community was launched in direct response to untoward behaviors and attempts by the US porphyria advocacy organization/experts to banish and silence them. Dubbed the “misfit porphs” by one intrepid patient, and “atypical presentation” in the book, Purple Canary, neither adjective quite fits. For this response, I settled on “a.p. missed diagnosis” although “intentional missed diagnosis”—at least in the United States of America—seems to be more appropriate.

Fortunately, porphyria experts outside the US continued to research, document, and produce information that our community participants scrutinized and shared amongst ourselves and with any physician who express(ed) interest. This response is made on behalf of this “a.p. missed diagnosis” community which was initiated by and is comprised of determined, intelligent human beings. Each holding his/her “maypole ribbon” contribution, our intent here is to illustrate why distrust of all things porphyria is at an all-time high in the US—and is increasing in countries where porphyria specialists are unwilling to move one iota from the not infallible acute porphyria first-line urinary biochemical proof diagnostic protocol (U-BP). 

None of us are trained medical doctors or scientists yet according to the New York State Rare Disease Alliance1 and author Philip R. Reilly, MD, JD (“Orphan: The Quest to Save Children with Rare Genetic Disorders”),2 we are each considered to be disease experts. Self-trained via experience and research, early “disease experts” came together and established online platforms to exchange information and tips aimed at self-treating the acute porphyrias that US porphyria experts insisted (and still insist) they didn’t/don’t have. Participation by similarly “dissed” patients/caregivers” burgeoned and continues to expand to this day—drawing in participants from outside the US.

We have no motive other than to help dreadfully ill patients (some of whom are also caregivers) who’ve been stonewalled, summarily dismissed, mislabeled and left to their own devices (some for decades) to face acute porphyria untreated and unheeded by porphyria specialists who curiously adhere to, in Europe what appears to be confirmation bias, and in the US, what appears to be a well-veiled, decades-long “agenda.” Neither fits with true scientific reasoning. At the opposite end of the AHP spectrum from ASHE, these patients share a commonality in that their bodies have not met the US acute porphyria diagnostic urinary biochemical proof (U-BP) criterion. They are low- and/or no-U-BP excreters and are the reason why serious, in-depth unbiased scientific genetic and functional AHP studies must be conducted (and connected) before an IDDVP&BV can ever be considered to be truly complete and reliable.

It has been recognized from the beginning of medicine that without a complaining patient there would be no raison d’etre for a physician. As author Dan Brown wrote, “Sometimes a change of perspective is all it takes to see the light.”3 We ask that each of you carefully and objectively consider what is presented herein because as patients and caregivers, we offer information/insight from that most important piece of the medical triad (illness/patient/ physician)—the patient. God-willing, we hope this communication will encourage some of you to seize research opportunities that have lain fallow or were never considered to begin with to make ground-breaking findings. Dedicated porphyria researchers with integrity can help put a stop to inhumane medical indifference and to salvage lives that have been cast aside like genetic garbage—and perhaps eventually provide effective (perhaps cost-saving) treatment options that can lead to better quality of life for acute porphyria patients and improve societies everywhere.

Looking at the big picture, there are tens, hundreds, perhaps even thousands of such patients strewn around the world. If I/we were to venture a guess, US might well have the highest prevalence of such erroneously labeled “misdiagnosed” or (worse), “asymptomatic” or “latent” patients. Because what they really are, are “missed-diagnosis” patients who suffer with undiagnosed, untreated acute porphyrias.  “Misdiagnosed,” Asymptomatic,” “Latent,” “Conversion Disorder.” All were labels attached to my daughter by medical professionals—beginning with US porphyria experts. All very wrong.  After her AIP diagnosis was stripped 5-1/2 years after having been bestowed by the same geneticist, I learned of the closed Facebook forums and got a “whole new perspective.” Based on years’ worth of evidence, I came to believe that my daughter’s AIP hadn’t been “misdiagnosed.” Her condition was not asymptomatic. Nor was it latent. No, her case was/is a calculatedly missed diagnosis. And she wasn’t/isn’t alone.

The IPMDC paper opens with the statement, “With the advent of precision and genomic medicine, a critical issue is whether a disease gene variant is pathogenic or benign.”4 That paragraph closes with “Here we describe the overall objectives and the initial efforts to validate pathogenic and benign variants in the respective heme biosynthetic genes causing the AHPs.”5

According to the current porphyria expert train of thought, if an AHP gene is benign it won’t cause AHP. However, evidence to refute the thinking that a single gene “causing” anything seems to be popping up “everywhere.” A genetics expert noted, “[b]e aware that single position genetic alleles rarely “cause” disease, but instead contribute to risk.”6 From the book, “She has her Mother’s Laugh: The Powers, Perversions and Potential of Heredity,” is this, “From the earliest days of genetics, researchers recognized that it was a fallacy to talk about a gene being “for” a trait or a disease. Genes don’t have so much power. They exist in an environment, and their effects may be very different in different surroundings.”7

An article in The Atlantic raises the point of an omnigenic model and notes, “There’s been this notion that for every gene that’s involved in a trait, there’d be a story connecting that gene to the trait… that’s only partly true. [T]here [are] “core genes” that follow this pattern. They will affect traits in ways that make biological sense. But genes don’t work in isolation. They influence each other in large networks, so that “if a variant changes any one gene, it could change an entire gene network…these networks are so thoroughly interconnected that every gene is just a few degrees of separation away from every other. Which means that changes in basically any gene will ripple inwards to affect the core genes for a particular trait.”8

A discerning patient in our community concurs, “This concept was embraced by the French and presented in the eloquently written paper, From a dominant to an oligogenic model of inheritance with environmental modifiers in acute intermittent porphyria.”9 She urges porphyria experts to organize a dedicated scientific group aimed at identifying possible oligogenetic influences on all eight types of porphyria phenotypes, testing methods, etc.

The objective of this response paper, though, can be found sandwiched within that opening paragraph, “To date, there is no public database that documents the likely pathogenicity of variants causing the porphyrias, and more specifically, the AHPs, with biochemically and clinically verified information.10 [Note: Emphasis author-added as this is the “elephant in the acute porphyria room” when it comes to diagnostics. As such it is at the core of both the IPMDC database’s justification and our “a.p. missed diagnosis” patient/caregiver community’s quandary.]

While there may not currently be a public genomic database dedicated exclusively to the porphyrias, there are worldwide accessible databases in which all of the porphyrias are included. Instead of recreating the wheel, why didn’t the IPMDC approach an established database service with the suggestion that it operate as a partner/ subgroup to contribute variant data for the porphyrias?  Based on the whole of the IPMDC paper—and more specifically, the acute porphyria genetic mutations spotlighted in it, a cadre of “missed diagnosed” patient/caregiver sleuths feels that such a partnership was likely never considered by the US contingent. Because doing so would have been detrimental to what appears to be a long-standing US agenda to insure that the US acute porphyria patient population remains within NIH’s rare disease parameters. This in turn all but assures FDA orphan drug consideration for medications—specifically Panhematin® (Recordati Rare Diseases and predecessors Abbott, Ovation, Lundbeck) and Givosiran (Alnylam Pharmaceuticals) as well as access to a range of services and funding provided by NIH and other governmental agencies. We in the “a.p. missed diagnosis” communities believe this agenda to insure that the acute porphyrias remain “rare” has resulted in the exploitation of very sick people being denied diagnoses for reasons that do not appear to be scientifically based.

Let us be clear. There is no intent whatsoever to minimize or take anything away from patients whose acute porphyria has been “expert-confirmed.” That is, those whose bodies excreted (and may still excrete) the hallmark of AIP diagnosis—requisite urinary biochemical evidence (even if only once) and so were granted the diagnosis of acute porphyria. But we also know that for so many of those “expert-confirmed” patients, having the diagnosis does not fully dispel the brutal agony that the acute porphyrias bring to bear.

This isn’t a competition—it’s about getting to the truth—for all who suffer with any type of acute porphyria. We believe what will be revealed throughout this response will invite (no, demand) paradigm shifts. And those shifts will be based on truth. And that truth will ultimately eliminate scientific restraints that for generations have held acute porphyria patients in bondage. We are together in this. We refuse to be denied a voice or to be shut down any longer.

Patient/Caregiver Commentary Response re: Introduction; The acute hepatic porphyrias; Biochemical and molecular diagnosis of the AHPs:

There is no dispute from any in our community that “AHPs are characterized by acute life-threatening attacks of non-specific symptoms” or “the major manifestations of the acute porphyrias [can include] excruciating abdominal pain, a progressive peripheral neuropathy, and mental disturbances (e.g. confusion, fatigue, insomnia, etc.).” or “[t]he autosomal dominant AHPs are distinct from other porphyrias because of their common overproduction of the porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) which are understood to [facilitate] the acute attack symptoms through a neurotoxic mechanism.”10 Patients/ caregivers in the “missed diagnosed” community experience and/or bear witness to such symptomatology daily.

What is disputed is the hyper-attention US porphyria experts routinely heap on the dogmatic first-line acute porphyria diagnostic criterion espoused by US and European porphyria experts of, “Acute attacks of porphyria are diagnosed by showing marked elevation of urinary PBG and ALA, the diagnostic “gold standard” of these diseases.”11 And the pervasive belief of US/EU porphyria experts that a normal urinary PBG or near normal ALA and/or PBG excretion in symptomatic new patients excludes the diagnosis of an AHP. By the way, urinary biochemical evidence wasn’t even mentioned in the IPMDC authors’ list of major manifestations of the acute porphyrias—yet it is the “gold standard” to diagnosis AHP?

US porphyria experts evidently adopted the European U-BP protocol very early, probably because Scandinavian immigrants were among the earliest of European groups to settle in America. As porphyria gained a medical presence here, it is logical that the Swedish Porphyria diagnostic protocol was followed. However, by the time the American Porphyria Foundation (APF) was up and running, generations had passed; European porphyria knowledge and technology had substantially expanded/improved yet the Swedish Porphyria diagnostic protocol held steady throughout Europe—and therefore, in the US—without dissent and without bona fide scientific support.

Given the ordeal that for a decade or so the APF cofounder herself, never having heard of porphyria, had suffered through, (more fully addressed in our response to the Porphyrin precursor measurements section), it is truly a wonder why the APF formulation team didn’t hearken back to her documented experience and recognize that other people might experience the same symptomatology of severe symptoms without U-BP. Instead, US porphyria experts apparently tightened its grip on the European/Swedish Porphyria diagnostic protocol.

The APF first quarter 2013 newsletter proclaimed, “Misdiagnosis has become a common problem in patients who do not have a Porphyria, but present with suggestive symptoms and have clinically insignificant small or non-specific elevations in biochemical tests.”12 That was followed in the section’s next paragraph with, “DNA analysis is considered the “gold standard” for porphyria diagnoses [followed by] “[b]iochemical testing is recommended prior to DNA testing to determine whether a diagnosis of porphyria is likely to suggest the specific type of porphyria.”13 By this time, Dr. Desnick, Mount Sinai and APF and Alnylam Pharmaceuticals had apparently entered into a partnership.

The next APF newsletter (2nd quarter, 2013), introduced an NIH-sponsored longitudinal study to be conducted by the APF-connected Porphyrias Research Consortium, provided a recap of the International Congress of  Porphyrins & Porphyrias’ successful Patient Day and noted that “[m]any of our Protect the Future trainees attended the conference as well as made presentations.”14 Three pages after that story was APF’s announcement that Alnylam Pharmaceutical’s president had made during his presentation at the International Congress about a “breakthrough discovery” regarding treatment for the acute porphyrias; the paragraph closed with “The APF will be announcing updates on the treatment and clinical trials.”15

It should be noted that prior to Alnylam Pharmaceutical’s involvement with APF et al, AIP had been the “darling” of the acute porphyrias with only the briefest attention given to HCP, VP and ADP. However, it appears after the Alnylam/APF partnership began, the US then the EU began referring to the acute porphyrias as AHPs (incorporating the four acute porphyrias)—and describing them as “ultra-rare.”

While porphyria experts in other countries have periodically stated through the years/decades that porphyria is not as rare as thought, we could only identify one paper in which the sentiment was stated that included US experts’ endorsement. APF SAB members Anderson, Bissell, Bloomer, Pierach were co-authors of Environmental Chemical Exposures and Disturbances of Heme Synthesis which stated, “Porphyrias are relatively uncommon conditions but are probably unrecognized. The prevalence of genetic predisposition to porphyria probably has been underestimated in the general population because of the limited availability of clinical tests for specific heme-synthesis enzymes and because prevalence studies generally have focused more on family members of affected individuals and less on the general population.”16 That was the first and last statement we’ve found about acute porphyrias being not ‘as rare as thought’ had APF-connected porphyria experts’ names attached to it.

Patient/Caregiver Commentary Re: Rationale for an International Diagnostic Database of Verified Pathogenic and Benign Variants (IDDVP&BV); The Human Gene Mutation Database; Direct-to-consumer testing and variant interpretation services; ACMG and AMP guidelines for sequence variant classification

            As patient/physician interest in disease identification via DNA testing rocketed upward, geneticists everywhere scrambled to get a handle on “precision medicine” molecular diagnostic techniques. Porphyria patients were/are among those who queued up, hoping that scientific proof of disease(s) would lead to treatment, perhaps even cures for their porphyrias, so it certainly makes sense that porphyria experts jumped on board.

IPMDC authors acknowledge the Human Gene Mutation Database (HGMD) as “the most reliable resource for variant data in the AHP genes”yet hinted at skepticism of HGMD’s curation policy, stating it “may be questionable.”17 However, if the concern that “porphyria diagnostic laboratories worldwide frequently identify additional novel pathogenic or benign variants that are not published and as such are not available in the HGMD”18 is in fact accurate, who’s to say that IDDVP&BV won’t face the same (or similar) compliance issues? Another point to be made is the (very) fine print disclaimer* closing out Mount Sinai’s genetic communications which states, “While mutation analysis by DNA sequencing is very accurate, rare errors can occur, for example, due to sample mix-up, laboratory errors and/or genetic polymorphisms. This test was developed and its performance characteristics were determined by the Genetic Testing Laboratory at the Icahn School of Medicine at Mount Sinai.It has not been cleared or approved by the FDA. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes. Pursuant to the requirements of CLIA ’88, this laboratory has established the test’s accuracy and precision.’”19 [*This disclaimer appeared on each the three communication documents I/my daughter received from Mount Sinai (2008, 2014 2018); however the 2018 version (Revised Report) was the only one to contain the term “polymorphism.”] This begs questions such as, does Mount Sinai report its data to other databases they are associated with—and from which they probably? How will IPDWC insure data integrity if there are other labs developing their own tests and performance characteristics (in the US, without FDA clearance or approval)? Further, according to Genomic variant sharing: a position statement, doing so can seriously jeopardize patients’ lives, “…patients with the same rare disease may be scattered across the globe currently benefit from shared data and derived knowledge in databases such as ClinVar and DECIPHER, and services that are not currently sharing their clinical data owe a substantial data debt and risk perpetuating current data biases.”20

That being said, the rationale behind the statement(s), “some variants’ pathogenicity may be questionable” and “In the case of AIP, of the total 423 HMBS variants in version 2019.1, 141 (33%) were missense variants, many of which were reported as disease-causing without sufficient evidence for verification”21 definitely got my attention; “Intronic variants that alter splicing can also be difficult to assess unless there is clear clinical and biochemical documentation [Note: emphasis author-added] of their pathogenicity. For example, HMBS c.613-31A>G, also known as IVS10-31A>G, was initially reported as a pathogenic variant, but subsequently found to be very common in individuals of African or Afro-Caribbean descent.”22

 “HMBS c.613-31A>G, also known as IVS10-31A>G, was initially reported as a pathogenic variant,” was the clincher. I apologize in advance to my patient/caregiver colleagues; the following might be hard to process. Hopefully the trained professionals reading this will be able to follow it. Before continuing, please note: I hold (and am able to provide upon request) duly notarized Connecticut probate court certification of “Conservator of Person” and “Conservator of Estate” for my AIP daughter. To that end, I am legally permitted to discuss her medical case—thankfully, with her enthusiastic endorsement. And so I shall.

The IPMDC authors state, “HMBS c.613-31A>G, also known as IVS10-31A>G, was initially reported as a pathogenic variant [Puy, 1997] but was subsequently found to be very common in individuals of African or Afro-Caribbean descent [ExAc 2016; Robreau-Fraolinim 2000]. Although HGMB currently classifies c.613-31A>G as questionably pathogenic, recent data in the United States indicate that c.613-31A>G heterozygotes or homozygotes have a benign HMBS polymorphism (gnomAD frequency in Africans: 0.43, Latinos: 0.021, and Caucasians: 0.0023).”22 This statement begs challenging. Here’s why: IVS10-31A>G was the only mutation that Dr. Robert J. Desnick of Mount Sinai identified in my daughter’s original (2008) AIP diagnosis then again five and a half years later (2014) when he revoked that same diagnosis. Except, in the original diagnosis, he’d identified it as IVS10-31A>G; his subsequent revocation letter identified it as IVS10-31A>G (c.613-31A>G) and was accompanied with, “Initially this alteration was reported as pathogenic, resulting in [AIP]. However, review of literature and porphyria physician experts suggests that this alteration is a polymorphism. Furthermore, the alteration is now listed in NCBI, dbSNP as a single nucleotide variant (rs28990987) with a frequency of 0.5% in the general population, including about 46% among African-Americans, 58% among sub-Saharan Africans, and 0% among Caucasians. Based on this information, we report that [your daughter] is most likely not affected with [AIP].”23 With that, Dr. Desnick had opened Pandora’s Box into which I jumped and settled in for what I expected would be a long haul. And so it has been.

In time, a porph patient/friend with remarkable sleuthing abilities tracked rs28990987 to a medical journal article published by out-of-U.S. porphyria experts. I made contact with the authors and received via email the confirmation I’d half-expected, “single nucleotide polymorphism [SNP] marker rs28990987…is not [causal for AIP] but it is a sure Negroid (African) marker and may eventually be present in any particular AIP patients who has a Negroid ancestry, regardless of its physical appearance or geographic origin.”24

That same email included a medical opinion refuting 2014and 2018 Mount Sinai’s diagnostic conclusions regarding my daughter’s AIP. Based on lab results I’d shared with the porphyria experts, they provided the following summary, “The critical result for a diagnosis of AIP is the level of enzymatic activity of hydroxymethylbilane synthase, whether the patient is presenting an acute crisis or if never one has occurred. The person is nonetheless a carrier of one mutation capable of producing an acute crisis. A large proportion of carriers indeed never had one. But it is not mandatory. In the presence of typical symptoms, a low enzymatic activity is diagnostic. Even with absent U-BP (read paragraph above again). We are willing to contribute to the finding (or confirmation) of the actual molecular diagnosis of [her] ailment…).25Additionally, these experts recommended that “splicing mutations in intron 2 (IVS2+insG), intro 10 (IVS10-1G>T and intron 7 (IVS7+1G>A) be tried.”26

Because these porphyria experts had noted, “The person is nonetheless a carrier of one mutation capable of producing an acute crisis”27 and offered expert advice as to which mutations to “splice,” I was curious to see what exactly Dr. Desnick’s lab had found. So a few months after receiving that medical opinion (and offer), I requested all underlying/ supporting data for my daughter’s DNA testing results from Mount Sinai’s genetic laboratory. When that report arrived, I was surprised to see a dozen different acute porphyria variants (7 AIP, including c.613-31A>G with rs28990987; 2 HCP, and 3 VP) on Dr. Desnick’s “Revised Report.” All were classified as benign. I cross-checked and confirmed each variant with ClinVar). With the exception of rs28990987 (which was reported “not found” by ClinVar), none of the other variants listed on my daughter’s underlying/supporting data had appeared on any of Dr. Desnick/Mount Sinai’s previous communications.

The 2018 “Revised Report” held an unexpected (but welcome) surprise—a reference/source for the heredity information that supported the revocation of my daughter’s AIP dx but hadn’t appeared in is 2014 revocation letter. This time, four years later, it had. It said, “Previously, we reported that [your daughter] has Acute Intermittent Porphyria alteration, IVS10-31A>G. Initially, this alteration was reported as pathogenic, resulting in Acute Intermittent Porphyria (Puy et al., Am. J. Hum. Genet, 60:1371-1383, 1997). However, the Puy group subsequently reported that the lesion was benign as it was found in ~38% of a population of African and Afro-Caribbean ancestry (Robreau-Fraolini et al., Hum. Genet.,107:150-159, 2000). The frequency of this variant in various genome databases includes that this alteration is a common benign variant. The alteration is now listed in NCBI dbSNP as a single nucleotide variant (rs28990987) with a frequency of 4% of the general population, including about 43% among Africans, 2% among Latinos, and 0.2% among Caucasians.”28

This reflected changes from previous supportive heredity info, i.e. significant ↑ in “general population” (change from 0.5 to 4%) and slight ↑ among Caucasians (from 0 to 0.2%). However, the African–American and sub-Saharan identifiers were dropped altogether, while African (43%) and Latino (2%) were added. No reference (source) was provided for this heredity information. But it didn’t matter—I now knew that the “change” in variant classification had happened ~2000. This was concerning. My daughter’s AIP diagnosis had been granted near the end of 2008. The Robreau-Fraolini et al study had been published eight years before (2000). Were we to believe that Dr. Desnick of Mount Sinai was unaware of this alteration’s “reclassification”/“re-assignment” when he’d first identified it in my daughter’s DNA in 2008 and/or when he used it nearly six years later to yank that same diagnosis out from under her? Oddly, no mention of the rs28990987 alteration could be found in the Robreau-Fraolini study. However, disconcertingly, the study addressed splicing defect IVS10-1 G to T, explaining that “two common new intragenic polymorphism sites” had been identified, one “in intron 10, A/G dimorphism at position 7052 (A:0.56; G:0.44).”29

In the 2010 journal article my friend had tracked it to, rs28990987 was identified “rs28990987 (IVS10 7052 T>C) whose allele C is absent in Europeans, Asians and Venezuelan individuals, but has a frequency of 0.583 in Africans.”30 This was confounding. Could it be that VS10 7052 T>C is yet another identifier for ISV10-31A>G (c.613-31A>G) or might it be connected to intron 7 (IVS7+1G>A), which the out-of-U.S. porphyria experts suggested splicing?

To confuse the matter further, a 2011 study conducted by Dr. Desnick and Mount Sinai lab colleagues/staff comprised of seven patients diagnosed with AIP, VP or HCP came to my attention. Diagnosed meant the subjects had met the U-BP criterion. One study participant (H-AIP-1) was a 33 year old female with the IVS10-31A>G/+ mutation and the clinical status of “Symptomatic, on hemin therapy;” with U-ALA of 5.6 and U-PBG of 0.4.31 If, in 2000,  IVS10-31A>G (aka “rs28990987”—and if this is the correct identifier) had been found to be benign, why would the 2011 H-AIP-1 study subject with mutation IVS10-31A>G’s status have been “Symptomatic, on hemin”? And why was my daughter, allegedly also with mutation IVS10-31A>G (aka “rs28990987”) but whose body had yet to excrete the “gold standard” benefit from glucose/Panhematin® treatments for five and half years—until out of the blue, deemed to not have AIP at all?

Finally, if she “definitely does NOT have any porphyria,”32 as Dr. Desnick’s APF SAB colleague, Dr. Tishler then of Brigham and Women’s Hospital insisted in a 2015 letter to me, why is it her symptoms resumed with a vengeance when those Panhematin® treatments stopped—and why is they can also be relieved by IV glucose?

The well-presented 2002 Molecular and Biochemical Studies of Acute Intermittent Porphyrias in 196 Patients and Their Families pours more fuel on this fire. In Figure 1 of the study, titled “Exon/intron organization of the human PBGD gene and reported mutations responsible for AIP,” the mutation IVS10a͢͢͢͢͢→g appears beneath the heading W198X.33 Published two years after the Robreau-Fraolini et al study, it’s hard to believe that these and other highly-respected genetic/porphyria experts had not known the mutation had allegedly been reclassified to benign status.

Further, IVS10 (splicing defect) 613-31A→G also makes an appearance in a 2002 study published by Italian porphyria experts. Hematologically Important Mutations: Acute Intermittent Porphyria identified this and more than a hundred others in the “Mutations in the HMBS Gene Responsible for Acute Intermittent Porphyria” category Note: emphasis author-added].34

It doesn’t end there. Based on a study of three homozygous dominant AIP cases in Spain, the IPMDC authors wrote, “If it [the c.613-31A>G variant] were pathogenic, all homozygotes would be expected to have infantile- or juvenile-onset of homozygous dominant AIP, which is a severe neurodegenerative disorder with early demise.”35They continued, “Further support for its [c.613-31A>G] benign status is the finding  of individuals with a known HMBS pathogenic variant and markedly elevated ALA and/or PBG, who were also heterozygous or homozygous for c.613-31A>G, but without severe early-onset symptoms36 [Note: emphasis author-added] Question—if this “further supports” the variant’s benign status (and if benign means not causative), why did the subjects (esp. heterozygous) have markedly elevated ALA and/or PBG in this and in Dr. Desnick’s previously mentioned 2011 study? It is just incredulous to imply that all of these experts (and there probably are many others) were not aware that IVS10-31A>G had been “reclassified” to benign status.

Patient/Caregiver Commentary Re:  Direct-to-consumer testing and variant interpretation services

Generally speaking, some Americans can at times be curiously inquisitive about another’s background (heredity). As it happens, both of our children are adoptees with the same bio-birth mother so knew of their maternal heredity but craved knowledge of their paternal side. So we ordered DTC genetic testing for them as Christmas gifts—Ancentry.com for our son; 23andme for our daughter. The results provided what our kids’ longed to know—paternal heritages. 23andme confirmed that my daughter does have sub-Saharan genetics and after having been left desperately ill and completely demoralized following the revocation of her AIP dx, she gratefully embraced the small “sense of self” that 23andme had provided. Too, she was able to trace her paternal ancestral trail from sub-Saharan Africa to Spain to Puerto Rico to America.

However, when I asked her if she wanted to investigate 23andme’s “health risk” component, she adamantly declined, saying, “I don’t want to know anything else that’s wrong with me.” She’d been burned so badly that I respected her wishes and backed off. For a while. My initial skepticism, diminished by 23andme’s having matched sub-Saharan genetic heredity data to Dr. Desnick’s 2014 and 2018 Revised Reports, gave way to curiosity. After reviewing the out-of-US porphyria experts’ medical opinion, I asked for help from a trusted friend with experience in downloading Livewello to look into my daughter’s porphyria status. Alarmed by her findings and needing to see it myself, I downloaded the raw data to Livewello, located the Porphyria Profile template (ALAD, ALAS2, CPOX, FECH, HFE, HMBS, PPOX, UROD, UROS) and printed the entire report. I then entered each of the report’s porphyria variants into ClinVar and produced “Interpretation Reports” for each of the Livewello variants attributed to her, regardless of phenotype designation (-/-;-/+;+/-;+/+; NG). Not unexpectedly, ClinVar identified the majority of variants as “benign” or (a few) “likely benign.” Nonetheless, given the runaround we’d found ourselves enmeshed in regarding my daughter’s horrific medical condition vs her “benign” DNA results received from Dr. Desnick/Mount Sinai, the totality of what I learned from the 23andme/Livewello to ClinVar trail raised flags:

  • The clinical significance of one ALAD variant came up “Conflicting interpretation of pathogenicity; Likely benign; Pathogenic;”
  • The clinical significance of one CPOX variant came up “Pathogenic;”
  • The clinical significance of one FECH variant came up “Conflicting interpretation of pathogenicity;”
  • The clinical significance of one HFE variant came up “Pathogenic, other, risk factor;”
  • The clinical significance of a different HFE variant came up “Conflicting interpretation of pathogenicity, association, other, risk factor;”
  • Several variants (including HMBS rs28990987) were “not found in ClinVar” however:
  • The clinical significance of two different HMBS variants came up “Pathogenic;”
  • The clinical significance of one UROD variant came up “Pathogenic;”
  • The clinical significance of one UROS variant came up “Uncertain significance.”

Other than rs28990987, none of the 23andme/Livewello variants (acute, hepatic and cutaneous porphyrias) appeared on the underlying/supporting data I’d received from Mount Sinai. So the question was/is does my daughter actually have all the variants identified by Livewello? And if so, are the ones identified as pathogenic by ClinVar correct? Given the years of persistent, recurring symptoms (including but not limited to abdominal pain; nausea; vomiting; bowel dysregulation; extremity pain and weakness; anxiety; restlessness and severe convulsions), frequent low (extremely low) PBGD readings, and the “possible” biochemical evidence” (U-BP) intermittently excreted over the years (but not collected)—yes, she has porphyria. What other disease with a constellation of neurologically-based symptoms (excruciating abdominal, back and leg pain; progressive peripheral neuropathy; mental disturbances and convulsions) successfully responds to glucose infusions and resolves with Panhematin®?

The direct-to-consumer aspect of genetic testing companies like 23andMe, AncestryDNA, MyHeritage DNA, etc. is precisely what attracts people to such service offerings. All things considered, as far as education, experience, intelligence and the ability to voice concerns/questions to their physicians, contemporary patients are eons above those of generations’ past. This aptly describes patients and caregivers in our “missed diagnosed” community. Having had their porphyria diagnoses flatly denied (withheld) and/or revoked, the need to know why their illness worsened compelled (and still compels) “missed diagnosed” patients to seek DTC services—even some who’d also had DNA testing completed by one or more “certified labs.” So it is no wonder why “individuals who have negative biochemical test results for the AHPs have obtained their underlying DTC genotype data and used third-party companies to interrogate the SNPs in the heme biosynthetic genes.”37Many if not most of these patients compared results between the various tests (DTC and certified labs) and, not surprisingly, noted discrepancies. Indeed, many “interrogated” ClinVar (and/or similar databases) for DTC results and turned up clinical significance(s) of “benign,” “uncertain significance,” “not found” and “pathogenic.” Yet the certified lab (specifically Mount Sinai, Invitae) results mostly returned variants of benign status which conflicted with one (or more) DTC results. As one would imagine, this fueled (and fuels) patient skepticism. Suspicions of possible manipulation of “certified laboratory” results and/or data input is rampant.

Not only did I “interrogate” DTC generated genotype data, I “interrogated” Mount Sinai-provided genotype data as well. Why? Because it is my job as a mother to listen to my gut and intuition. My kid’s life is still on the line and no professional’s ego, feelings or agenda is above my doing anything within the law to help her. I, like every other mother/caregiver in this coalition, will never apologize to anyone for that.

Furthermore, supplying results directly to consumers appeals to patients. Unlike European guidelines of not sending reports directly to patients but rather to physicians/clinicians who may provide the patient with a copy,US federal HIPPA laws were enacted for that very purpose. Patients are entitled to receive medical reports pertaining to their health in order to make informed decisions—and physicians must comply with that request.  

Another DTC genetic testing aspect that appeals to patients is that the collection receptacles are anonymized. Consumers who go the DTC route sign an agreement stating that any raw data generated can be sold to third parties such as drug companies and universities for, essentially, “greater good” research. Scientists use the data to learn more about genetics and various conditions and diseases in hopes of learning more about diseases and to possibly find cures and treatments. Law enforcement can also obtain consumers’ DNA data via a court order.

Countless desperate “missed diagnosed” patients flocked to DTC genetic information services. Some shared the status of porphyria mutations identified by the companies they’d purchased data from. Apparently unnerved, APF addressed the issue in its March 2016 newsletter, “people unknowingly were turning to websites like 23andme and Livewello to find out if they had porphyria. Since many of the reports had genetic information that seemed similar to porphyria, people diagnosed themselves with the disease.”38 The non-profit gave “renowned geneticist and porphyria expert, Dr. Robert Desnick”39 a platform in that newsletter to address the matter. He noted, “It has come to our attention that some Porphyria patients have sent their DNA to 23andMe or to other commercial companies, and have gotten results suggesting that they have “DNA confirmed Porphyria.”40 We are concerned that results from companies other than DNA testing laboratories that have experience in diagnosing porphyrias may provide patients with misleading information. A major issue with DNA testing is whether a gene alteration (variant or mutation) is pathogenic (disease-causing) or benign (a change in the gene that does not cause or make one at-risk for the disease). For example, 23andMe does NOT do gene sequencing, but does determine if you have various gene alterations in the porphyria genes, all 57 of which are benign, and are not disease-causing but occur in a particular gene in which other lesions are in fact disease-causing. The benign lesions usually are identified by an “#rs” number. These benign changes are quite common but may lead a patient to believe that he/she has one or more porphyrias. They do not affect the heme biosynthetic enzymes, as they are not pathologic lesions. Of the gene lesions that cause disease, over 98% would be identified by gene sequencing as is done for all the Porphyrias at the Mount Sinai Laboratory and four Porphyrias at the Mayo Laboratory. The Mount Sinai Genetic Testing Laboratory provides Porphyria DNA testing for all eight Porphyrias, and has a full-time Porphyria Genetic Counselor…who is available to assist in arranging testing and interpreting the results. Typical time from receipt of sample to result is about two weeks. If the patient has “biochemical-positive” results and a DNA alteration cannot be found, there is a 1-2% chance that the patient has a “cryptic” mutation or a large deletion in the porphyria gene that is difficult to find by sequencing. The Mount Sinai Laboratory will do additional analyses to find the Porphyria gene lesion, if the patient has one.”41

It is true that 23andme doesn’t “do gene sequencing.” However, Livewello does—albeit not Sanger (or higher) quality. Disputing Dr. Desnick’s claim made in in his DTC opinion, at the time I’d downloaded my daughter’s raw data from 23andme, Livewello’s Porphyria Profile Report contained 111 (not 57) #rs numbers. A review of ClinVar results (based on #rs numbers) and subsequent communications with ClinVar personnel revealed that not all rs numbers are benign.

Evidently, leaks are common in the data world. While they’d signed the agreement that their anonymized raw data could be sold to third parties for the “greater good,” some patients were astonished to learn that their DTC genetic results had evidently been accessed by or possibly provided to “certified DNA labs.” These patients discovered that the underlying/supporting DNA test results they’d requested from the “certified clinical lab(s) that had produced the reports addressed some of their Livewello results. I was perplexed. My daughter’s 23andme raw data had been downloaded to Livewello too—months before I’d thought to request her underlying/supporting DNA test results data. Livewello had identified more than one pathogenic porphyria yet nothing about her Livewello variants appeared on her underlying/supporting “Revised Report.”

In sum, DTC genetic testing results provided our family the peace of mind that nothing else before had—heredity information corroborating the recollections of their birth mother and foster/adoptive agencies’ records. Maybe not verified by a certified high-brow lab, but certainly good enough at a time when our kids needed it most—particularly my daughter. As it turns out, her inherited porphyria(s) was/were a legacy from the birth father she will likely never meet.

Patient/Caregiver Commentary Re: ACMG and AMP guidelines for sequence variant classification

The IPMDC authors credit the American College of Medical Genetics (ACMG) and the Association for Molecular Pathology (AMP) for guidelines that “[provided] a framework”42 [for] variant classifications: pathogenic, likely pathogenic, uncertain significance, likely benign, or benign. However, reference was given to the Association for Clinical Genomic Science (ACGS) for the statement, “It has been noted that more focused guidance regarding the classification in specific genes is required as is the applicability of certain criteria may vary by disease and gene.”43Actually, this concept appeared in the Methods section of the ACMG/AMP May 2015 published paper, Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology as, “We should also note that those working in specific disease groups should continue to develop more focused guidance regarding the classification of variants in specific genes given that applicability and weight assigned to certain criteria may vary by gene and disease.”44 Regardless of where it came from, this assertion likely inspired the “need” to “establish a disease-specific criteria and public database providing up-to-date information that will allow porphyria specialists to make informed decisions on the classification of variants in the AHP genes.”45

The authors put forth impressive efforts to convince readers of the alleged need for this database. However, a big picture perspective begs questioning such as, if acute porphyrias are considered so rare (less than 1 in 2000 in the European Union; <200,000 in the US) and now, “ultra-rare,” why is porphyria-specific genetic criteria so critical at this time? After all, the term “ultra-rare” surely doesn’t portend potential for rapid, substantial disease growth.

Theoretically a genetic database specific to a disease could be expected to be welcomed by patients and physicians. In reality, long years of miserable experiences have fueled skepticism for too many “a.p. missed diagnosis” patients/caregivers that this IPMDC IDDVP&BV endeavor is seen as just another tactic championed by US porphyria experts to keep the acute porphyria patient population within NIH rare disease boundaries.

With the exception of recognizing ACMG/AMP for producing “guidelines that take into account population, computational, functional, and segregation data”46which “provides a framework to enable classification of variants”47 the IPMDC authors essentially glossed over the well-established and respected collaboration’s mighty contributions to the worldwide genetic/genomic sequencing database endeavor. Anticipating an impending international flood of increasingly complex molecular diagnostic demands (for countless diseases), stakeholders of ACMG, AMP and CAP in 2013 convened a workshop to “revisit and revise the standards and guidelines for the interpretation of sequence variants.”48

The workshop participants considered a revised variant classification system and two potential scoring systems. While the majority supported a points based system to determine which category a given variant should be placed, in the end “the workgroup felt that the assignment of specific points for each criterion implied a quantitative level of understanding of each criterion that is currently not supported scientifically and [did] not take into account the complexity of interpreting genetic evidence.”49 Our “a.p. missed diagnosis” community applauds this decision. Though medically untrained we may be, we nonetheless recognize the critical importance of the experts’ staid commitment to maintaining scientific support in molecular diagnostics—especially where IEMs are concerned. An insightful patient/analyst colleague reminds us again of the oligogenic nature of AIP (and other acute porphyrias) and in referring to a source referenced in the IMPDC paper, ACGS Best Practice Guidelines for Variant Classification 2017 she notes, “of the 7000 rare diseases, nearly 5000 of these are claimed to be monogenic but low penetrance. This shouts that something is missing; either there is another, or several, genes involved or the penetrance is higher than claimed.”50 She continues, “The discovery of the ABCB6 gene’s influence on the severity of some proves that. Both CEP and EPP now include a variation on this, which is regularly included in genetic testing. There is no reason to believe that the situation does not apply to the other porphyrias.”51

The ACMG concurs, “Clinical molecular laboratories are increasingly detecting novel sequence variants in the course of testing patient specimens for a rapidly increasing number of genes associated with genetic disorders. While some phenotypes are associated with a single gene, many are associated with multiple genes.”52 The concept is not novel; applying it—or not to the acute porphyrias should be based on scientific evidence—never to fulfill a human-driven agenda. As does the ACMG statement re pathogenicity, “A variant should not be reported as pathogenic in one case and not pathogenic in another simply because the variant is not thought to explain disease in a given case. Pathogenicity should be determined by the entire body of evidence in aggregate, including all cases studied, arriving at a single conclusion…this approach will reduce the substantial number of variants being reported as “causative” of disease without having sufficient supporting evidence for that classification.”53

While the IPMDC touts its plans to validate “pathogenic variants in the heme biosynthesis genes causing the AHPs”54 and to “verify the published and currently unreported variants detected by expert porphyria laboratories in patients with the eight major porphyrias,”55 it is the last point, “based on their diagnostic biochemical findings,”56 that the “a.p. missed diagnosis” patient/caregiver community decries. Not a chance this group will support this experts-acknowledged highly fallible (as far as the urinary component is concerned) diagnostic method—especially since we are in total agreement with the ACMG when it comes to “entire body of evidence”—which has yet to be scientifically (not US Agenda-driven) determined. For those “a.p. missed diagnosis” patients with an established diagnosis, adhering to the method will likely result in revocation of that diagnosis, treatment plans ripped away and the patient’s (and his/her family’s) credibility and self-worth ruined. Such damage has been done over and over again for decades. That is why the IPMDC’s rationale for the IDDVP&BV falls flat with our group. I/we am/are here to speak for those who’ve been sentenced to a slow, hellish death—not to add to their anguish.

Patient/Caregiver Commentary Re: Formation of the International Porphyria Molecular Diagnostic Collaborative Database Information; Criteria for contributing laboratories; Genetic variant validation

It is not at all surprising to any in our “missed diagnosis” community that one of the authors (R.J.D), a US porphyria expert, proposed at the 2017 ICPP that this International Collaborative be launched.57

Given that several within our patient/caregiver community have reached over and beyond US borders to obtain additional information and/or second opinions (drawing ire and reprisals from US porphyria experts), this particular IPDMC author no doubt expected that inviting the European contingency to partner in an “international” porphyria collaborative effort would shut us up once and for all. It won’t. This is not just “sour grapes;” lives are at stake.

IPMDC authors allege that “[p]orphyria experts from countries worldwide indicated their support of this International Collaborative, including the European Porphyria Network (EPNET) and the US Porphyrias Consortium.”58 It is the latter’s endorsement of the collaborative effort that fuels cynicism about a US agenda-driven “need” for this IPDMC. Table 4 appears to be proof pudding to support that cynicism.

The IPMDC paper also states that “contributing laboratories will be expected to participate in the quality assurance program of the European Molecular Genetics Quality Network (EMQN) and in the EPNET External Quality Assessment Scheme for the porphyrias or other similar quality assurance program.”59  Why the International Collaborative selected these particular laboratory quality assurance criteria makes sense—at least for northern Europe—because by all accounts northern Europe has the highest prevalence of AIP-affected phenotypes most likely to excrete first-line urinary “biochemical evidence.” Nonetheless, that doesn’t mean that “a.p. missed diagnosis” patients don’t exist in those areas. They do. Atypical they may be, these patients deserve answers and appropriate medical care, too.

Perhaps because US was largely settled by European immigrants, Scandinavians being among the earliest, that made sense in this country, too—generations ago.US porphyria experts evidently adopted European guidelines, largely based on Swedish Porphyria (AIP) to diagnose the acute porphyrias. However, with APF’s founding, several generations had passed and potential patients that didn’t “fit the diagnostic mold” (aka “negative” U-BP) evidently began to approach the patient advocacy organization for help. One would think someone with a scientific perspective would have wanted to investigate the “anomaly.” But sadly that didn’t (or wouldn’t) happen. American porphyria experts chose to adhere to a diagnostic protocol that has yet to be documented as “supported scientifically” (as is evidently required by the ACMG/AMP/CAP).60

EPNET’s guidelines appeal to US porphyria experts because many EU porphyria experts reference increased urinary excretion of PBG and more precisely because, “[p]orphyrin biochemistry diagnostic of a specific AHP can be used within the Association for Clinical Genomic Science (ACGS) guidelines as strong evidence toward pathogenicity, as it is an aspect of the disease that is measurable and is pathognomonic of a defect in one of the AHPs.”61 This supports our belief that US porphyria experts expect the agenda they established nearly forty years ago to hold steady.

However, that agenda could well be compromised or even thwarted by the European Porphyria Initiative’s (EPI), which in its 2005 “Platform to Develop a Common Approach to the Management of the Porphyrias and to Promote Research in the Field” acknowledged, “In almost every European country at least one porphyria diagnostic and advisory centre exists; however, these centres often do not collaborate and may even be in competition with each other. This approach goes against the progression of knowledge and the drive within Europe to centralize data on rare diseases.” 62 A review of EPNET’s “Clinical features of an acute neurovisceral attack of porphyria” lists ten features—darkened urine is not among them.63

Patient/Caregiver Commentary Re: Methods for Variant Validation: Porphyrin precursor measurements; Enzyme assays; RNA analysis; In silco analysis

Since the time of Hippocrates, “darkened” urine excreted during attacks time has been a hallmark of extreme sickness. 2,000+ miles to the north and many generations later, Dr. Jan Waldenström developed a curiosity about reddish urine-evacuation holes surrounding farm houses in northern Sweden, applied his physician/scientist faculties—and ultimately identified Swedish Porphyria.

Given the AIP founder populations in Europe, it makes layman’s sense that that continent (particularly northern Europe and even more particularly, the Scandinavian countries as mentioned previously) would have the highest prevalence of AIP—and therefore also the highest ratios of patients who excrete the hallmark darkened urine. Indeed, Sweden reports that 100% of AIP patients excrete elevated porphyrin precursors.64Sweden’s neighbors, Finland and Norway respectively reported that 89% of patients had/have “[d]ark or red urine” as a clinical feature65 and 64% of patients exhibited “[d]ark/reddish urine.”66 Whether these statistics represent occurrence during inaugural attacks, subsequent attacks or both was not specified.

Via its partnership with Alnylam Pharmaceuticals, the US entered the “international” AHP “attack symptoms” stats arena in 2015/2017. Results of Alnylam’s 2015 “Patient-reported Attack Symptoms” screening questionnaire of 31 symptoms revealed that “Change in urine color” was reported at ~78%. Two years later (2017) “Change in urine color” registered at ~82%. It should be noted that while the US had the highest number of study subjects enrolled in Alnylam’s “Explore” study, participants from twelve other countries (Italy, France, Bulgaria, Germany, UK, Poland, Switzerland, Czech Rep, Finland, Netherlands, Spain and Norway) also took part in the study.67 To our knowledge, no such statistics have ever been published strictly for USA’s acute porphyria patient population.

Nonetheless, it is evident that not all AIP patients excrete porphyrin precursors with every attack—inaugural or successive. Way back in 1939, Dr. Jan Waldenström reported such an occurrence, “I have been able to observe a case where porphyrins could be detected neither in urine nor bile during an attack…Two brothers of the patient suffer from typical a.p…Porphyrins and red pigment, however, were found in the urine at a later date, when the patient showed no abdominal symptoms…The diagnosis: porphyria without porphyrins and chromogen was discussed. It has now been proved.”68 He also noted that the porphyrins and red pigment were found in the urine at a later date, when the patient showed no abdominal symptoms—which some in our “missed diagnosed” community as well as “expert-confirmed” acute porphyria patients report has happened.

Several decades after Dr. Waldenström witnessed the AIP attack with no visible porphyrins/red pigment phenomenon, an American teen began experiencing painful, sometimes debilitating symptoms (abdominal pain, breathing difficulty, arm and leg weakness) which continued to appear and disappear in mysterious fashion for ten long years. Standard lab tests yielded no clues. This individual occasionally noticed “strange colored” urine (although she doesn’t clarify what age that had been noticed) which was attributed to menses. She visited multiple doctors who, when unable to find biochemical explanations for her condition, minimized or dismissed her concerns entirely. She was given (mis)diagnoses with deprecating labels such as over-anxious, hypochondriac, postpartum depression, possible manic depression, etc. Ten years later, still suffering, she was prescribed Dilantin for “minor seizure activity” which sparked a life-threatening attack for which she was hospitalized. While in the hospital, she was catheterized and dark, purple-red colored urine began to spill into the urine bag. Blood and urine samples were collected and sent to NIH for testing; AIP was diagnosed. She was transferred to NIH (Washington, D.C.) A physician later confirmed that Dilantin had caused the AIP attack. She was treated with Panhematin®, survived, and eventually improved enough to, with a friend, co-found the American Porphyria Foundation.69

 Today this woman is APF’s director. Her 2004 book opens with the statement, “I was only seventeen years old when I suffered my first attack of Porphyria.”70How much time had passed from the time of her first porphyria attack till APF was established was not disclosed but it is nonetheless obvious that AIP knowledge and technology had advanced significantly from Dr. Waldenström’s 1939 observation. The point to be made here is that more than twenty-two years after APF had been established, the co-founder wrote the book that essentially acknowledged that what she’d struggled with for ten long years beginning at age seventeen had been porphyria. Yet the same recognition (that such symptoms are porphyria-based) for patients with the debilitating, life-altering symptoms (abdominal pain, breathing difficulty, arm and leg weakness) that appeared and disappeared in mysterious fashion without biochemical proof (U-BP) would not be acknowledged by APF and its SAB as porphyria.

Because these patients were effectively abandoned by APF, opportunities to more thoroughly investigate acute porphyria were lost. We submit, had the APF director not taken that Dilantin, attributed to having triggered the life-threatening AIP attack she suffered, and had Panhematin® not been effective, APF might not have happened—not as or when it did, anyway.

As it is, the (at the time) future APF co-founder appears to have been designated as the Index Case of the entire US AIP patient population for all time. This was good for her, as well as the APF SAB team. But as it turned out, not for the US advancement of acute porphyria studies—nor for the multitude of “misdiagnosed” patients who came after and were shoved into a never ending, gruesome Groundhog Day scenario like the APF director herself had suffered from age seventeen to about twenty seven.

Oddly, nine years after her book w published, recollection of the APF director’s first attack of porphyria changed. In the 4th quarter, 2013 APF newsletter, she wrote, “I remember being so afraid when I had my first attack of AIP. I was in terrible pain and so sick I was sent on an air ambulance to the NIH in Washington, DC.”71 However according to her book, the attack described happened years after her inaugural attack of Porphyria at age seventeen.72 Perhaps confusion or “brain fog” (AIP symptoms) caused her to disremember? Probably not. Adherence to the porphyria agenda—perhaps this “recollection” was meant to coincide with and lend support to the Alnylam Pharmaceuticals article introducing impending clinical trials of ALN-AS1 that appeared in the same newsletter? Probably so. Alnylam, like the company/companies) that produces/produced Panhematin®, used U-BP to test the efficacy of their specific treatment/therapy. That meant acute porphyria patients who did not produce U-BP were of no use to the APF/pharmaceutical partner team(s) in clinical trials. This apparently has been the basis of decades worth of “a.p. missed diagnosis” patients/caregivers complaints about APF’s “cherry-picking” of study subjects. This is also likely why the “a.p. missed diagnosis” AHP patient population has continued a steady expansion while “expert-confirmed” AHP patient population maintains a different type of “steady.”

To that end, revocation of a patient’s acute porphyria diagnosis was also documented by the APF director in her book. She wrote, “there are people who are taking Panhematin® but clearly do not have Porphyria…Eventually, after discussing the tests with [the patient] at length, she [the patient] requested that [her tests] be redone…Although the results were the same, one of the physicians reviewing the tests knew how to interpret them correctly and was convinced from the results that she did not have Porphyria. Nonetheless, he ordered a 24-hour urine, plus blood and stool tests to be sent to a Porphyria center. When [the patient’s] test results were returned, her ALA and PBG levels were within the normal range…Considering the biochemistry and the symptoms, it was clear that the woman did not have Porphyria. However, since she became a bit confused when she did not feel well and had been told in the past that she had Porphyria, she insisted that she had the disease regardless of the test results…The patient’s physician [stopped the Panhematin® treatments]…I am not sure what happened in the end, but I felt sorry for her because she was hanging on to a misdiagnosis and would then miss the true problem.”73 The US “agenda” was in play. The ill-fated patient was left to her own devices. “Misdiagnosed” is the operative word for those who approach(ed) APF having been diagnosed with porphyria by a doctor/specialist not on the non-profit’s scientific advisory board.

Our ever-expanding patient/caregiver community’s dilemma is that “massive amounts of porphyrin precursors excreted during attacks” is just not true for every patient. This does not mean that none of these patients hasn’t ever excreted odd-colored urine—indeed some have. So why weren’t they diagnosed? Many reasons: no awareness of AHP; didn’t mention “it” (colored urine) to physician(s); “it” was attributed to “something else” (for females, generally menses); sample was not collected; when became aware, “it” was not the dark, purplish, port wine color so often referred to by experts  but various gradations of pink, orange or brown; urine retention during attacks; collection process was compromised; sample was “mishandled,” “dropped,” “lost,” “mis-identified,” “mis-directed,” “not fresh,” “too old,” etc.

Some patients had been diagnosed with an acute porphyria by a physician who took an interest in their case, thought for him/herself and did his/her own “homework” (a scarcity in US where increasing bureaucracy and legalities have impinged on physicians’ ability to practice qualitatively)—and worked with the patient to develop effective treatment programs. But sometimes, circumstances changed; the patient moved—or the diagnosing doctor moved, left practice, died. When the patient sought a “new” physician for medical assistance, s/he was inevitably “re-tested” but this time didn’t meet the quantitative measures (established by APF et al). As a result, they were left in limbo. Some contacted APF directly for help in locating a physician who might help them and were inevitably referred to an APF/SAB-connected physician. The vast majority came away devastated—and disillusioned with the US porphyria-expert group.

Some time ago, a patient (who didn’t meet U-BP requirements but nonetheless had been receiving Panhematin® treatments) reported to some in the patient/caregiver community that his/her Mount Sinai DNA test results had been returned with a cryptic notation—the identification of a mutation with potential PBG retention qualities. Meaning there was a biological reason why the patient didn’t excrete U-BP. The patient shared that, under Dr. Desnick’s direction, his/her blood was being “checked” on a regular basis. Not surprisingly, this information ran rampant through the “a.p. missed diagnosis” patient/caregiver community. Unfortunately, said patient expressed fear that his/her treatments might be curtailed and essentially cut off communications with those in our group with who he/she’d been in touch.

Patient/Caregiver Commentary Re: Enzyme assays

            Due to the inheritance of faulty gene mutations,the substantive evidence most often provided as the reason for acute porphyria symptomatology by porphyria experts is deficient enzyme activity. In Molecular aspects of the inherited porphyrias, Sass and Kappa’s noted, “the enzymatic defect at every subsequent step [of the biosynthetic pathway] leads to tissue accumulation and excessive excretion of porphyrins and/or their precursors…”74Twelve years later, porphyria experts in Spain noted, “AIP [and the other AHPs are] metabolic disease[s] of haem synthesis, whose haem precursors may accumulate in the body.”75NORD agreed with that statement, “This enzyme deficiency can result in the accumulation of porphyrin precursors in the body.”76 And Merck Manual’s online Professional Version, edited in part by an APF SAB member, chimed in with “These [enzyme] deficiencies allow heme precursors to accumulate, causing toxicity.”77 We took such statements to mean that it was possible (perhaps probable) that not all heme precursors “spewed out” from the heme biosynthetic pathway left some patients’ bodies via urine excretion; some stayed in the body. To our non-medically trained minds, that they were “toxic” explained the severe neurological symptoms that befalls the patients among us. It’s a theory that merits more thorough scientific investigation.

Since the IPMDC authors tossed out the first pitch about erythrocyte HMBS activity, we’ll follow that lead. The IPMDC paper states “Measurements of erythrocyte HMBS activity have been used in the past [Note: emphasis author-added]to help confirm the diagnosis of AIP.”78 The reference for that statement was a 2002 source. Oddly, nine years after that 2002 source had been published, the 2011 published edition of Nelson Textbook of Pediatrics’ Chapter 85, titled  “The Porphyrias” co-authored by Karl E. Anderson, Chul Lee, Manisha Balwani and Robert Desnick noted, “Erythrocyte PBGD activity is decreased in most AIP patients and helps confirm the diagnosis in a patient with high PBG.”79 Something is amiss. The 2019 version of the Nelson Textbook of Pediatrics is not yet available in hard cover; it will be interesting to see if the same statement appears in that version. With its most recent website re-vamp, the reference to PBGD testing for AIP “latency” disappeared from the APF website’s DIAGNOSTIC TESTING FOR THE ACUTE PORPHYRIAS – CLARIFICATION OF TESTING RESULTS section.

Porphyria experts (at least those in US and Europe) have known for decades that PBGD activity is decreased in the majority of AIP patients. Even the APF-favored Porphyrias Consortium, on the Rare Disease Network website, acknowledged that (although they referred to it as “HMBS activity in RBCs Decreased in ~90% of cases).80

Prior to the era of DNA diagnostics, CRIM analysis was relied on by many porphyria experts to differentiate subtypes of AIP, which were classified based on PBGD enzyme activity. Sassa and Kappas identified three AIP subtypes and determined that in one, Type II, the erythrocyte PBGD measurement is normal. Yet the APF director has claimed on several occasions that she’s never heard of acute porphyria “sub-types.” After nearly forty years at the helm of the organization during which the widely respected Dr. Sassa had served for a time on the APF scientific advisory board?

At the time, Sassa and Kappas also noted that more than “100 mutations of the PBGD activity have been described.”81 It is obvious that these US porphyria experts worked comfortably in the genetics field.

Patient/Caregiver Commentary Re: RNA analysis

            According to an extensive study (UK) of 467 acute porphyria patients, Sanger sequencing evidently did identify over 98% if HMBS, CPOX and PPOX variants. But not ALAD, which brings up the point—if ALAD is never tested for, it is no wonder why so few patients have actually been identified. It is the only acute porphyria that doesn’t appear on Mount Sinai’s DNA testing requisition form and “a.p. missed diagnosis” patient/caregiver community participants from out-of-US have indicated the similar. Nonetheless, according to EPNET’s Specialist Porphyria Laboratory Table, testing for ALAD gene is available in Denmark, France, Italy, Spain, Sweden, Switzerland, The Netherlands, UK.82 Research indicates that the highly competitive, ever-growing intelligence of the DNA testing industry offers an improvement (albeit a very costly one) to Sanger sequencing.

Patient/Caregiver Commentary Re: In silico analysis

            Interesting. IPDWC authors cite, “It should be noted that current prediction accuracy plateaus at approximately 80% and many programs have low specificity, resulting in overprediction of genetic variants as pathogenic” and attribute the statement to five and seven year old sources.83 Actually, ACMG’s more recent (2015) paper states, “Most

[in silco algorithms]

tend to have low specificity, resulting in overprediction of missense changes as deleterious, and are not as reliable at predicting missense variants with a milder effect.”84AMCG professionals agree that in silco analysis should not be used as the sole source of evidence to make clinical assertions.

Patient/Caregiver Commentary Re: OVERLOOKED/UNADDRESSED Relevant Topics:

Powerhouse PBGD (ad CPOX, PPOX too?); Heme deficiency=Acute Porphyria Trigger; Beyond urine—acute porphyria biomarkers; Blood; “Latent” vs. “Asymptomatic” vs. “Misdiagnosed”

  • Powerhouse PBGD (and CPOX, PPOX too)?

From the first look I had of the results from my daughter’s lab tests ordered by a newly- minted neurologist who’d “heard of this thing called porphyria in med school,” I’ve focused on PBGD results. My daughter was deathly ill but her urine test results were “normal” (“porphyrin profile, 24 hr” was “Creatinine C.714 L”  “Uroporphrin 1.8 L.”64); her PBGD level was “Indeterminate”—6.9 L vs “Expected range >7.0.” Knowing absolutely nothing about AIP at that point, I hadn’t realized the neurologist had ordered the wrong urine test. But it mattered not; mother’s intuition told me, “It’s in the blood—follow that PBGD thing.” A few days later, another trip to the ER resulted in a “brown” urine sample, identified as such on the ER discharge paper. By then I’d read some about AIP and asked that the urine sample be sent to be tested for AIP. My request was ignored. Less than two weeks later, blood tests were drawn and urine samples taken again. Her PBGD had decreased to 5.3 (expected range >7.0). In addition to “textbook” AIP symptoms, she’d been struggling with almost daily periods of convulsions, breathing difficulties, increasing periods of grave physical, neurological and cognitive complications. ER visits were required multiple times a week—sometimes daily. This cycle went on for weeks—until, fearing for her life and being that she was an adoptee, I insisted on DNA testing. Having found APF’s website, I read about DNA testing being the preferred diagnostic method for porphyria and that Mount Sinai was to place to go. So I began making calls. I had no intention of stopping until I’d secured DNA testing for my child. Only three acute porphyria genetic tests were available through Mount Sinai—actually four if one counted the three-acute-porphyria option which is the one I selected. I followed the directions provided by MS’s genetic counselor, inserted a prayer card with the blood sample into a sturdy box, forked over the fee and sent the precious package off to Mount Sinai. Weeks later, the “good news/bad news” call came. My daughter had been diagnosed as having AIP. 

The relief was amazing. It didn’t last long. The rest of the story is documented in a book my daughter and I wrote about the hell that childhood-onset AIP wreaked on her young life—and on our family.

Following the aggressive treatment protocol that a Swedish/US transplanted AIP specialist who’d been referred to us by the mother of a young-adult woman with acute porphyria, my daughter’s live had been saved and she’d  been doing relatively well for five and half years. Then out of the blue, Dr. Robert J. Desnick, PhD, MD, Director, Mount Sinai Genetic Testing Laboratory inexplicably revoked her AIP diagnosis. She has steadily declined physically, neurologically and mentally since. That “PBGD thing” at the forefront of my mind, I requested the test be included with every “new” doctor’s blood test orders. Sure enough, her PBGD levels definitely correlated to her AIP presentations. The weaker she became, the more symptoms she displayed and the lower her PBGD levels turned out to be. Though they probably thought I was a nutty, over-protective mother who wouldn’t “cut the apron strings,” carrying my daughter’s binders of medical records to every appointment, a few benevolent hematologists responded to my pleas and ordered IV glucose and/or Panhematin® for her. Although I couldn’t get any of them to order PBGD tests after she’d received Panhematin® (even a few days or a week after), it was evident that hematin was beneficial. In every instance, she’d gone from being a “droopy” to young adult able to stand up and think for herself again—for a while.

I knew I’d found a reliable biomarker that helped identify my daughter’s AIP activity. However, because PBGD measurement was not acknowledged by APF (US “porphyria experts”), local and regional doctors ignored my repeated insistence that it was an effective barometer.

A 1976 medical article gave me hope, “Measurement of the activity of uroporphyrinogen I synthase activity provides an excellent laboratory aid in the diagnosis of acute intermittent porphyria, particularly in those patients who are asymptomatic or in whom the disease is not biochemically manifested by porphyrin precursor excretion.”85 [Note: Emphasis author-added] But no one connected to the US porphyria advocacy foundation would accede this “old” article.  With no way to find or contact the authors, I swallowed my angst yet again.

Then I happened upon an exciting 2007 Japanese study, written the year before my daughter overtly presented with AIP symptoms that confirmed I was on to something. It stated, “The [PBGD] activity normalizes as the patient improves, suggesting that this enzyme is a more sensitive monitor for acute intermittent porphyria attacks than the urinary parameters currently used for its diagnosis”86 [and] PBG-D is a good indicator to predict or detect the AIP attack before its onset.”87 It also stated, “it is known that AIP patients show an abnormal urinary profile of ALA, PBG, UP and PBG-D and that this profile shows wide variations from status to status within the same subject.”88 The paper concluded with, “Presently PBG-D testing is performed for the diagnosis of chronic or acute AIP. We propose that monthly range PBG-D monitoring is crucial for prediction of the acute phase in AIP patients by using the negative deviation of PBG-D from the mean value as a clinical benchmark to predict and prevent AIP attacks. Physicians treating porphyric patients should use monthly testing schedules to estimate the potential risk of an AIP attack and to establish opportune heme therapy.”89 Had I come across this awesome paper years earlier, perhaps our family might have relocated to Japan, might have even met Dr. Sassa himself and we would have avoided the torturous US porphyria agenda debacle entirely. A cursory review of ICPP lists of abstracts showed no indication that this very beneficial information ended up on an international porphyria experts’ platform which is truly unfortunate.

My daughter’s PBGD lab results undoubtedly contributed to the (out-of-US) porphyria expert teams’ 2018 finding because they noted, “The critical result for a diagnosis of AIP is the level of enzymatic activity of hydroxymethylbilane synthase, whether the patient is presenting an acute crisis or if never one has occurred. The person is nonetheless a carrier of one mutation capable of producing an acute crisis. A large proportion of carriers indeed never had one. But it is not mandatory. In the presence of typical symptoms, a low enzymatic activity is diagnostic. Even with absent U-BP (read paragraph above again).”90  I realized that the porphyria expert team that had submitted a professional opinion on my daughter’s case had corroborated the Japanese porphyria experts’ eleven year old study, even if they had been unfamiliar with it. They’d also validated the approach taken nine years earlier by the kind, compassionate and AIP knowledgeable Swedish/US transplanted pediatric hematologist/oncologist/AIP specialist who’d saved my daughter’s life after she/we’d been set adrift by APF/Dr. Desnick following her November, 2008 DNA diagnosis. I wondered why our US porphyria experts, surely as intelligent as any of these physician/scientists, refused to show interest in any AIP diagnostic method that is “more sensitive” than U-BP and why they lacked the compassion shown by experts born, bred and medically trained outside the US.

  • Heme deficiency=Trigger

Dr. Cecil Watson’s New York Times obituary remembered him as “chief researcher in the discovery of hematin, the most effective treatment of the disease porphyria, an inherited disorder of the liver.”91Dr. Watson’s unique understanding and interest in “the many biosynthetic intermediates and degradation products of heme which are eliminated in human excreta”92 resulted in diagnostic and treatment discoveries that are still relied on by porphyria experts.

With coworker Dr. Samuel Schwartz, he developed a qualitative method for detecting porphobilinogen in urine—still used to identify “patients who carry the genetic traits of hepatic porphyrias associated with neurologic lesions.”93 The Watson-Schwartz test was quickly embraced by US and European porphryria experts, essentially cementing its position in the acute porphyrias diagnostic protocol. But it was “long after retirement from academic responsibilities [that Dr. Watson] had the “intellectual satisfaction of discovering a highly effective and often life-saving therapy for a disease which had preoccupied him for over forty years—the successful treatment of acute [porphyria] attacks [by infusing] hematin.”94

This was by no means easily achieved and Dr. Watson’s lab was not the only one working to “elucidate the mechanism and regulation of heme synthesis in the liver.  Contributions were also made by many other laboratories in [US] and Great Britain. But it was Cecil who eventually put it all together when he recognized that porphyric attacks are associated with severe heme depletion in the liver.”95 [Note: Emphasis is author-added.]

Built on years of witnessing my daughter’s AIP presentations, reviewing lab tests and speaking with countless medical professionals and “a.p. missed diagnosis” patients and caregivers, I developed a theory about heme deficiency’s role in acute porphyria activity with PBGD being a sort of “barometer”—at least for my daughter. But nothing about any such connection could be found in any US porphyria experts’ APF-produced materials or in any of their published papers/documents. Certainly, “heme deficiency” was mentioned in several papers, often with APF SAB member Dr. Herbert Bonkovsky’s name appearing as author or co-author and usually about hematin infusions with references to the free heme pool.

For instance, in Porphyrin and heme metabolism and the porphyrias, Bonkovsky et al states that hematin infusion “repletes a critical regulatory heme pool in hepatocytes—which leads to downregulation of hepatic ALA synthesis, which is a biochemical hallmark of all forms of porphyria in relapse.”96

Dr. Watson’s heme depletion finding was explained in the Textbook of Peripheral Neuropathy as, “Cytochrome inducers like barbiturates increase the synthesis activity of hepatic cytochrome as much as  40- to 50- fold; this increases the incorporation of intracellular heme into hepatic cytochromes, leading to the depletion of the reserve of heme.”97

A few months later, Dr. Bonkovsky released another paper with a different research team; it didn’t take a rocket scientist to figure out that Heme status affects human hepatic messenger RNA and micoRNA expression was connected to Alnylam’s development of a new drug (ALN-AS1) which targeted ALAS-1 or that APF was wholly involved in the matter. At the time I had more interest in learning about study team’s objective “to characterize…the comparative effects of heme excess vs heme deficiency in human hepatocytes,”98 however, this paper did give credence to my theory about heme deficiency contributing to acute porphyria affected-patients’ performance. While it was good to learn more detail about the toxic effect of excess heme, it was the statement, “[a] deficiency of hepatic heme is well-known to be associated with disease phenotypes, especially the acute porphyrias in relapse”96that provided the answer I and others sought. Still, the “in relapse” part niggled my brain as did the ending, “partial defects in genes and enzymes of the heme synthesis, which with other genetic and environmental factors, lead to a critical deficiency in the regulatory heme pool of hepatocytes and hence to uncontrolled and marked up-regulation of hepatic ALA synthase-1, which normally is the rate-controlling enzyme of heme synthesis.”99 It would be beneficial to specifically know the effects “partial defects in genes and enzymes of heme synthesis” have in heme depletion—without additional triggering effects.

Approximately a year and a half after the release of Dr. Bonkovsky’s Heme status affects human hepatic messenger RNA and micoRNA expression paper, Alnylam Pharmaceuticals expressed an interest in the heme deficiency issue. However, based on comments made during an Alnylam Roundtable session by Dr. Karl Anderson concerning heme deficiency, it doesn’t appear that the US porphyria experts had then or have now any interest in pursuing it [heme deficiency]. During the roundtable session, a slide titled “Pathophysiology of AIP” stated that ALAS1 is induced by “depletion of ‘free’ home pool”—and “ALAS1 induction [is] accentuated by partial deficiency of PBGD [which] limits heme supply to the regulatory “free” heme pool.”100

The next slide, also titled “Pathophysiology of AIP” contained one bullet point, “Neurologic manifestations,” beneath which read, “Heme deficiency→hemoprotein dysfunction?? and beneath that, “e.g. vasospasm due to NOS deficiency???”101 During the Q&A session, the Alnylam executive conducting the session said/asked Dr. Anderson to, “Explain the potential of heme deficiency in targeting ALS-1. Do you see that in patients that might have heme deficiency treatment with ALN-AS1 might exacerbate that deficiency?102 Dr. Anderson responded, “I think the evidence of heme deficiency and the acute porphyrias is pretty weak. But it might be possible looking to animal model to see if any, in the brain, for example, if MRI changes occur that are similar to what’s been described in humans. But I think people agree that the best hypothesis is that intermediates in the pathway, particularly ALA may be responsible. The problem is that that’s not really proven, but most of the evidence points towards that, we know it’s something from the liver. And so because transplantation cures the disease, so it would be something in the liver, coming from the liver that cause the heme efficiency say in the—in the nervous system. And that’s rather kind of a stretch.”103

A “a.p. missed diagnosis” caregiver of two children with HCP (with a porphyria expert’s professional opinion to support her) disputes Dr. Anderson’s statement that heme deficiency is “rather kind of a stretch.” This is her story:

In a family of more than 10 sufferers of HCP, an Australian mother has 2 children (youngest and oldest) with HCP. At age three, the oldest child (F) began exhibiting HCP symptoms. A paternal family member, who happens to be a physician in paediatrics/genetics/metabolics, confided that porphyria was in the family. After thorough testing this physician’s opinion was that porphyria was the best explanation for the child’s symptoms, despite the literature excluding the possibility of children having attacks before puberty. She explained that in rare diseases, little is known about them and that the literature can often be incomplete, especially in metabolic diseases. She has stated that as porphyria is a genetic metabolic disease it would be more likely to be active from birth and that family accounts have reported active disease from a very young age. This information proved of little help when seeking a diagnosis for the children due to the lack of insight from porphyria experts in their state. The younger child (M), dx with epilepsy and a brain disorder at a very early age began exhibiting porphyria symptoms due to unsafe epilepsy medications. The child’s neurologist insisted that genetic and biological testing be done on all three children in the family, previously refused by the porphyria specialist in their state due to the assumption that children do not have acute attacks. All 3 children were tested, the two who were suffering symptoms came back with positive DNA, the stool biomarker of HCP (Copro III:I reversed) and the male child also had high urinary PBG due to years of taking unsafe epilepsy medications since his birth. The female was 16 and the male child was 7 at the time. Because the younger child excreted U-BP, he was considered in an acute attack and removal of the offending epilepsy medications proved to stop the symptoms. No treatment was offered or received by the porphyria expert but the child is frequently placed on glucose IV by doctors at his regular hospital in order to avoid attacks. The older child, continuing to suffer severe symptoms and attacks, did not excrete first-line U-BP and so was denied treatment—for eighteen years. Having left school, unable to eat or sleep, often being taken to emergency via ambulance, she was left to suffer due to a lack of high urine PBG, despite her having seen a multitude of specialists over more than a decade who ruled out common causes for her symptoms, despite her family history of porphyria and even despite the DNA result. In 2016, the child/young woman became deathly ill. The mother sought contact with an Australian porphyria expert in another state who confirmed that her daughter was indeed suffering from porphyria, citing the DNA result combined with the stool ratio indicating HCP plus symptoms and triggers synonymous with an acute attack of porphyria. He began treating the young woman with glucose/Normosang (the European/Australian version of Panhematin®) treatments. Her condition has improved considerably. Previously in a wheelchair, she is now walking, but she remains chronic, needing numerous treatments with heme infusions per year. She currently has another excellent specialist in her state who regularly tests her heme levels and organizes treatment when heme levels are depleted and symptoms worsen. She also has been found to have high urinary ALA during most attacks –something never tested previously when urinary PBG was assumed to be the only relevant indicator. She has never had high U-PBG yet her doctors are now well aware that it is not a good indicator of acute attacks in her and she receives regular Normosang as she needs it. It is her specialist’s opinion that she has been heme deficient for years and will need many years of treatment before her body recovers from years of medical neglect.104

Another mother’s straight-A chemistry major high school age daughter began suffering with symptoms during twelfth grade senior finals that forced her first ER visit. As her health progressively worsened, her parents made the rounds of every conceivable doctor and specialist they could find or were referred to. Medications made the daughter sicker yet she was offered antidepressants over 25 times while her actual serious and life threatening symptoms of tachycardia 224 bpm, labile hypertension 200/100, and stomach pain were discounted. She was accused of being on drugs, pregnant, lying or crazy. “How do you lie about a 195 heart rate when the monitor clearly shows it?” the parents wondered. After a time, porphyria was mentioned and testing started. However, proving one has porphyria in the US is almost harder than having the disease. Her clinical history was “textbook” porphyria including rare signs and symptoms like temporary vision loss. Except for U-BP, everything fit—HCP was highly suspected. Multiple excreta testing were ordered. HCP fit, except she hadn’t excreted U-BP so treatment is not available to her. DTC genetic testing leaned toward HCP. With no ability to do HCP enzyme testing in the US [according to EPNET’s website, US does not provide full molecular services (enzyme assays)],105 the parents took their daughter to France seeking professional opinions and enzyme assays from porphyria experts there. Her daughter’s HCP enzyme level was reported at 292 which when compared to a diagnosed, de-identified study patient (data provided in published medical journal paper) whose reported level was 300—in “compound heterozygous HCP.”106 Close but no cigar. As with my daughter’s dx revocation—and so many other hapless patients whose diagnoses have been withheld or revoked, no U-BP means no diagnosis. No diagnosis means no treatment. No diagnosis means loss of credibility. No diagnosis means not being counted. In the US, not being counted means the US acute porphyria patient pool remains within US-agenda expected parameters. The family returned to the US, still seeking answers. APF reprisal was typical and this time posted on a public Facebook forum which met with ready response from “a.p. missed diagnosis” community members:

    “UPDATE ON ACUTE PORPHYRIA TESTING: FRENCH PORPHYRIA CENTER (CFP) A US individual seeking acute porphyria testing has posted widespread misinformation about the French Porphyria Center (CFP) and their diagnostic and testing capabilities. Due to this plethora of misinformation, the Director of the CPF [name] informed the APF that they will no longer accept US patients at their facilities except for diagnosed patients, who are presymptomatic or symptomatic, and are living or traveling in France. The French will certainly care for these patients just as US experts care for French patients traveling or living in the US. This decision was made after great concern that some of this same misinformation was attributed to him [Director of CPF] and his well-respected facility.

    “The APF, the USA experts, the CPF and the other European Porphyria Centers have worked together diligently to offer accurate data regarding diagnosis and proper testing, including data about enzyme testing. In the past, certain enzyme deficiencies were measured to help determine the type of porphyria, but now DNA is used to determine pathogenic mutations. The enzyme deficiency test can still be useful in research and when people have positive biochemistry, but their DNA is cryptic. If you have testing concerns, call the APF or seen the APF website.

   “porphyria is serious diseases, ppl cant tout their nonsense science with a bunch of scientific words but no factual evidence. now scientists are mad…it is bizarre to think that the apf has anything to do with diagnosis or treatments. we only publish what the scientists tell us

   “and it is important where a person gets their medical info…not patient-generated medical info that is different from personal experience which is so great to share…personal experience is not medical info from drs…ppl should not change that…or alter what a dr said. or think porphyria experts who have devoted their lives to patients dont know what they are talking about…that is ridiculous.

   “its super important to get info from experts/science based…there is also an issue re certain mutations that ppl think are disease causing because a number of them have the same mutation. instead, this same mutation appears is widespread in the population is not disease causing.

   “another thing that is confusion is that ppl think that since their mutation has not seen yet, they think they may have porph…instead, they do know the gene is a porph gene…like pbgd for aip…but it will have a lot of different family mutations.”107

Response from Caregiver:

   “This is very sad for the people who have porphyria who can’t get a diagnosis in the US because they are not excreting high levels of PBG or have a DNA diagnosis. If only APF would acknowledge that many with porphyria are not obtaining a diagnosis and treatment and broaden their information about thorough testing for a complex disease people wouldn’t feel the need to travel outside of the US to get treatment. So many desperate people in excruciating pain…it breaks my heart. There are many academic papers showing no elevations in PBG in porphyria and genetic testing is in its very early stages. Every geneticist will tell you this. To rely on either one means diagnoses can be missed. I find it abhorrent that the APF feels the need to control people’s choices regarding diagnosis. This is a situation created by APF; desperate people take desperate measures. Scientists are not gods. Much is still to be learned about the mechanisms of porphyria and the APF’s goals should be in helping people not in controlling people and slandering those who are trying to help [a] family member stay alive while fighting for a diagnosis. There is much to be done regarding testing in porphyria and the APF doesn’t seem to be doing anything about it. It’s a dire situation that is ruining lives.

   “And let’s not forget that university educated, academically minded, research-experienced people can also be parents and sufferers of porphyria. My family has many Drs and one, a metabolic geneticist who first diagnosed my [child’s] symptoms at the age of 6 as being porphyria, does not agree with using the PBG test to diagnose an attack and determine treatment. Her advice was find someone who is willing to do comprehensive testing that is specific to HCP. The PBG test is not enough. She also suggested contacting researchers as new findings are coming out about rare diseases every day. I don’t think patronising people is the way to go. We are not all idiots in tin foil hats. My [child] does have chronic attacks of porphyria and DOES NOT HAVE HIGH PBG! Thankfully, [s/he] now gets treatment DESPITE all of the misinformation from so-called experts.”108

The parent who was lambasted by APF post re the “French CPF” had this to say, “Upon our return from France, I posted on FB that [my daughter’s] enzyme test results showed more deficiency than another patient who had been diagnosed and whose case had been written up in a research paper by that same center. The APF director bashed the test. I pointed out that it was done at a French porphyria center by the director (who is doing the Alnylam drug trial ) and she said, “I’m contacting the French.” And she did. My daughter has been very sick with six hospitalizations consistent with porphyria attacks since our return.”109

That makes three young women, two of whom have suffered for years (one nearly for the whole of her life) and one whose life has been more recently similarly shafted, yet all were dismissed by porphyria experts because they didn’t achieve the diagnostic urinary “gold standard.” Two eventually received treatment with glucose/Panhematin® and remarkably well to the modality. In a callous and highly suspicious manner, one’s diagnosis (my daughter’s) was revoked. Without treatment, the third young woman’s health has severely deteriorated, her enzyme deficiency wholly dismissed by experts. The intent of including these reports/responses is to reflect the urgency of need and dismissive manner that US porphyria experts respond—from the top down, and in unison. Our “a.p. missed diagnosis” patient community includes toddler to octogenarian patients and is comprised of caring, intelligent, well-researched patients and caregivers. We must, for the greater good of acute porphyria patients everywhere and to come, continue to speak out and share our knowledge. Acute porphyria won’t stop. It’s in the genes of an uncounted number of people on this planet. Acute porphyria shouldn’t be allowed to continue to bankrupt the lives and finances of individuals, families, societies, private and single payer insurance sources.

Recalling the (at the time) future APF co-founder’s report of having suffered for ten years before ultimately taking the dose of Dilantin that incited the life-threating attack that ultimately produced the AIP diagnosis, I wondered if perhaps she, too, had been “heme deficient” for all of those years. There are case studies of patients who’d ingested Dilantin with no untoward effects, which substantiates another great physician/scientist’s finding—Sir Archibald Garrod’s concept of chemical individuality.

Unfortunately, instead of US porphyria experts exhibiting even a modicum of interest, all three cases drew interference and retaliatory acts from APF leadership and/or associates. That being said, and knowing that other individuals who’ve presented clinical acute porphyria symptoms without excreting “gold standard” U-BP had/have received treatment with glucose and/or Panhematin® therapies, successfully mitigating and/or resolving their symptoms too, it seems reasonable enough evidence to encourage launching a thorough scientific study to determine the role that heme deficiency plays (alone or in concert with the gamut of triggers generally noted as inducers) in triggering acute porphyria activity.

It has been nearly five years since the Alnylam/Dr. Anderson Roundtable Q&A interchange—nothing seems to have changed with regard to US interest in heme deficiency. Based on observations made over more than eleven years of caring for my porphyric daughter, hundreds of attacks and heaven knows how many glucose and/or Panhematin® treatments she has had, I (along with the foregoing mom/caregivers and patients who know the benefits of hematin treatments) submit that severe heme deficiency in and of itself can be an attack trigger. And we are confident that enzyme assay (PBGD for my daughter and CPOX for the young woman whose parents sought French experts’ help) appears to be a suitable warning signal that heme levels are falling into danger status.

However, my (and others’) online posts concerning enzyme monitoring, heme deficiency or any other topic not APF-endorsed were (and still are) routinely denounced by the patient-advocacy organization. In providing information which confirmed experiences and/or provided scientific reasoning behind acute porphyria presentations exhibited by many “a.p. missed diagnosis” patients from the wealth of information available by worldwide porphyria experts, we’d clearly stepped over the APF protectionism of “only posting and publishing what [its] scientific advisory board of experts says.”110 

To that end, APF has gone so far as to amend its various public communications to counter attempts to share experiences and/or information from other sources outside of APF’s SAB’s provisions. For example, after I posted info online about the PBGD/attack connection, an APF website section (apparently no longer available) titled “Misinterpretation of Test Results” appeared. In typical fashion of minimizing “a.p. missed diagnosis” patients it stated, “Incorrect diagnoses of Porphyria can occur in patients having minimal abnormalities in laboratory tests, such as small elevations in urinary porphyrins or porphyrin precursors that in fact have little or no diagnostic significance. Incorrect diagnoses are less likely if reliance is placed on a few first-line tests in most clinical situations as described above. Overuse and over-interpretation of minor abnormalities in results of second-line tests, including erythrocyte PBGD, other enzyme assays, and fractionation of urinary and fecal porphyrias, account for many incorrect diagnoses of Porphyria.”111

To that we question when and why the Watson-Schwartz test went from a being qualitative to a quantitative acute porphyria testing tool. When my son was diagnosed with Type 1 diabetes (via first-line urine test then second blood testing to arrive at a diagnosis), I’d asked the endocrinologist , “How bad is [his diabetes] that he needs to test eight time a day?” S/he replied, “All diabetes is bad. It doesn’t matter how often one has to test. It’s all bad.” Surely, the same can be said about acute porphyria. Studies have shown that PBG excretion levels vary between patients and even within each patient; there does not appear to be any correlation to the level of pain/acute porphyria symptomatology. As with diabetes—all acute porphyrias are “bad” and should not be gauged solely on presence of U-BP.

When porphyria experts from different countries provide information that disputes US “findings,” or provide assistance that US would/could not concerning intelligent young women who (as the APF co-founder did decades ago) know they are very sick, not faking and not mentally ill, it is well past time for unbiased, authentic science to take over. It was apparent to many in the “a.p. missed diagnosis” patient/caregiver population that APF website “changes” were intended to discredit, disparage and silence those who refuse to fall in line with the nonprofit’s agenda. Having been blacklisted by this group (like the Australian mother before me—APF’s tentacles reach far and wide—and many others before me), I began challenging the unconscionable revocation of my daughter’s AIP diagnosis. Shortly thereafter, APF posted a link on an open Facebook porphyria forum page to a paper titled Feigning Acute Porphyria. The four authors were University of Texas Health Science Center at Houston; the lead author earned her medical degree from University of Texas Medical Branch—where Dr. Karl Anderson, chair of APF’s SAB runs a Porphyrias Consortium Porphyria Center. Although no acknowledgement or thanks to him are proffered in the paper, given the relationship between the two medical entities and the fact that one-third of the paper’s references are attributed to him, it’s reasonable to assume that Dr. Anderson’s AIP “expertise’ was extended to the UTHC psychiatrists’ research, writing and/or reviewing the text of this paper.

The paper reviews the case of a man who’d presented to a “sister hospital” of UTHCD with complaints of a “porphyria attack” and request[ed] opiate analgesics.” He had no medical documentation to support the diagnosis of AIP he alleged to have. He was evaluated by a “multidisciplinary psychiatry service and found to have ‘irritable mood, no suicidal ideation, no psychosis, no manic behaviors, was future-oriented and looking forward to receiving housing assistance and free pain medication.’” He was discharged from the sister hospital with a diagnosis of “adjustment reaction with anxiety (he’d recently moved to Texas from New York but later stated he’d moved from Virginia), nonopiate medication and [with a] follow-up hematology appointment.”112Upon being discharged from UTHCD, he went directly to UYHSC’s ER complaining of severe abdominal pain and stating he’d go home and ‘shoot myself if the pain doesn’t go away.’113 “In addition to suicidal ideations, he complained of depressed mood, decreased sleep, anhedonia, poor energy, nausea, vomiting, abdominal pain and homicidal ideations toward his landlord.”114 His vital signs, including sodium were in normal range; his abdominal exam, bowel sounds, motor strength unremarkable and his abdomen not distended. However, even as he acknowledged being anxious he “calmly described his intentions to end his life if [his pain was not adequately controlled]. ”  He also told the nursing staff that he would go and get a gun and ‘kill you all’ if he were discharged to home. He later stated that he was only frustrated we would not give him the medicine he needed to treat his porphyria.”115

Evidently, the ER “obtained medical records from the hospital where a significant portion of [the patient’s] AIP treatment occurred.”116 While initial diagnosis records were not available, accounts of a reported AIP flare with postprandial vomiting and twenty-five lb weight loss were obtained. “Although his qualitative [U-PBG] was negative, he was started on IV hemin 350 mg intravenously every two weeks. He also received morphine and fentanyl transdermal patch as needed for pain.” He’d been treated with hemin in two more occasions, but was “poorly compliant with follow-up appointments.” Subsequently, [the patient] presented with abdominal pain for which he was treated with IV hydromorphone despite two negative qualitative PBGs and negative 24-hr quantitative porphyrins. He had two more negative qualitative PBG tests in 2006 and one more 24-hr quantitative porphyrin test In 2009 he was evaluated for abdominal pain [in the ED] and had a normal porphyrin profile at that time. In total, his urine has been tested on 11 different dates likely secondary to nine different AIP episodes to diagnose [AIP] and each test has been negative. No genetic testing was ever received.” From that point forward, the patient “failed to keep any of the outpatient hematology clinic appointments. A month later he appeared at the ED with complaints of acute abdominal pain; “his vital signs were all within normal limits. He was discharged with three more outpatient hematology appointments, which he did not” keep.117 He then moved to Texas where the AIP cycle started again.

The Feigning Acute Porphyria paper states, “While feigning symptoms for secondary gain is common for some illnesses such as chronic pain, the presentation appears unique”118and “We found one other study with a similar presentation, in Polish.”119

Posting the link to this paper was a cheap shot aimed at “a.p. missed diagnosis” caregivers, our daughters and every other patient whose symptoms have been dismissed, minimized and ignored as well as those who’ve died from lack of appropriate medical treatment  because his/her acute porphyria was neither acknowledged nor treated.

Actually, many “missed-diagnosis” acute porphyria patients/caregivers identified with various aspects of the patient’s state of mind and body and thought it absolutely reflective of the highly skeptical attitude and indifference US medical professionals have about acute porphyria. Many “a.p. missed diagnosis” patients have had similar experiences themselves and caregivers have observed similar in those they care for. The consensus of these untrained porphyria experts was that the patient was not feigning anything, rather what happened to him is consistent with the treatment not only they but many “expert-confirmed” acute porphyria patients report they’ve been confronted with by medical professionals. It aptly demonstrated how the medical staff  are simply not equipped to handle the multi-dimensional aspects of acute porphyria nor the individuality of each patient. Neither did any of the professionals (previous or at the time the documented events) understand effective treatment—providing at minimum, IV glucose or if needed IV heme regimen until the patient’s liver is satiated enough to function well.

None of us missed the jab intended by APF’s posting of Feigning Acute Porphyria. Clearly conceived and written by highly skeptical medical professionals, the article points out many things that generations of “missed diagnosed” patients understand/understood only too well because they repeatedly experience/experienced escalating untreated acute porphyria.

The paragraph, “Clinicians should consider this diagnosis in all adults with unexplained symptoms seen in acute porphyrias especially if the patient presents with severe abdominal pain with or without constipation, muscle weakness, hyponatremia, hypertension, tachycardia, and dark or reddish urine,”120 begins appropriately enough. However, it ends on a note which, from the “missed diagnosed” patient/caregiver perspective is based on US porphyria experts’ deficient foundational information which then perpetuates medical practitioners throughout the US erroneous interpretation of the acute porphyrias’ confoundedly varied yet oddly similar presentations, diagnosis and treatment protocols.

This in turn unfortunately sustains the US porphyria experts’ Agenda—and upholds EU’s (more understandable) apparent diagnostic confirmation bias.

Assuming that the patients of the “a.p. missed diagnosis” communities “want” to have acute porphyria is a wholly inappropriate deduction made by people of intelligence who don’t actually have the complete medical knowledge they claim to have earned. This is not surprising because there doesn’t appear to be one US porphyria expert/physician who suffers with an acute porphyria or has cared for a loved one 24/7 who has acute porphyria. The Swedish doctor who saved my daughter’s life came from the “region of Sweden with the highest prevalence of AIP.” She knew AIP. She knew that glucose and hematin treatment needed to be done “until” (until the liver is satiated—and that the treatment is not meant to be taken like aspirin for a headache). She knew that AIP patients can and do sometimes present as though they have mental illness. She knew what to do when the 12 year old bedraggled youngster with exhausted parents walked into her office.  She speculated that my daughter “may not produce U-BP until late teens or early adulthood.” Unlike the US experts who’d effectively abandoned my daughter, she knew AIP.

From a “missed diagnosed” patient perspective, the Feigning Acute Porphyria patient’s presentation is heart breaking-ly familiar. Parts of it were reminiscent of my daughter’s AIP attack presentations on occasion. From our book, Purple Canary, “Once again, blood was drawn and a urine sample taken…She was given 650 milligrams of Tylenol every 4 hours and put on a drip with 5 milligrams of oxycodone hydrochloride. When asked what level her pain was on a scale of zero to ten, ten being the worst, she readily rated it a ten. Hours later, the ED report noted, “…pain still a 10 out of 10, post oxycodone. Pain is still constant.” Still early in her ordeal (pre-diagnosis), she was politely responsive to the medical personnel’s questions and submitted to their prodding and pushing tests. The records reported, “Child laying on bed, conversive [sic] and interactive,” [yet her abdominal pain was raging]. When the ED doctor decided to discharge her “[she] began sobbing and begged to stay in the hospital.” Alarmed, I took up her appeal. She was admitted, received an IV drip through the night and was discharged the next day with an appointment for a follow-up appointment with her GP. At that meeting, we were given an order for another porphyria blood test and an order for a thoracic/lumbar x-ray. 121 Subsequent recurrent pre-dx AIP episodes/attacks earned her the erroneous diagnosis of conversion disorder.

The Feigning Acute Porphyria patient’s affect also was reminiscent of a patient who has suffered with acute porphyria for decades and shared one of his stories. His mother (passed) had porphyria (type unknown). Post-HCP diagnosis, he said during a particularly severe attack he’d behaved “bizarrely,” which ended with him being arrested and committed to a psychiatric ward. There he was given “a lot of medications” that did nothing or mostly exacerbated his illness.122

That the patient in Feigning Acute Porphyria avoided hematology appointments identified with “a.p. missed diagnosis” patients, one who shared, “I can understand stopping hematology appointments. I stopped mine…they were worthless. Vital signs are always within normal limits for me aside from sometimes being tachycardic, which they do not care about. An acute porphyria attack is a weird thing for a grown man to just make up and go into a hospital to try to get help with. He knew what he needed and like we all do, tried to get help and being anxious and talking about ending his life if pain wasn’t controlled sounds pretty normal for a porph attack to me. The fact that he had records of prior attacks being treated says a lot. We all know it ain’t easy to get heme! He was probably functioning better after some heme treatments, tried to be optimistic and thought he was in remission, was stressed by the move and found himself in this awful situation.123

 “This sounds a lot like my [brother]. Very self-sabotaging. Makes statements that he’s fine but then threatening to kill himself due to pain. At first I thought [this was a story] about my [brother]. Very similar except he does have positive tests on blood.”124

“An endocrinologist I saw a few years ago espoused the philosophy of “treat the patient, not the lab work”. I forget what the term is, but if you are a physician groping for a diagnosis, and try something [resulting] in the patient [getting] better or well, you conclude that you treated the right thing. It’s a method of functionally diagnosing someone. If it walks like a duck, quacks like a duck it’s probably a duck (even with negative lab work), treat it like a duck (as long as the risks of doing harm are factored in).125

In other words, “missed diagnosis’ patient/caregivers have been there, done that. If nothing else, heme deficiency likely exacerbates the effects of other triggering (endogenous and /or exogenous) factors in acute porphyria patients. This, in fact, was Dr. Watson’s finding in 1977: “[t]here is compelling, indirect evidence of hepatic heme deficiency due to the respective genetic errors of the three inducible hepatic porphyrias, [AIP, VP and HCP]…[the] induction is enhanced by exogenous inducers such as barbiturate, estrogens and other “porphyrinogenic” chemicals and factors, including glucose deprivation.”126

  • Beyond urine—acute porphyria biomarkers

For years, maybe decades, the fallibility of urinary biochemical proof (U-BP) has been acknowledged from around the world by various porphyria experts (except in the US), yet as far as diagnostics are concerned, many of not most contemporary porphyria experts still turn to first-line urinary test results to determine if a diagnosis of acute porphyria will be pursued. The “a.p. missed diagnosis” patient/caregiver community understands that as darkened urine (ultimately supplanted by U-BP) has been a hallmark of AIP’s presence since Hippocrates’ time.

Nonetheless, in spite of having been part of the Swedish team to report that 100% of Swedish AIP patients excrete U-BP, in the September 7, 2017 Alnylam Roundtable, Dr. Eliane Sardh of Sweden nonetheless recognized that “there are several unmet needs and areas of improvement in [the]field of acute hepatic porphyria. To that, she added, “We need better biomarkers for the disease [acute hepatic porphyria] since ALA and PBG probably are just surrogate markers, and the specific levels of porphyrin precursors do not correlate to the disease severity or the risk for a patient to become recurrent.”127 That statement resounded (and still resounds) throughout the “mixed diagnosis” patient/caregiver community.

The next year, porphyria experts in neighboring Norway published results of a comprehensive study, Lifestyle factors including diet and biochemical biomarkers in acute intermittent porphyria: Results from a case-control study in northern Norway. Interestingly, study subjects consisted of symptomatic and asymptomatic patients. The objective of the study was to measure the effects of various triggering factors and diet on porphyria patient’s biochemicals (in urine, serum and plasma) and compare the results achieved from symptomatic and asymptomatic patients. Triggering agents studied included diet, nutritional supplements, physical energy expended, emotional stress, medications, alcohol, smoking, present and chronic diseases and surgeries prior to the start of the study. A total of thirty-four biomarker levels were measured and recorded including urinary ALA, PBG, total porphryins, cholesterol, triglycerides, hemoglobin, ferritin, iron, potassium, magnesium, phosphate, sodium, cortisol, epinephrine and others. Given that most, if not all, “missed diagnosed” patients rely on simple sugars as part of DIY treatment regimens, I found it interesting that the report noted “U-ALA correlated significantly and negatively with S-pre-albumin and sugar/candies intake.”128In other words, it works. “a.p. missed diagnosis” patients heartily endorse it. Besides the acute porphyrias, not many (if any, besides hypoglycemia) diseases are relieved or are resolved with sugar intake.

Dutch porphyria experts had also recognized the need for better biomarkers and developed “an enzyme assay for plasma [ALA] and [PBG] which is a more sensitive test for AIP than urine ALA and PBG analysis.”129 They also found that the combination of plasma ALA and PBG, and fluorescence scanning could be used as a screening test for AIP, VP and HCP the assays had been assessed in a “large group of subjects characterized for AIP, VP and HCP at the DNA level.”130 Notably, none of the “patients had acute porphyria complaints at analysis.”131 Further, the Dutch porphryria scientists noted that “[one] family had combined HCP and VP mutations” and “All patients who had previously had an acute porphyric attack had abnormal plasma ALA, PBG or fluorescence results in the asymptomatic period.”132

The acute porphyria “a.p. missed diagnosis” patient/caregiver are excited about the promise that Dutch porphyria experts appear to be within striking distance of “breaking the code” of the too-long-endured U-BP acute porphyria diagnostic hallmark.

Before any of these studies or comments had been made by out-of-US porphyria experts, the US Porphyrias Consortium had launched an NIH-sponsored clinical trial titled Acute Porphyrias: Biomarkers for Disease Activity and Response to Treatment. The study start date was scheduled for January 2014 though it wasn’t posted until October 2016 with the estimated study completion date slated for December 2021. The estimated enrollment was 50 “well documented” AIP, HCP and VP symptomatic and asymptomatic patients. US porphyria experts expected to measure “[e]xpression of heme biosynthetic and heat and stress response genes in potential biomarkers” for metabolites in blood, urine and stool samples.133

All study subjects had been “expert-confirmed,” meaning they’d been granted the diagnosis of acute porphyria based on U-BP. The breakout of AIP, HCP and VP subjects was not disclosed, nor was the ratio of asymptomatic vs symptomatic patients. The last update was posted on July 25, 2018. As of this writing, no outcome measures have been posted and with a completion date of December 2020, obviously, no study results are available.

US porphyria experts’ commitment to U-BP being the “gold standard” to diagnose the acute porphyrias remains steadfast. That being said, a relatively recent “maypole ribbon” contribution was provided by a gentle, intelligent and resourceful “a.p. missed diagnosis” acute porphyria patient in the form of a discovery that would surely make Dr. Cecil Watson and Dr. Freidrich Meyer Betz darn proud of his efforts and findings. It is the basis for the perhaps the most telling section in this response and follows.

  • Blood

The porphyria world owes a huge debt of gratitude to Dr. Watson whose “insatiable curiosity stimulated countless medical students to search for the why of clinical phenomena observed at the bedside.”134 However, even as he is heralded for discovering hematin and the infusion of same to successfully treat afflicted patients, for whatever reason, it appears Dr. Watson, with a PhD in hematology and pathology—and virtually every acute porphyria expert before and since neglected the importance of a critical part of the acute porphyria diagnostic/treatment puzzle. That “part” is the end product of the heme biosynthetic and bone marrow pathway mechanisms known as the “fluid of life”135—blood. To be sure, blood components (porphyrins, precursors, enzymes, particularly as in PBGD being used to determine that AIP is allegedly “latent” even as patients with “negative U-BP” are suffering with clinical symptoms equal to or worse than “expert confirmed” patients’ misery) have been mentioned throughout porphyria history. However, knowing that inherited mutated genes results in deficient enzymes that cause dysfunction in the heme biosynthetic pathway, why porphyria experts before, since and including Dr. Watson leapfrogged over blood testing (aggregate and cell characteristics) in acute porphyria diagnostics and treatment to concentrate on urine remains a mystery to us. Even the Japanese, who noted, “[e]ventually, they [blood cells] enter circulating blood and are excreted in urine and feces.”136 So, what becomes of those who aren’t excreted in urine and feces? What are the characteristics of those “enzyme deficient” blood cells? So many questions; too few answers. Not medically trained doctors/scientists, we nonetheless know that blood cells are continuously made and destroyed and that when, for acute porphyrics, the demand for new blood cell production dramatically escalates, all hell can break loose. 

Awash in the misery of debilitated physical, neurological and emotional health and weary of the decades-long erroneous insistence emanating from US porphyria experts that U-BP is the diagnostic gold standard for acute porphyria, the previously mentioned resourceful patient decided to take it upon himself to at long last prove that his illness was not “latent.” During his lifetime, this man has lost five family members to porphyria, including his mother who after twenty-five exhausting years of fighting, succumbed to pain-wracking AIP—sadly, on her son’s birthday in 2010. Having spent the better part of his youth working hard to help his father pay for his mother’s medications and other medical care, he himself began presenting with the “family disease” in 2007. Nine years after his mother’s passing, he describes his financially and emotionally bankrupt father as “still numb.” Now twelve years later he believes that HCP, not AIP controls his life; doctors weren’t able to tell the difference when his mother was suffering. He remembers, “they used her like a guinea pig; they kept trying everything possible to control her seizures and pain. With all the different doctor changes, she would forget what medications she had taken. Because each doctor wanted to start over from scratch, I began to keep a list of safe and unsafe medications. Once we learned of the APF back in the early ‘90s, I shared the list with them and told them we should start [a safe/unsafe drug list]. As far as getting any closer to APF we stopped at around 1995. I am so disheartened after all these years, APF and the US porphyria expert community has hardly done anything but push Panhematin® which killed the   woman [who’d] told us about APF and [Panhematin®]. I’d found her [porphyria patient] through the internet in about 1992 and we had contact until around 1994. Then it stopped; her son finally contacted me the next year to say she’d been given two doses of Panhematin® within four hours which had killed her. Tragic news. My mother and his mother, both nearly the same age, talked a lot on the phone like we do here and compared notes.  It did help both women and I wish it had not turned out as it did.” 137

For too long, like his mother before him, this man’s house has been his prison; his body his tormenting jailer. With the exception of his father, his family is “all dead.” Friends are long gone, save for those he’s connected with through the online “a.p. missed diagnosis” patient/caregiver community. With plenty of time to reflect on the past and dreary pain-filled present he said, “What this disease does to the body is really horrible. Each day is a challenge. It

[porphyria]

rolls through families over and over. I’m so sick of it. It’s just one endless tragedy after another rippling into the future of an entire family spreading out. It’s really bad struggling to fight when you are sick inside. You so want to just give up. So few care anymore about solving problems and mask them with pain medications. It is sad. This is America; we are supposed to overcome. [Regarding this disease, we] aren’t anymore.”138

Weary that “sitting around just waiting to die isn’t good for the coming generations,” he made the decision to “do everything I can to help turn the page to find answers for anyone with this strange disease.” With that, he remembered that before ‘I even considered I had porphyria, I’d paid someone who’d been studying blood his whole life to look at mine.” That’s when his interest in monitoring his own blood began. Then about two+ years ago, his porphyria raging, he with met someone who, “did a live microscopy of my blood with a scope. He told me that my white blood cells were not attacking the viruses and being very dormant.”139 Interest renewed, he purchased his own digital microscope and began to periodically monitor his own blood cell activity during and outside of attacks—something no doctor or expert had ever suggested be done for his mother or himself. What he’s found is forehead-smacking—strangely misshapen blood cells.

Occasionally, others in our patient/caregiver community had shared information of reports of misshapen blood cells that had been shrugged off by hematologists, internists, etc. Before she was DNA diagnosed with AIP, my daughter’s hematologist informed us that her red blood cells were oddly-misshapen, “but I don’t know why.” Other patients described similar reports—one whose blood cells at the time of collection were lemon-shaped (sharp on both ends). She shared the memory, “the doctor who showed me my lemon shaped red blood cells, a world-renowned MD and HMD, seemed extremely taken aback by the appearance of my blood and remarked that I must be anemic, but I’m not. Not in the traditional sense anyway. He seemed very upset and shocked by what he saw, so much so that he showed me and I’ve never forgotten it.”140 She said she’d learned from an “expert-confirmed” AIP patient that the individual had seen a physician decades earlier who, when told s/he’d been diagnosed with AIP, had quipped “Ah, Caucasian Sickle Cell!” The expert-confirmed patient also shared s/he’d recently been asked by APF to write a paper about that encounter so it could be presented during a conference call between APF and a Sickle Cell organization “to discuss our mutual problem of extreme pain.”141

The following article was published in APF’s 1st quarter 2019 newsletter, titled, Sickle Cell Disease and Acute Porphyria:

“APF was asked by the government Pain Task Force to participate in a conference call with the Sickle Cell Organization to discuss our mutual problem of extreme pain. Sickle cell disease is an inherited blood disorder marked by flawed hemoglobin. Sickle cell, like the acute porphyrias, is an excruciating group of diseases that involve heme. Normally, hemoglobin allows red blood cells to carry oxygen from your lungs to all parts of your body. Normal red blood cells are smooth, rounded, flexible and can flow freely. In Sickle Cell disease, when these red blood cells lose their oxygen, they become rigid, sticky and misshapen, like a sickle, and live only 10 days as opposed to the normal 120 days. These sickle-shaped cells obstruct capillaries and restrict blood flow to an organ resulting in pain and other serious damage. The crises are extremely painful and often require pain management with opioids.”142

The article prompted the a bit more research and the following short comparison of similarities by our “a.p. missed diagnosis” patient/caregiver “investigating blood team” of the two conditions:

Sickle Cell Disease                                       Acute Hepatic Porphyria

Inherited                                                         Inherited

Molecular disease                                          Molecular disease

Involves hemoglobin—oxygen                    Involves hemoglobin—oxygen transporters of the body                                transporters of the body               

Abnormal hemoglobin protein identified       Hemoglobin studies unknown (1948) or unreported                   

RBCs lose their oxygen; “de-oxygenated,”    Documented problematic become rigid, sticky & misshapen oxygen-heme binding. No data

re RBC characteristics post- heme biosynthesis

RBCs live only 10 days as opposed to 120    Unknown (or unreported

Sickle cell shape obstruct capillaries and        Condition/shape/volume

restrict blood flow to organ(s)     unknown (or unreported)

resulting in pain/ other serious damage       Resulting damage unknown

Crises are extremely painful; often require     Chronicity is and crises are

pain management with opioids. extremely painful; may require opioid pain management

While it is remarkable that Sickle Cell Disease (first characterized in the US in 1910) and the Acute Porphyrias (first publicized case ~1899) have several similarities, it is mind-blowingly sobering to see in “black and white” that information about acute porphyrias’ blood cell characteristics in this day and age is so severely lacking. Given that Dr. Waldenström, “father of AIP,” was considered to be one of the giants of hematology and that Dr. Watson’s “pioneering scientific work [was on] the metabolism of hemoglobin, porphyrins and bile pigments,”143it seems odd that the resulting product of the acute porphyrias—blood—hasn’t been granted the respect it surely deserves. Other than to use it to deem AIP’s latency (erroneously as it turns out in some cases), why scientists were smitten with shiny objects (aka excreted) metabolites that for generations have been given preference time and again over the blood cells that had been churned through the heme biosynthetic pathway and entered the circulating blood versus those that had been “spewed out of” the pathway is staggering.

Intriguingly, the APF co-founder/director wrote multiple times throughout her book of having blood drawn before, during and after the life-threatening attack that precipitated her AIP diagnosis. She recalled a time, evidently about 20 years after that life-altering event when unrelenting porphyria pain sent her back to her internist where she was informed that, “my blood was not as oxygenated as it should be.”144 She was admitted to the hospital where she learned that “[medication] had compromised my breathing. In addition, my feet were terribly swollen, and I was having difficulty urinating….these symptoms paled in comparison to the tremendous pain…I lay in bed for days on end almost out of my mind with pain. The IV of morphine did not make a dent in the agony. The doctors had to be extremely careful as my oxygen level with dangerously low and could decrease even more from [medication] use.”145 Which raises an obvious question, why had she not been administered supplemental oxygen—even at very low levels? It is highly unlikely that this had not been reported to APF SAB members; the APF co-founder writes that Dr. Anderson (SAB chair) intervened and “assured

[the attending doctor]

that I had endured 20 years of intermittent pain and almost never asked for prescription drugs [she had asked for morphine].”146 So we know that the APF SAB chair had some involvement—yet didn’t think that arterial blood gas analysis might be an informative measure to determine influencing acute porphyria activity? Or, most likely, the US porphyria Agenda had taken precedence. Oxygen deficiency can be a very real problem for acute porphyria patients. In my ‘mom’ opinion, it seems most likely in concert with heme deficiency and can be assuaged with supplemental oxygen. In fact, supplemental oxygen alone has been used by some “a.p. missed diagnosis” acute porphyria patients to relieve symptoms and/or to head off attacks

Because she’d continued to have intermittent breathing problems/respiratory distress, I’d asked my daughter’s various doctor(s) to get an arterial blood gas baseline then to monitor it during AIP problems. My requests were dismissed.

It is telling that APF’s scientific advisory board (SAB) has long been weighted to MD gastroenterologists and MD hepatologists and (very) light on MD hematologists, MD biochemists, MD endocrinologists, MD  neurologists, MD pathologists,  MD pediatricians—to the point of non-existence of the several latter specialties. So it is not surprising that only four papers by-lined by APF/SAB members addressing the blood/acute porphyria connection turned up in a search. Though vintage, Blood Volume and Bilirubin Production in Acute Intermittent Porphyria is by far the most informative for sleuthing patients/caregivers. While the focus was on bilirubin production, it also provided some snippets that “a.p. missed diagnosis” patients/caregivers might share with their own physicians/hematologists who are generally appreciative of receiving this type of information, if only for a “starting point:”

  • “[m]ean blood volume in thirteen AIP patients was 80 per cent of normal;
  • “the total blood volume and total red-cell volume in AIP patients were significantly reduced from normal values, whether compared as an entire group or by sex;
  • “bilirubin is a product of heme degradation;
  • “changes in the bilirubin production rate closely paralleled changes in the red-cell volume;
  • “effective erythropoiesis is frequently decreased in patients with AIP;
  • “the decrease (of erythropoiesis) is of variable magnitude and will not be detected by routine hematologic studies since the hematocrit is not reduced.”147

Ironically, this thoroughly focused paper on blood components relating to acute intermittent porphyria paper was based on AIP patients selected because they had “[demonstrated] increased urinary excretion of porphobilinogen (PBG) which was measured by the method of Marver et al.”148 No investigation of blood characteristics was even considered. However, the point about decrease in erythropoiesis not being revealed in hematocrit readings is important and raises the question—can that be tracked, and if so, how?

The only other paper with an APF/SAB member by-line that actually addressed blood components in acute porphyria was the more recent (2013) Heme status affects human hepatic messenger RNA and microRNA expression, researched and published by APF/SAB member Dr. Bonkovsky and research team. However, the apparent reason for that research, which was supported by a grant from NIH/NIDDK, was to assist Alnylam/APF in achieving success for its product, Givosiran.

The last two papers’ titles allude to providing information pertaining to blood regarding the acute porphyrias. In actuality, the focus of both Neurovisceral Porphyrias: What a Hematologist Needs to Know by Dr. Bonkovsky and research team and What Hematologists Need to Know About Acute Hepatic Porphyria by Dr. Balwani is the “US-obligatory” enzyme deficiencies, biosynthetic pathway (blood building process) agenda with emphasis on urinary output and heme pool repletion with hematin. To be fair, Neurovisceral Porphyrias: What a Hematologist Needs to Know did address erythrocyte PBG and plasma porphyrin levels as “second-line testing” to be done “If the [urinary] porphobilinogen level is increased….”149 However, his discussion of erythrocyte PBGD and AIP was probably more than a hematologist would expect—and less than what s/he really needed/wanted: “Worthy of emphasis is that about 10% of patients with AIP have normal erythrocytic PBG deaminase levels. There is a single gene encoding PBG deaminase, but erythroid cells utilize different promoters and transcriptional sites than hepatocytes and other cells. As a result, the erythrocyte enzyme lacks the amino terminal residues encoded by exon 1. Therefore, in the 10% or so of patients with AIP who have mutations in exon 1, erythrocytic PBG deaminase activities are entirely normal. Another limitation is that there is a large range of variation in activity of the enzyme, and there is an overlap between normal and carriers of the deficiency.” 150

Interestingly, Dr. Bonkovsky noted in the Heme status affects human hepatic messenger RNA and microRNA expression paper that he had been led to “to develop heme as a potential therapy for acute porphyria in relapse.”151 This apparently was a reference to case thirty or so years earlier in his career when he worked for the NIH Public Health Service under Dr. Tshudy, who would go on to become an inaugural member of APF’s SAB. The case bears sharing here as an analysis of the case had been documented in the paper, Repression of the Overproduction of Porphyrin Precursors in Acute Intermittent Porphyria by Intravenous Infusion of Hematin which describes how the patient presented at the NIH Clinical Center in late February 1971 with an attack that had started earlier in that month. By report, at the time she was excreting “a large amount of PBG.”152 For the next month or so various treatments (medication, high carb diet, insulin, supplements) were tried with no improvement until the patient’s condition “slowly but inexorably” deteriorated; “she became bedridden and totally incapable of self-care.”153

By April (a month and half after admittance), due to continued deterioration (dysphagia, inability to clear broncho-pulmonary secretions) a tracheostomy was performed and continuous ventilation provided. Intravenous hematin was started in mid-April, 250 mg amounts were given twice daily three days in a row; one of those days, two doses were given, “in part subcutaneously. There was no apparent clinical response.” Within a day or two, the patient developed “acute gastric bleeding;” a gastrectomy was performed which was followed by “severe renal failure.” In response, peritoneal dialysis was done; the patient “became totally anuric [unable to pass urine]…[then] became comatose and developed opisthotonus. Hematin was resumed “on May 7, again, without clinical response…[t]he patient died on May 29 [almost 3 weeks later], of profound central nervous system failure attributed to acute porphyria and uremia.”154 Unfortunately, it appears that a scientist mindset appears to have overridden the physician’s creed throughout this poor woman’s final AIP battle.

Forty-four years after the scientific review of the case had been released to the medical world, APF’s 1st quarter 2015 newsletter featured an article authored by Dr. Bonkovsky about the case, titled DR. BONKOVSKY CREATES HEMATIN.

The APF SAB member recounted his perspective of the NIH team’s three month long attempt to battle AIP in 1971. Having only been associated with NIH’s Public Health Service for a year or so at the time, Dr. Bonkovsky’s account definitely leaned toward the scientist side of the equation. His report of that account states that [a month and a half after the patient had been admitted and after numerous therapies had been tried to improve her condition] he’d “proposed to Dr. Tschudy and other senior leaders of our Branch that we should try giving her heme intravenously, in hopes that some of it would find its way into her liver cells and perhaps other cells that were deficient in heme and were over-producing ALA and PBG….”155

            His proposal to Dr. Tschudy questions his understanding at the time that a “revved-up” HBP mechanism, not the liver and other cells, was responsible for the “over-produc[tion]” of porphyrins/precursors. Nonetheless, I do applaud the first part of that thought, “some of it [heme] would find its way into her liver cells and perhaps other cells that were deficient in heme,” as that had been my thinking for so long—not just repleting the heme pool—but replacing cells (porphyrins and precursors) with donated, “normal” blood cells.

In any event, that is when Dr. Bonkovsky’s APF newsletter recount of the 1971 case turned to a scientist’s enthusiasm of “creating heme.” The NIH is a hospital dedicated to clinical research; it is highly unlikely that Dr. Bonkovsky worked alone but more than likely was one of a team of interns, residents and others in this endeavor. That being said, his perspective of the fatal 1971 case’s hematin story follows:  

“Accordingly, I obtained several pints of outdated blood from the blood bank of the NIH clinical center, and I set out to purify and crystallize hemin chloride from these units of blood. The purification involved several steps, including eventual crystallization of the product from boiling acetic acid. I worked all day and all night, and by the next morning, I had beautiful, extensively washed and purified crystals of the desired product. The final yield was about 1,000 mg of hemin chloride. Of course, we had no real idea of what the right dose would be for patients with AIP, but, based upon the results in rats, we believed that 3-5 mg per kilogram body weight would be reasonable. Our patient weighed about 60 kg, so we decided to administer 250 mg every 12 hours in our initial study. The next challenge was to redissolve these crystals in an aqueous solution, suitable for administration to humans. Hemin is not very soluble at physiologic pH [7.4], but it is soluble at high pH. I decided to dissolve the precious crystals into a solution of 1% sodium carbonate, which has a pH of about 10-11. I was able thus to dissolve the 250 mg [about 10 ounces] of hemin in 25 mL of the sodium carbonate. Heme at this pH is actually in the form of hydroxy-heme, with OH – anions replacing the Cl – ions, and this form of heme had been named hematin by Hans Fischer, MD, PhD, the outstanding pioneering German chemist, who had won the Nobel Prize for chemistry in 1930 for his work on pyrroles, porphyrins, and the chemical synthesis of heme. Thus was hematin for human use first born.”156

Actually, Dr. Watson happened to have worked with and learned directly from the highly venerated organic chemist Dr. Hans Fischer whose studies of hemoglobin fueled synthesis of hemin.157 However, it was Dr. Cecil Watson who is rightfully recognized for developing hematin.158 Dr. Bonkovksy continued, “After dissolution, the pH was adjusted downward slowly and carefully with hydrochloric acid to a final pH of 7.5, and the final solutions were put into brown vials for immediate administration. We felt the latter was important because it was known that hematin in aqueous solutions undergoes rapid ‘aging’ reactions, with formation of polymers and degradation products that may not have the desired therapeutic effect and that also may cause adverse effects. The biochemical effects of the first four infusions, 250 mg given every twelve hours, on April 13 and 15, 1971, were dramatic, with marked decreases in urinary and serum ALA and PBG. Unfortunately, in this woman who had been severely ill for months and, by now, was totally paralyzed, we did not observe clinical improvement. Nevertheless, it seemed worthwhile to treat her with additional doses of hematin. Thus, for the next several weeks, I spent all day and most of the night, purifying, crystallizing, and preparing hemin chloride for further infusions. We gave several more infusions of hematin to the patient during the next month or so, with further strongly positive effects of decreasing levels of ALA and PBG, both in the serum and in the cerebrospinal fluid. (By this time, due to the ravages of AIP with severe systemic arterial hypertension, acute on chronic renal disease, and superimposed sepsis, the patient had developed severe kidney failure and had stopped making urine. We reported these findings, so that other physicians and scientists around the world could benefit from our experience and could further test the effects of hematin earlier in the course of acute porphyric attacks. I finished my two-year appointment at NIH in June, 1971.”159

Note: “severe systemic arterial hypertension” is emphasized by this author to call attention to the need to identify de-oxygenation during acute porphyria activity—and to the need to recognize one of the most basic (and critical) efficacious components of acute porphyria treatments.

Five years later after that 1971 ill-fated AIP battle, three of Dr. Bonkovksy’s co-authors of Repression of the Overproduction of Porphyrin Precursors in Acute Intermittent Porphyria by Intravenous Infusion of Hematin (Bosssenmaier, Cardinal, Watson @ Abbott-Northeastern Hospital, Minnesota) published another case of “a young woman with acute porphyria in profound relapse.” This time, earlier intravenous infusions had resulted in “remission of symptoms and rapid recovery to the point “that she was able to leave the hospital in less than a month.”160 Interestingly, this team completed “[s]erial studies of serum and urinary levels of porphryin precursors and serum level of hematin provided highly important information about the effect of hematin on acute porphyria.”161 [Note: Emphasis author-added.] At least adding serum testing to the mix was a start. The scientists published a paper about this hematin success, Hemin Treatment of Acute Porphyria: Early Remission of an Almost Fatal Relapse.

Six years passed between that experience and APF’s founding. Dr. Bonkovsky makes note of other physician-scientists, particularly [those] in Minneapolis and explains how they came to use hematin early in attacks of AIP with excellent results. To that end, it is fairly obvious that the APF scientific advisory board of porphyria experts had knowledge of this and other successful reports so one is left to wonder if the reference to serum testing was intentionally overlooked—and why, with knowledge of the APF co-founder’s bout with “dangerously low oxygen level” arterial blood gas investigation hadn’t been moved up on the acute porphyria diagnostic—or treatment—scale.

The most recent of those four papers by an APF/SAB member (actually it is an interview with Dr. Manisha Balwani of Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, and the journal Hematology & Oncology about hematology aspects relating to the acute porphyrias. Coordinated eleven years after the publication of Dr. Bonkovsky’s Neurovisceral Porphyrias: What a Hematologist Needs to Know paper, Dr. Balwani’s interview What Hematologists Need to Know About Acute Hepatic Porphyria, too, pushed the heme biosynthetic pathway agenda through and through. With the exception of the mention of “half-normal” enzyme activity and Panhematin® treatment, no blood components or measurements were discussed. Not being a hematologist, but having spent many hours over years as a “a.p. missed diagnosis” acute porphyria patient’s caregiver in the company of hematologists, I surmise they would probably have preferred learning more about the blood effects of AHPs.

The Caucasian Sickle Cell conversation with “expert-confirmed” acute porphyria patient and the APF article reverberated with the “a.p. missed diagnosis” patient’s recollection of her own “lemon-shaped” cells and other patients/caregivers’ reports of “weird blood” lab reports. Theorizing that Sickle Cell Disease and Acute Porphyrias might have more in common than excruciating pain, she and the aforementioned amateur lab analysist/patient put their heads together and another theory brewed. What if those genetically-based enzyme deficiencies, blamed for heme biosynthetic pathway dysfunction in the acute porphyrias similarly resulted in impaired blood cells?  Wouldn’t that cause pain?

For your review, following are several samples (albeit not “certified lab” approved) of this not-professionally-trained scientist’s own blood cells photographed on a digital microscope. Note the remarkably-odd shapes, positions and distributions of blood cells. Given the IEM nature of acute porphyrias who’s to know if taken in the same sequence at different days/times would show similar—or worse characteristics? He submitted several photos (in no particular order, time and/or date not identified) of his own blood samples for review:

Desperation motivated (and still motivates) this individual to “test on myself until I can find an answer to solve this [missed diagnoses] problem. I feel I am getting closer and with God’s help and a few others in this group, I think I can.” With the death of his mother and other bio-family members’ ever present in his mind, his commitment is unambiguous, “It just depends on His will and what strength I have each day to get up to fight again. I may die doing it but at least we can know more and my sacrifice won’t go unnoticed in this Godforsaken world.”162

This gentle man has never experienced the benefit of infused Panhematin® as my daughter and others have so he has not been able to “check” his blood samples before and after such treatments—as surely he would. And yes, we are aware that Panhematin® has had involvement with deadly effects on true acute porphyria heroes—unintended human guinea pigs. Dr. Watson and Dr. Bonkovsky bore witness to such, but evidentially neither thought to investigate the before/after blood effects. The question is, are some of these blood cells misshapen because of acute porphyria, or are they the product of another (others) condition(s)? Seems coincidental that the report of misshapen cells from patients (through their doctor) is purely coincidental.

Given my daughter’s experiences and my observations, my theory about Panhematin® is that it works because donated “normal” blood cells (that is, fully formed with adequate oxygenation and other components) replete the heme pool. That acute porphyria blood cannot be guaranteed to be “normal” at all times is probably the reason why, generally speaking, porphyria-patients aren’t preferred blood donors.

Thanks to my having just read Rachel Carson’s Silent Spring chapter about cellular oxidation and my having a medical article on hand in the hospital about the AIP heme/oxygen binding “problem,” my daughter and I long ago also performed an (unintended) experiment.

It happened in the hospital when my daughter was being administered Panhematin® but her severe attack wasn’t seeming to be responding as had always happened previously With only a short time left to go of the Panhematin® treatment, I finished reading the chapter, showed the attending doctor the paragraph I was reading and the medical article and begged him to administer supplemental oxygen to her immediately. He complied. The supplemental O2 switch on through the remaining IV glucose post hydration, my daughter responded famously. We left the hospital within 15 minutes of the post-treatment IV glucose finishing, her walking upright, with good eye contact, appropriate response to conversation and without the usual after-hemin complaints of severe aches and pains. I then shared the experience, the Silent Spring chapter and the medical info with her hematologist. From that point forward, supplemental oxygen (via face mask) during IV glucose w/ ½ NS + 10q KCL/L at 150 ml/hr and/or IV Panhematin® treatments became the norm. The supplemental oxygen suggestion has benefited other “a.p. missed diagnosis” patients, for which we (and they) are thankful.

Perhaps if all those decades ago the porphyria experts had thought to check the APF co-founders blood before, during and after her life-threatening attack instead of focusing solely on U-BP, the non-profit patient advocacy and physician education organization APF would have followed a different path and truly would today be able to say with integrity, “dedicated to improving the health and well-being of all individuals and families impacted by Porphyria.”163 [Note: Emphasis author-added/intended.]

 Surely, building on these findings and theories presented herein, trained, interested and porphryria experts—absent the US-agenda will be encouraged to at long last take leaps beyond Dr. Cecil Watson’s marvelous discoveries. Doing so just might turn the long-held acute porphyria diagnostic “gold standard” into “fool’s gold.”

•     “Latent” vs. “Asymptomatic” vs. “Misdiagnosed

When asked to describe what acute porphyria is to them; “missed diagnosed” patients/caregivers replies included: “severely lacking quality of life;” “a living hell;” “a life shredder;”  “never being believed—by anyone;” “like being in a weird ‘Alice in Wonderland;’” “not understood;” “doctors acting like I’m crazy;” “excruciating, mind-bending pain, and more pain, vomiting, heart racing like crazy, not being able to breathe, brutal, just brutal;” “like wrangling unicorns;” “horrible;” “praying that the next attack won’t be my last—but will be the one when I finally pee pbgs;” “ERs, hospitalizations, no answers, no help, no interest;” “being told over and over that everything is normal—but I know it isn’t;” “being treated like or talked to like you’re a hypochondriac, a junkie or mentally ill;”  “being treated with contempt by doctors, families;” “involuntary commitment to psyche wards—the worst;”  “very isolating, very scary and very, very painful;” “seeing umpteen doctors who just don’t give a f-ck, don’t give a shit, don’t listen, don’t believe you, just don’t care;” “losing friends, jobs, life, self;” “the experts say that acute porphyria can become chronic. What they (experts) don’t get is that acute porphyria chronicity develops early—especially when left untreated. They just really don’t know what it’s all about, do they?”164 According to one discerning non-U.S. porphyria specialist, “Porphyria is as bad as cancer.”165Yet when it comes to receiving adequate attention, acute porphyria doesn’t seem to be on any medical/agency radar. As long as information like the following is sanctioned by European porphyria experts, it won’t be: “It is important to know that ~80% of people who have changes in their Porphyria genes (called mutations) never have symptoms of the acute Porphyrias. These people are said to have ‘latent acute Porphyria.’”166  “If urine ALA and PBG are normal during an attack, it essentially rules out an acute porphyria.” 167

The foregoing represents an undisputable disconnect between “missed diagnosed” patients and porphyria experts’ understanding of latent and asymptomatic. The most recent (2012) medical dictionary defines “latent” as, “[n]ot manifest, dormant, but potentially discernible” and “asymptomatic” as “[w]ithout symptoms, or producing no symptoms.”168

At one point or another, both terms have been applied to my daughter and many if not most (or all) of those in the “missed diagnosed” patient/caregiver community. Clearly, all US and most EU porphyria experts consider “negative” U-BP (not making the grade) to be an indication that a patient’s acute porphyria status is dormant, completely dismissing the “potential discernable” aspect of the definition. Similarly the “asymptomatic” has been applied to too many patients whose horrific suffering is routinely minimized, as IPDMC authors did when writing, “symptoms and signs may mimic other, more common conditions…”169 or in denying that what they suffer (often requiring ED, clinic or hospital admittance) are not attacks because the patient didn’t excrete, collect or test positive for U-BP.

APF’S co-founder did exactly that in an email response to me following Facebook communication she’d had with my daughter after her diagnosis had been revoked in which the girl’s obvious distress had been evident. The APF director stated ,  “I feel badly for you as you are back at square one…you might want to contact the best of the experts in Europe [because I’d already communicated with a Swedish porphyria expert at which Dr. Desnick obviously took offense] and ask them about [your daughter’s] situation…It is so hard. As I mentioned to her with 7000 rare diseases, it can be very difficult to obtain a diagnosis. We have several patients in the same situation with DNA but no attacks.”170[Note: “no attacks” is intentionally author-emphasized.] She essentially said my daughter did not have porphyria attacks. Remembering that the APF co-founder had described experiencing debilitating “Porphyria” activity and attacks for years before ingesting the Dilantin that prompted the attack that produced U-BP in her memoir, I was more than dismayed. But we weren’t alone. This individual’s contemptuous comments had been heard before—by patients that the APF co-founder/director and/or SAB members had dismissed as having been “misdiagnosed.” Many, if not most of these patients had attacks—but no (or low) U-BP.

Patients who’ve approached the APF for help, reporting they’d been “fine,” “normal” until “the symptoms” inexplicably struck and included excreting “weird, darkened urine (collected, tested and met U-BP parameters) were welcomed with open arms into the non-profit’s fold. So, too, were the ones who reported they’d taken (or been given) medication(s) that resulted in worsening symptoms—and excretion of “weird, darkened urine” that had been collected and tested positive for porphyria. However, others reported a more concerning case history—“sick [sometimes] since I was born” or “since I can remember,” “no doctor could find answers,” “horrific childhood,” “sick all the time,” etc. These seldom included mention of odd-colored urine and if it did, the color range noted was wide—from pink-ish to orange-ish to cola-colored—and generally were not collected or tested. But while the patient reported ongoing “sickness,” massive quantities of excreted U-BP

[and collected]

was elusive. Those were/are the ones dismissed. What resulted was a divide between the patient groups—one that grew wider, deeper and more acrimonious as the years passed.

A few years ago, “expert-confirmed” AHP patients began approaching the closed “a.p. missed diagnosis” patient/caregiver online forums. Many were simply curious, not understanding why someone who didn’t excrete U-BP would even think they had porphyria. Some came with a purpose—to push the APF agenda (thinking they were doing the closed forum participants a favor).  More than a few came to bully, some through private messaging, and did incomprehensible damage to people who’d already been damaged by the APF “machine;” they were met with blazing, protectionism responses. More recently, some “expert-confirmed” AHP patients, apparently realizing that individuals within the “a.p. missed diagnosis” patients/caregivers communities provide helpful ideas, tips and information based on experience generally (but not always) centered on communications with their own clinicians (if they have them) be it MDs, NDs, ODs, etc. and/or research obtained from the wealth of information published by porphyria experts throughout the world, have begun to do likewise.

SUMMARY—Questions Galore, Still

 Every single “a.p. missed diagnosis” patient’s story deserves to be told to and/or read by porphyria experts. These patients are survivors. Wrenched out of society by a wretched illness that refuses to show itself within the highly fallible, narrow guidelines set by experts whose refrain is “that’s the gold standard,” each has become a self-researching, self-study subject by necessity. Enmeshed in pain, despair, fear and destitution each uses his/her own body’s reactivity to guide him/her through each and every day and night. Carrying the burden of society, family, self-loathing, each bears his/her angst and discovers all he/she is able concerning acute porphyria(s), the body and their own seemingly ever-changing physical/neurological responses in order to attempt self-treatment so they could live. another. pain-filled. day. another. woeful. week. another. depressing. month. another. miserable. Year—all the while remembering and mourning the life he/she lost. For these hapless patients, most days end up being experimental undertakings.

 “a.p. missed diagnosis” patients didn’t get to live because of APF and its SAB’s paltry agenda-driven studies and medical information; they lived (and survive) in spite of APF et al’s indifference and not-infrequent interference. These patients (and their caregivers, if they have them) do the best because they’ve fought (and continue to fight) to know the most. Scorned by the US non-profit “dedicated to improving the health and well-being of all individuals and families impacted by Porphyria,”170 we lean on each other’s compassion and sharing of experiences—and  information provided in porphyria studies from the truly worldwide porphyria expert community.

To that end, the “a.p. missed diagnosis” community offers kudos and thanks in particular to porphyria experts in Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czech Republic, Denmark, Finland, France, Germany, India, Israel, Italy, Japan, Nepal, The Netherlands, Norway, Poland, Romania, Russia, Saudi Arabia, Singapore, Slovakia, South Africa, Spain, Sri Lanka, Sweden, Switzerland, United Kingdom and early United States (pre-1980s), Venezuela and so many more for publishing useful, explanatory research findings.

Porphyria experts in these countries have served as the “a.p. missed diagnosis” community’s de facto doctors—and has helped (and still helps) patients/caregivers navigate pain-drenched and perilous existences.  Among the points that the “missed-diagnosis” patient/caregiver community find irritating is that many, if not most, US reports, speeches, etc. about acute porphyria inevitably include statistics (prevalence, incidence, symptoms, etc.) from European sources—about Europe. Never any US statistics—or information beyond what APF’s experts “say.” To that point, is a 2017 report from Cancer Therapy Advisor written by a member of APF’s SAB. Interestingly, though the obligatory US portrayal of the heme biosynthetic pathway was included, CRIM subtypes were discussed. I found the next sentence to be typical of APF SAB communications, “The occurrence of type II explains why only ~95% of all AIP subjects have decreased erythrocyte PBGD activity.”171 Note, the emphasis on “only” was author-added because 95% is a significant number; it is misappropriate to attach “only” to it—particularly where genetics are concerned. Besides, it doesn’t match the ~90% reported in the Porphyrias Consortium’s Rare Disease Network chart as HMBS activity in RBCs mentioned on page 17 of this response. 5% is a considerable difference and we have figured out that the 90 or 95% number plays better with keeping the US-Agenda going. We believe the number (or percentage) of AIP patients with normal (or perhaps, increased) PBGD erythrocyte is only ~5% should be the accurate portrayal.

As noted at the beginning of this response document, the reason this “a.p. missed diagnosis” population exists—at least in the US—appears to be to insure that the acute porphyrias stay within the parameters of NIH’s rare disease category. This helps achieve/maintain FDA orphan drug status for the medications APF has partnered with pharmaceutical companies to treat acute porphyrias. This thinking quite likely began with the APF/Abbott Laboratories’ Panhematin® partnership and carried through to the current APF/Mount Sinai/Alnylam partnership. This was all but confirmed in Alnylam Pharmaceuticals’ Q2 2018 Results’ Earning Call (August 2, 2018) during an interchange between an Alnylam executive and an investor analyst. To wit: the analyst asked Alnylam about the “potential opportunity” that is a “patient queue that’s building”172 [re Givosiran]. The Alnylam executive replied, “…let me emphasize that porphyria will remain an ultra-rare disease, we believe, and our key is, within an ultra-rare, frankly, to find everybody…we’ve been working with the porphyria network to strengthen the next set of physicians that are coming up and looking for the disease, younger, kind of, more aggressive types that are going out to the community to educate and we’ve seen good uptake with that.”173

The latter part of that response alludes to APF’s Protect the Future program which, according to APF’s website, as of this date comprises eighteen (18) PTF doctors. This is concerning. Several current APF SAB members actually worked with/for porphyria experts from an era of integrity, honesty and absolute credibility—a few of whom were also members of APF/s SAB at various (and relatively short) times. Unfortunately, what the “a.p. missed diagnosis” patient/caregiver community sees happening is manipulation of these younger/ “newer” doctors’ thought processes and/or discouraging inclinations to research anything outside the “US Acute Porphyria Agenda.” This, of course, defeats the purpose of performing traditional clinical research in concert with practicing patient-centered medicine. Combined with the nineteen (19) scientific advisory board members, that’s thirty-seven (37) physicians putting emphasis on the heme biosynthetic process of building red cells and being taught that Panhematin® is the rescuer to treat acute porphyrias. My daughter and the Australian woman’s daughter can attest to that. They can also attest to Panhematin® efficacy as a panacea for heme deficiency. However, while it is true many lives have been saved thanks to Panhematin®, the drug has also had its problems. In our opinion, continuing to put together research studies about Panhematin® (which may include APF PTF doctor/researchers’ participation) as APF SAB chair, Dr. Karl Anderson is planning yet another (Panhematin® Prevention Study)—without in-depth research on the full range of acute porphyria patients’ biomarkers, including enzyme assays (HMBS, CPOX, PPOX, etc.) and patient’s blood characteristics is pure folly and in our opinion, only being done with the intent to insure the US Acute Porphyria Agenda endures.

Perhaps one of the better quotes said about the acute porphyrias that the “a.p. missed diagnosis” patient/caregiver community can relate to and endorse was stated by Dr. Balwani in her interview with Clinical Advances in Hematology & Oncology, “One important thing to note is that no sign or symptom is universal and presentations are often atypical.”174And yet, presentations “atypical” from the “gold standard” isn’t accepted in US porphyria experts’ agenda—in which APF PTF doctors receive their “training.”

The acute porphyrias continue to take tremendous financial toll on people, families, communities and societies. As quintessential physician/scientist Dr. Sardh of Sweden said a couple of years ago in an Alnylam Roundtable Session, “We still have very limited knowledge of the pathophysiology of the disorder as well as the natural history.”175 This, coming from Sweden—AIP epicenter, no less—where surely, there must be some Swedes who, like the one Dr. Waldenström observed so long ago sometimes don’t excrete U-BP but do exhibit a.p. activity or attack symptoms. It is to be noted that the venerable Dr. Waldenström did not disregard or comment that the patient was thought be “feigning” acute porphyria as heard too often in the US. If nothing else, APF has succeeded in spreading the word that acute porphyria is RARE. Unfortunately, many physicians and specialists are inclined to put RARE conditions into the too-hard basket.

Many patients in our “a.p. missed diagnosis” communities have serious illnesses in addition to acute porphyria. It is an extremely delicate balance to manage but most agree that knowing what they are dealing with and keeping the acute porphyria aspect of their illness contained as best can be done (especially when working with medical providers for treatment, i.e. surgery/medications, of the other illnesses) makes a huge difference in their quality of life.

They’ve come to know their individual body’s extreme sensitivities to chemicals, even certain medications that APF labels “safe” including vaccinations, “shots” e.g. tetanus, flu, etc., alcohol/preservatives used in injectable meds; foods (natural and added chemicals); anything that contains a sulfur ion; meds that are known to reduce cellular oxygen (heparin), supplements (like vitamin Bs, C, D, E, glycine, niacin, magnesium, melatonin, folic acid)—even in minuscule amounts, stress, exercise, toxins—again, even in the minutest amounts, including plastics/rubber in medical devices and the dreaded scented products. For the most part, they live by NAPOS’ porphyria drug list and have learned to dose-down everything to start, even in the safest of meds. Vials, ultra-mini tablets, sublingual applications—to survive, they essentially live Dr. Archibald Garrod’s chemical individuality concept every single day. Dangerous? Perhaps, but what choice did/do they have?

If one wants to know the devastation that untreated acute porphyria has on the human body, “missed diagnosis” patients are sources just waiting to be tapped—most are eager to submit to DNA and other acute porphyria testing—without a US or Alnylam bias.

This paper, in response to the IPMDC announcement was prepared with the intent of sharing findings from our community and to appeal to the greater worldwide porphyria expert community to review—and God willing, to act on them. For consideration, we’ve offer the following concerns and suggestions for the worldwide porphyria expert assemblage’s consideration:

  1. overall, US “a.p. missed diagnosis” patient/caregivers report dissatisfaction with diagnostic test report results received from “certified” laboratories and express concern about possible manipulation of testing results (DNA, U-BP, F-BP, enzyme assay (PBGS, HMBS, CPOX, PPOX));
  2. deeper investigation and resolution of the oligogenetic nature* of the acute porphyrias and what impact that may have on symptom presentation, testing, treatment modalities is warranted;
  3. investigation and resolution that a “retention” or “inhibitor” gene or genes may indeed contribute to the silencing of PBG excretion;
  4. efficacy of PBGS, PBGD, CPOX, and PPOX enzymes as biomarkers to gauge acute porph activity/attack and need for treatment;
  5. to that end, getting a better understanding of HCP, VP, and ALAD prevalence and while recognizing that each case is unique, identifying nuances (similarities) for each of these acute porphyria manifestations is imperative;
  6. deeper investigation and resolution of porphyrin/precursor whereabouts for those that make it through the heme biosynthetic pathway mechanism and 1) enter the blood stream, 2) are lodged in tissue/organs, 3) are spewed out during the process and are excreted in urine/feces, 4) any other possible destination;
  7. recognition of heme deficiency and the role it plays in triggering attacks—alone and/or in conjunction with other triggers;
  8. or those patients who agree; either consider periodic infusions (some patients do weekly) and/or early use of IV glucose as treatment (with appropriate Na and K supplementation) and with supplemental oxygen administered during the infusion (may reduce need for expensive hematin);
  9. for those patients who agree; use of IV hematin as treatment (with appropriate Na and K supplementation)—until the liver is satiated—and with supplemental oxygen administered during the infusion;
  10. investigate the misshapen blood theory put forth by the “a.p. missed diagnosis” patients—and its role in the “porphyrin/precursor whereabouts;
  11. with a scientific mindset, research Sickle Cell Disease/Acute Porphyria (and/or other IEMs) similarities. Successful treatments for other IEMs have happened in the past. There may be something to take away from treatments developed for these other IEMs (especially in comparison to SCD re potential de-oxygenation).

*To be fair, at one time the Porphyrias Consortium did address the possibility of “additional genes” in an answer to a FAQ “general question” presented on the Rare Disease Network site (printed out 6/2011). The question, “What is “latent” porphyria? If my doctor told me that I have “latent” porphyria, does this mean I will never have any symptoms?”176 The Porphyrias Consortium answer to that is lengthy, but included, “There may also be additional factors, including additional genes, that modify the symptoms.”177 Note: as of 7/13/2019 this site can’t be reached.

CONCLUSION—Attention: European participants of the International Porphyria Molecular Diagnostic Collaborative and the Worldwide Porphyrin and Porphyrias Experts Assemblage: Proceed with caution.

It is extremely concerning to the “a.p. missed diagnosis” community that the International Porphyria Molecular Diagnostic Collaborative intends to use the May 10, 2019 paper to support its position at the 2019 ICPP in Milan’s roundtable session to establish a definition for acute porphyria attacks. While it all seems appealing, it is imperative that the reason for creating “an evidence-based database of verified pathogenic and benign variants for the porphyrias” have a scientific base—not a US agenda-driven base. This agenda must be recognized and curtailed for it is the antithesis of precision medicine.             

The IPMDC paper’s Disclosure section is revealing—more than a dozen connections between Alnylam and co-authors of that paper; many of whom are also involved with Alnylam’s ENVISION (Givosiran) clinical trials. These relationships as well as Alnylam sponsorships of websites and paid attendance for various individuals to pricey conferences, meetings, etc. smacks of conflicts of interest. As one insightful “a.p. missed diagnosis” patient noted about the IPMDC paper, “This publication does nothing to show me that they care about all patients. If you’re in the perfect presentation club, you are placed on the pedestal as a martyr for the cause. If not, then you are a usurper who must be punished.” 178 Regarding the IPMDC author who proposed International Collaborative, s/he had this to say, “[This individual] has the most to gain.”179

In my/our “a.p. missed diagnosis” opinion, what the IPMDC is doing (unintentionally by some participants, but most certainly deliberately by others) is nothing more than the continuation of my daughter’s ten year IVS10-31A>G/APF/Desnick/Mount Sinai nightmare, as well as the denigration of a particular CPOX patient/caregiver mom duo and of a certain PPOX patient.

At the present time, for my daughter, PBGD, heme deficiency and genetic influence/expression remains a jumbled mess still within that US Pandora’s box Dr. Desnick opened five years ago. As if to demonstrate our “missed-diagnosis” patient/caregiver theory that not all porphyrins/precursors excess resulting from “dysfunction” of a revved-up heme biosynthetic pathway are excreted out of the body through urine and/or feces but rather, remain the body, my daughter, suffering with intermittent convulsions and fainting episodes, severe ongoing kidney and abdominal pain and other acute porphyria symptoms, recently reported that a personal hygiene product removed from her body during menses was purple.

We believe that it wasn’t coincidence that any of these variants appeared in IPMDC’s paper—they were selected because they represent patients and/or caregivers targeted for silencing by the US porphyria powers that be. No doubt the variants highlighted in the IPMC paper are the ones planned to “pilot” IPMDC’s program—if it hasn’t already happened.

Our community includes toddler to octogenarian patients and is comprised of caring, intelligent, well-researched patients and caregivers. Lives have been torpedoed—shattered beyond all recognition. The souls of our daughters, mothers, sons, fathers and too many other loved ones have been destroyed. No doctor or scientist has the right to do that—to anyone—and get away with it. Besides pain, degradation and desperation, many in the “a.p. missed diagnosis” patient community feel exploited, victimized and/or traumatized which they attribute to medical maleficence. Most are extremely dissatisfied with their quality of life. Try as they might, many of these once vibrant, brilliant individuals have lost their grasp of Nietzsche’s, “If you have a way to live, you can bear almost any how.” Attempting to keep them from suicide or joining The Final Exit network180 (an American 501 nonprofit right to die which holds that mentally competent adults who suffer from terminal illnesses, intractable pain, or irreversible physical conditions have a right to voluntarily end their lives) is a daily heartrending reality for those who care. With the right diagnosis and treatment, though not irreversible, the condition could be made manageable. Two mothers have done it for their daughters. More than one patient did it for herself.  Suicide needn’t be the answer. God will call them when they have fulfilled their purpose on this earth.

The US may have the loudest group of “a.p. missed diagnosis” patients but our closed online forums increase weekly with patients/caregivers from around the world desperately seeking assistance, knowledge, help, understanding. We must, for the greater good of acute porphyria patients everywhere (and those up-and-coming) continue to speak out. Acute porphyria won’t stop. It’s in the genes of untold numbers of people on this planet. Acute porphyria shouldn’t be permitted to continue to bankrupt the lives and finances of individuals, families, societies, private and single payer insurance sources. The intelligence of physicians (GP and/or specialists) who attempt to help members of our community should not be affronted by the arrogance of “experts” whose logic and research trails seem to defy scientific reasoning.

Of course, changing “a.p. missed diagnosis” patients to active status will blow porphyria statistics right out of the water—for a while. Long-term, gaining better, more accurate knowledge of the true, full acute porphyria pathophysiology will have favorable impacts not only for patients but for families, communities, and societies for eons to come. For one, reducing or eliminating the need for multiple medical testing to go on ad nauseam and at great expense. Developing more cost effective treatments for another. Returning people to the work force. Testing infants at birth and monitoring throughout the lifetime. So many positive possibilities to replace so much despair and cost. That’s what precision medicine, personalized medicine, and/or genomic medicine—aka as patient-centered care is meant to do, isn’t it?

Thank you all for the time and patience granted to reading this patient/caregiver perspective prepared work. We hope it will guide you toward Sir William Osler’s professional commitment, “The good physician cares for the disease; the great physician cares for the patient.”  

###

FOOTNOTES/REFERENCES

1.         New York State Rare Disease Alliance; nysrda.com

2.         Reilly MD, JD, P.; Orphan: The Quest to Save Children with Rare Genetic Disorders: Cold Spring Harbor Laboratory Press; 2015; 313.

3.         Brown, D.; https://www.goodreads.com/quotes/488064-sometimes-a-change-of-perspective-is-all-it-takes-to

4.         Chen, B. et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 1.

5.         Ibid.

6.         Brookes, A.; email response to author; May 10, 2018.

7. Zimmer, C.; She Has Her Mother’s Laugh: The Powers, Perversions ad Potential of Heredity, New York, 2018; 133.

8.         Young, E.; The Atlantic: What If (Almost) Every Gene Affects (Almost) Everything?; Global Genes; June 25, 2017; https://globalgenes.org/2017/06/25/the-atlantic-what-if-almost-every-gene-affects-almost-everything/

9.         Anonymous “missed diagnosis” patient contributor.

10.       Chen, B. et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 1.

11.       Ibid, 1-2.

12.       APF; 1st Quarter, 2013 Newsletter; Testing and Latent Porphyria; 6. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/1st%20Quarter%202013%20News%20Letter%20part%202_2.pdf

13.       Ibid.

14.       APF: 2nd Quarter, 2013 Newsletter; International Porphyria Congress; 4. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/2nd%20Quarter%202013%20News%20Letter.pdf

15.       APF: 2nd Quarter, 2013 Newsletter; Exciting New AIP Treatment in Development; 7. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/2nd%20Quarter%202013%20News%20Letter.pdf

16.       Daniell, W. et al; Environmental Chemical Exposures and Disturbances of Heme Synthesis; Environmental Health Perspectives 105, Supplement 1; February 1997; 3. http://www/herc.org//news/mcsarticles/daniell-full.html

17.       Chen, B et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 3.

18.       Ibid.

19.       Desnick, Dr. R.J.; Mount Sinai; original AIP diagnosis communication; November 25, 2008; author’s personal health records.

20.       Wright, CF. et al; Genomic variant sharing: a position statement; Wellcome Open Research 2019; Last updated Feb 5, 2019; 6.          

21. Chen, B et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 4.

21.       Ibid.

22.       Ibid.

23.       Desnick, Dr. R.J.; Mount Sinai; revoked diagnosis letter and revised report; June 12, 2014; author’s personal health records.

24.       Porphyria experts’ identity withheld; Index Case Medical Opinion; February, 2018; personal health records.

25.       Ibid.

26.       Ibid.

27.       Ibid.

28.       Desnick, Dr. R.J., Mount Sinai; underlying DNA revised report; May 9, 2018; author’s personal health records.

29.       Robreau-Fraolini, AM et al; Porphobilinogen deaminase gene in African and Afro-Caribbean ethnic groups: mutations causing acute intermittent porphyria and specific intragenic polymorphisms; Human Genetics 2000 Aug; 107(2):150-9; 157.

30.       To protect porphyria experts from potential harassment, author chooses to withhold this resource info.

31.       Zhang, J. et al; A LC–MS/MS method for the specific, sensitive, and simultaneous quantification of 5-aminolevulinic acid and porphobilinogen; J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Aug 15; 879(24): 2389–2396; 16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269068/

32.       Tishler, P.V.; Letter to author on Brigham and Women’s Hospital letterhead, June 4, 2015.

33.       Kauppinen, Fraunberg; Molecular and Biochemical Studies of Acute Intermittent Porphyria in 196 Patients and Their Families; Molecular Diagnostics and Genetics; November 2002, 3. http://clinchem.aaccjnls.org/content/48/11/1891.long

34.       Cappellini et al; Hematologically Important Mutations: Acute Intermittent Porphyria; Blood Cells, Molecules and Diseases; Jan/Feb 2002; Table 1.

35.       Chen, B et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 4.

36.       Ibid.

37.       Ibid.

38.       Desnick R.; SELF DIAGNOSIS: THE GOOD AND BAD; APF March 2016 Newsletter. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/Newsletter%20March%202016%201st%20qtr.pdf

39.       Ibid.

40.       Ibid.

41.       Ibid.

42.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 5.

43. Ibid

44.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, March 2015.

45.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 5.

46.       Ibid.

47.       Ibid.

48.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine; March 2015; 1.

49.       Ibid, 2.

50.       Anonymous “missed diagnosis” patient.

51.       Ibid.

52.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, May 2015; 1.

53.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, March 2015; 7.

54. Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 5.

55.       Ibid.

57.       Ibid.

58.       Ibid.

58.       Ibid, 6.

59.       Ibid.

60.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, March 2015 and May 2015.       

61.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 6.

62. Deybach, J.-CH. et al; European Porphyria Initiative (EPI): A Platform to Develop a Common Approach to the Management of Porphyrias and to Promote Research in the Field; Physiological Research; April 25, 2005; 2.

63. EPNET “The Porphyrias” @ https://porphyria.eu/en/content/porphyrias

64.       Harper, P., Sardh, E.; Management of acute intermittent porphyria; Expert Opinion on Orphan Drugs; April 2014; 353. [https://www.researchgate.net/publication/263245362_management_of_acute_intermittent_porphyria]

65.       Mustajok, S.; Table 2.2.; Molecular Genetics of Acute Intermittent Porphyria in Finland thesis; Helsingin yliopiston verkkojulkaisut;1999. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/mustajoki/index.html

66.       Myketun, M. et al; Porphyrias in Norway; Tidsskriftet; Issue 8, April 29, 2014; Table 2.  https//tidsskriftet.no/en/2014/04/porphyrias-norway.

67.       Alnylam EXPLORE presentation; Natural History Study 12-Month Study Enrollment and Follow-Up; April 2017; 3. https://www.alnylam.com/wp-content/uploads/2017/06/ICPP-2017-EXPLORE-Presentation-Capella.pdf

68.       Waldenström, J.; Neurological Symptoms Caused by Socalled Acute Porphyria; Acta Psychiatrica Scandinavica; June 1939

69.       Lyon Howe, D.; Porphyria: A Lyon’s Share of Trouble; Howerite, Inc.; 2004.

70.       Ibid, 2.

71.       Lyon, D.; Lyon’s Share; APF 4th Quarter 2013 Newsletter; 3. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/APF%20Newsletter%204th%20Quarter%202013%20part%202.pdf

72.       Lyon Howe, D.; Porphyria: A Lyon’s Share of Trouble; Howerite, Inc.; 2004; 20-24

73.       Ibid, 195-197.

74.       Kappas, Sassa; Molecular aspects of the inherited porphyrias; Journal of Internal Medicine 2000; 247:169-178; 169. https://www.ncbi.nlm.nih.gov/pubmed/10692079

75.       García-Diz, L. et al; Assessing nutritional status of acute intermittent porphyria patients; Eur J Clin Invest. 2012 Sep;42(9):943-52; 1. https://www.ncbi.nlm.nih.gov/pubmed/22519672

76.       Anderson, Badminton; NORD; Acute Intermittent Porphyria, 2019 version; 1. https://rarediseases.org/rare-diseases/acute-intermittent-porphyria/

77.       Bonkovsky, Rudnick; Overview of Porphyrias; Merck Manual’s online Professional 2019 Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/porphyrias/overview-of-porphyrias

78.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 7.

79.       Anderson, K., et al; Nelson Textbook of PEDIATRICS; Chapter 85 The Porphyrias; 517.

80.       Porphyrias Consortium; Acute porphyrias; Table 2.; undated. https://www.rarediseasesnetwork.org/cms/porphyrias/Healthcare_Professionals/diagnosis

80.       Sassa, Kappas; Molecular aspects of the inherited porphyrias; Journal of Internal Medicine 2000; 247: 169-178; 172.

82.       EPNET; European Porphyria Network; Specialist porphyria laboratory table. https://porphyria.eu/en/content/specialist-porphyria-laboratory-table

83.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 8.

84.       Richards, S., et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, May 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544753/

85.       Peterson, LR. et al; Erythrocyte uroporphynogen I synthase activity in diagnosis of acute intermittent porphyria; Clin Chem, 1976 Nov; 22(11): 1835-40. https://www.ncbi.nlm.nih.gov/pubmed/976654

            86.       Tanaka, H. et al; Long-Term Follow-up of Erythrocyte Porphobilinogen Deaminase Activity in a Patient With Acute Intermittent Porphryria: The Relationship between The Enzyme Activity and Abdominal Pain Attacks; Bulletin of the Osaka Medical College 53 (3); June 18, 2007; 155.

87.       Ibid, 159.

88.       Ibid, 156.

89.       Ibid, 159.

90.       This author chooses to protect the identities of these porphyria experts.

91.       New York Times archives; Obituary; Dr. Watson was the chief researcher in the discovery of hematin.; APRIL 14, 1983.

92.       Schmid, R; The National Academies Press Open Book; Biographical Memoirs V.65; Chapter: 19. Cecil James Watson; May 31,1901-April 11, 1983; 9.

93.       Ibid, 10.

94.       Ibid, 2.

95.       Ibid, 10.

96.       Bonkovsky, H., et al; Porphyrin and heme metabolism and the porphyrias; Comprehensive Physiology; Jan 3, 2013 (1) 365-401; https://www.ncbi.nlm.nih.gov/pubmed/23720291

97.       Abou-Zeid, A., Donofrio, P.; Texbook of Peripheral Neuropathy  Chapter 21, Porphyric Neuropathies; Porphyrins & Porphyria Diagnosis; April 2012; 289. https://books.google.com/books?isbn=1936287102

98.       Bonkovsky, H., et al; Heme status affects human hepatic messenger RNA and microRNA expression; World Journal of Gastroenterology; March 14, 2013; 3.

99.       Ibid, 8.

100.     Alnylam; RNAi Roundtable: ALN-AS1 for the Treatment of Hepatic Porphyrias; August 21, 2014; slide #19.

101.     Ibid, slide #20.

102.     Alnylam Phamaceuticals RNAi Roundtable Transcript Q&A; August 21, 2014; 17. http://www.alnylam.com/web/assets/082114Alnylam.pdf

103.     Ibid.

104.     Anonymous “missed diagnosis” caregiver 1 report.

105.     Anonymous “missed diagnosis” caregiver 2 report.

106.     Ibid.

107.     APF director; Porphyria Sucks FB posts ~5/13/2018.

108.     Anonymous “missed diagnosis” caregiver 1; Porphyria Sucks FB posts ~5/13/2018.

109.     Anonymous “missed diagnosis” caregiver 2 response.

110.     APF director; FB post; 9/16/2016, 10:02 pm.

111.     APF website; MISINTERPRETATION OF TEST RESULTS ~4/20/2019. https://porphyriafoundation.org//patients/abpit-porphyria/testing-porphyria/misinterpretatio

112.     Elkhatib, R. et al; Feigning Acute Intermittent Porphyria; Case Reports in Psychiatry; 2014:152821.  [https://www.hindawi.com/journals/crips/2014/152821/]

113.     Ibid.

114.     Ibid.

115.     Ibid.

116.     Ibid.

117.     Ibid.

118.     Ibid.

119.     Ibid.

120.     Ibid.

121.     Gould, J and J; Purple Canary: The Girl Who Was Allergic to School, The True Story of How School Chemicals Unleashed a “Rare” Illness That Devastated a Young Girl’s Life; 2016.

122.     “Expert confirmed” acute porphyria (HCP) patient, anonymity respected.

123.     “Missed diagnosis” acute porphyria patient, anonymity respected.

124.     “Missed diagnosis” acute porphyria patient/caregiver, anonymity respected.

125.     “Missed diagnosis” acute porphyria patient, anonymity respected.

126.     Watson, et al; Postulated deficiency of hepatic heme and repair by hematin infusions in the “inducible” hepatic porphryias; Proceedings of the National Academy of Sciences of the United States of America; National Academy of Sciences   May, 1977; Vol 74. No.5; 2218. https://www.jstor.org/stable/67179?seq=1#page_scan_tab_contents

127.     Sardh, E.; Alnylam RNAi Roundtable: Givosiran, in development for the treatment of acute hepatic porphyrias; Transcript; 9/7/2017; 4.

128.     Storjord, E. et al; Lifestyle factors including diet and biochemical biomarkers in acute intermittent porphyria: Results from a case-control study in northern Norway; Molecular Genetics and Metabolism; December 2018. https://www.sciencedirect.com/science/article/pii/S1096719218305286?via%3Dihub

129.     Wilson, Edixhoven, Koole, de Rooij; EPNET, European Porphyria Network; The Diagnosis of Acute Hepatic Porphyria by Plasma, ALA, PBG, Fluorescence Scanning and Enzyme Assays, Using DNA Analysis as Reference; 2018; 1.

130.     Ibid.

131.     Ibid.

132.     Ibid, 2.

133.     NIH Clinical Trials; Acute Porphyrias: Biomarkers for Disease Activity and Response to Treatment; October 17, 2016.  https://clinicaltrials.gov/ct2/show/NCT02935400

134.     Schmid, R.; Biographical Memoirs: V.64 (1994), Chaper 19: Cecil James Watson; The National Academic Press OpenBook; 2. https://www/nap.edu/read/4548/chapter/20

135.     NIH; National Cancer Institute; Seer Training Modules; Blood. https://training.seer.cancer.gov/anatomy/cardiovascular/blood/

136.     Tanaka, H. et al; Long-Term Follow-up of Erthrocyte Porphobilinogen Deaminase Activity in a Patient With Acute Intermittent Porphryria: The Relationship between The Enzyme Activity and Abdominal Pain Attacks; Bulletin of the Osaka Medical College 53 (3); June 18, 2007; 158.

137.     “Missed diagnosis” acute porphyria patient, anonymity requested.

138.     Ibid.

139.     Ibid.

140.     “Missed diagnosis” acute porphyria patient, anonymity requested.

141.     Ibid.

142.     APF; Newsletter; 1st Quarter 2019; Sickle Cell Disease and Acute Porphyria; 3. https://porphyriafoundation.org/sites/default/files/2019-05/APF-Newsletter-1Q2019_v1.pdf

143.     Schmid, R.; Biographical Memoirs: V.64 (1994), Chapter 19: Cecil James Watson; The National Academic Press OpenBook; 2. https://www/nap.edu/read/4548/chapter/20

144.     Lyon Howe, D.; Porphyria: A Lyon’s Share of Trouble; Howerite, Inc.; 2004; 172.

145.     Ibid.

146.     Ibid, 173.

147.     Bloomer, J. et al; Blood Volume and Bilirubin Production in Acute Intermittent Porphyria; The New England Journal of Medicine; January 7, 1971; 284:17-20

148.     Ibid.

149.     Bonkovsky, H.; Neurovisceral Porphryias: What a Hematologist Needs to Know; Hematology; 2005.

150.     Ibid.

151.     Bonkovsky, et al; Heme status affects human hepatic messenger RNA and microRNA expression; World Journal of Gastroenterology; 2013 Mar 14; 19(10); 1593–1601.

152.     Bonkovsky et al; Repression of the Overproduction of Porphyrin Precursors in Acute Intermittent Porphyria by Intravenous Infusions of Hematin; PNAS, Vol. 68, No. 11; November 1, 1971; 2725.

153.     Ibid.

154.     Ibid, 2726.

155.     APF; DR. BONKOVSKY CREATES HEMATIN; 1st quarter 2015 Newsletter, 5. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/Newsletter%20March%202015.pdf

156.     Ibid.

157.     Hans Fischer; Encyclopedia of World Biography; The Gale Group Inc. https://www.encyclopedia.com/people/history/historians-miscellaneous-biographies/hans-fischer; https://www.thefamouspeople.com/profiles/hans-fischer-7254.php

158.     New York Times archives; Obituary; Dr. Watson was the chief researcher in the discovery of hematin.; APRIL 14, 1983.

159.     APF; DR. BONKOVSKY CREATES HEMATIN; 1st quarter 2015 Newsletter, 6. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/Newsletter%20March%202015.pdf

150.     Peterson, A. et al; Hematin Treatment of Acute Porphyria: Early Remission of an Almost Fatal Relapse; JAMA The Journal of the American Medical Association 235(5):520-2 · March 1976. https://www.researchgate.net/publication/22209063_Hematin_Treatment_of_Acute_Porphyria_Early_Remission_of_an_Almost_Fatal_Relapse

161.     Ibid.

162.     “Missed diagnosis” acute porphyria patient, anonymity respected.

163.     APF; website landing page. https://porphyriafoundation.org/

164.     “Missed diagnosis” acute porphyria patients, anonymity respected.

165.     Out-of-US porphyria expert—as told to a long-suffering “missed diagnosis” patient.

166.     APF website; https://www.porphyriafoundation.org/content/diagnostic-testing-acute-porphyrias-clarification-testing-results/?page=13

167.     The Porphyrias Consortium; Diagnosis of the Porphyrias; undated; https://www.rarediseasesnetwork.org/cms/porphyrias/Healthcare_Professionals/diagnosis

168.     Farlex Partner Medical Dictionary © Farlex 2012 https://medical-dictionary.thefreedictionary.com/asymptomatic; https://medical-dictionary.thefreedictionary.com/latent

169.     Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence–based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 2.

170.     APF director; email correspondence to author 1/14/15.

171.     APF; website landing page. https://porphyriafoundation.org/

172.     Bonkovsky, H.; Acute Porphyrias; Gastroenterology/Hepatology; Cancer Therapy Advisor; Decision Support in Medicine, LLC.; 2013, 2017; 4.

173.     Alnylam Pharmaceuticals (ALNY) Q2 2018 Results-Earnings Call Transcript; August 2, 2018; 23. https://seekingalpha.com/article/4194126-alnylam-pharmaceuticals-alny-q2-2018-results-earnings-call-transcript

174. Balwani, M.; What Hematologists Need to Know About Acute Hepatic Porphyria; Clinical Advances in Hematology & Oncology; November 2016 – Volume 14, Issue 11; 3. https://www.hematologyandoncology.net/archives/november-2016/what-hematologists-need-to-know-about-acute-hepatic-porphyria/

175.     Sardh, E.; Alnylam RNAi Roundtable: Givosiran, in development for the treatment of acute hepatic porphyrias; Transcript; 9/7/2017; 4.

176.     Porphyrias Consortium; Patients and Families; Frequently Asked Questions, General Questions. http://rarediseasenetwork.epi.usf.edu/porphyria/patients/learnmore/FAQ.htm

177.     Ibid.

178.     “Missed diagnosis” acute porphyria patient, anonymity respected.

17

Patient/Caregiver Commentary Response re: Introduction; The acute hepatic porphyrias; Biochemical and molecular diagnosis of the AHPs:

There is no dispute from any in our community that “AHPs are characterized by acute life-threatening attacks of non-specific symptoms” or “the major manifestations of the acute porphyrias [can include] excruciating abdominal pain, a progressive peripheral neuropathy, and mental disturbances (e.g. confusion, fatigue, insomnia, etc.).” or “[t]he autosomal dominant AHPs are distinct from other porphyrias because of their common overproduction of the porphyrin precursors, 5-aminolevulinic acid (ALA) and porphobilinogen (PBG) which are understood to [facilitate] the acute attack symptoms through a neurotoxic mechanism.”10 Patients/ caregivers in the “missed diagnosed” community experience and/or bear witness to such symptomatology daily.

What is disputed is the hyper-attention US porphyria experts routinely heap on the dogmatic first-line acute porphyria diagnostic criterion espoused by US and European porphyria experts of, “Acute attacks of porphyria are diagnosed by showing marked elevation of urinary PBG and ALA, the diagnostic “gold standard” of these diseases.”11 And the pervasive belief of US/EU porphyria experts that a normal urinary PBG or near normal ALA and/or PBG excretion in symptomatic new patients excludes the diagnosis of an AHP. By the way, urinary biochemical evidence wasn’t even mentioned in the IPMDC authors’ list of major manifestations of the acute porphyrias—yet it is the “gold standard” to diagnosis AHP?

US porphyria experts evidently adopted the European U-BP protocol very early, probably because Scandinavian immigrants were among the earliest of European groups to settle in America. As porphyria gained a medical presence here, it is logical that the Swedish Porphyria diagnostic protocol was followed. However, by the time the American Porphyria Foundation (APF) was up and running, generations had passed; European porphyria knowledge and technology had substantially expanded/improved yet the Swedish Porphyria diagnostic protocol held steady throughout Europe—and therefore, in the US—without dissent and without bona fide scientific support.

Given the ordeal that for a decade or so the APF cofounder herself, never having heard of porphyria, had suffered through, (more fully addressed in our response to the Porphyrin precursor measurements section), it is truly a wonder why the APF formulation team didn’t hearken back to her documented experience and recognize that other people might experience the same symptomatology of severe symptoms without U-BP. Instead, US porphyria experts apparently tightened its grip on the European/Swedish Porphyria diagnostic protocol.

The APF first quarter 2013 newsletter proclaimed, “Misdiagnosis has become a common problem in patients who do not have a Porphyria, but present with suggestive symptoms and have clinically insignificant small or non-specific elevations in biochemical tests.”12 That was followed in the section’s next paragraph with, “DNA analysis is considered the “gold standard” for porphyria diagnoses [followed by] “[b]iochemical testing is recommended prior to DNA testing to determine whether a diagnosis of porphyria is likely to suggest the specific type of porphyria.”13 By this time, Dr. Desnick, Mount Sinai and APF and Alnylam Pharmaceuticals had apparently entered into a partnership.

The next APF newsletter (2nd quarter, 2013), introduced an NIH-sponsored longitudinal study to be conducted by the APF-connected Porphyrias Research Consortium, provided a recap of the International Congress of  Porphyrins & Porphyrias’ successful Patient Day and noted that “[m]any of our Protect the Future trainees attended the conference as well as made presentations.”14 Three pages after that story was APF’s announcement that Alnylam Pharmaceutical’s president had made during his presentation at the International Congress about a “breakthrough discovery” regarding treatment for the acute porphyrias; the paragraph closed with “The APF will be announcing updates on the treatment and clinical trials.”15

It should be noted that prior to Alnylam Pharmaceutical’s involvement with APF et al, AIP had been the “darling” of the acute porphyrias with only the briefest attention given to HCP, VP and ADP. However, it appears after the Alnylam/APF partnership began, the US then the EU began referring to the acute porphyrias as AHPs (incorporating the four acute porphyrias)—and describing them as “ultra-rare.”

While porphyria experts in other countries have periodically stated through the years/decades that porphyria is not as rare as thought, we could only identify one paper in which the sentiment was stated that included US experts’ endorsement. APF SAB members Anderson, Bissell, Bloomer, Pierach were co-authors of Environmental Chemical Exposures and Disturbances of Heme Synthesis which stated, “Porphyrias are relatively uncommon conditions but are probably unrecognized. The prevalence of genetic predisposition to porphyria probably has been underestimated in the general population because of the limited availability of clinical tests for specific heme-synthesis enzymes and because prevalence studies generally have focused more on family members of affected individuals and less on the general population.”16 That was the first and last statement we’ve found about acute porphyrias being not ‘as rare as thought’ had APF-connected porphyria experts’ names attached to it.

Patient/Caregiver Commentary Re: Rationale for an International Diagnostic Database of Verified Pathogenic and Benign Variants (IDDVP&BV); The Human Gene Mutation Database; Direct-to-consumer testing and variant interpretation services; ACMG and AMP guidelines for sequence variant classification

            As patient/physician interest in disease identification via DNA testing rocketed upward, geneticists everywhere scrambled to get a handle on “precision medicine” molecular diagnostic techniques. Porphyria patients were/are among those who queued up, hoping that scientific proof of disease(s) would lead to treatment, perhaps even cures for their porphyrias, so it certainly makes sense that porphyria experts jumped on board.

IPMDC authors acknowledge the Human Gene Mutation Database (HGMD) as “the most reliable resource for variant data in the AHP genes”yet hinted at skepticism of HGMD’s curation policy, stating it “may be questionable.”17 However, if the concern that “porphyria diagnostic laboratories worldwide frequently identify additional novel pathogenic or benign variants that are not published and as such are not available in the HGMD”18 is in fact accurate, who’s to say that IDDVP&BV won’t face the same (or similar) compliance issues? Another point to be made is the (very) fine print disclaimer* closing out Mount Sinai’s genetic communications which states, “While mutation analysis by DNA sequencing is very accurate, rare errors can occur, for example, due to sample mix-up, laboratory errors and/or genetic polymorphisms. This test was developed and its performance characteristics were determined by the Genetic Testing Laboratory at the Icahn School of Medicine at Mount Sinai.It has not been cleared or approved by the FDA. The FDA has determined that such clearance or approval is not necessary. This test is used for clinical purposes. Pursuant to the requirements of CLIA ’88, this laboratory has established the test’s accuracy and precision.’”19 [*This disclaimer appeared on each the three communication documents I/my daughter received from Mount Sinai (2008, 2014 2018); however the 2018 version (Revised Report) was the only one to contain the term “polymorphism.”] This begs questions such as, does Mount Sinai report its data to other databases they are associated with—and from which they probably? How will IPDWC insure data integrity if there are other labs developing their own tests and performance characteristics (in the US, without FDA clearance or approval)? Further, according to Genomic variant sharing: a position statement, doing so can seriously jeopardize patients’ lives, “…patients with the same rare disease may be scattered across the globe currently benefit from shared data and derived knowledge in databases such as ClinVar and DECIPHER, and services that are not currently sharing their clinical data owe a substantial data debt and risk perpetuating current data biases.”20

That being said, the rationale behind the statement(s), “some variants’ pathogenicity may be questionable” and “In the case of AIP, of the total 423 HMBS variants in version 2019.1, 141 (33%) were missense variants, many of which were reported as disease-causing without sufficient evidence for verification”21 definitely got my attention; “Intronic variants that alter splicing can also be difficult to assess unless there is clear clinical and biochemical documentation [Note: emphasis author-added] of their pathogenicity. For example, HMBS c.613-31A>G, also known as IVS10-31A>G, was initially reported as a pathogenic variant, but subsequently found to be very common in individuals of African or Afro-Caribbean descent.”22

 “HMBS c.613-31A>G, also known as IVS10-31A>G, was initially reported as a pathogenic variant,” was the clincher. I apologize in advance to my patient/caregiver colleagues; the following might be hard to process. Hopefully the trained professionals reading this will be able to follow it. Before continuing, please note: I hold (and am able to provide upon request) duly notarized Connecticut probate court certification of “Conservator of Person” and “Conservator of Estate” for my AIP daughter. To that end, I am legally permitted to discuss her medical case—thankfully, with her enthusiastic endorsement. And so I shall.

The IPMDC authors state, “HMBS c.613-31A>G, also known as IVS10-31A>G, was initially reported as a pathogenic variant [Puy, 1997] but was subsequently found to be very common in individuals of African or Afro-Caribbean descent [ExAc 2016; Robreau-Fraolinim 2000]. Although HGMB currently classifies c.613-31A>G as questionably pathogenic, recent data in the United States indicate that c.613-31A>G heterozygotes or homozygotes have a benign HMBS polymorphism (gnomAD frequency in Africans: 0.43, Latinos: 0.021, and Caucasians: 0.0023).”22 This statement begs challenging. Here’s why: IVS10-31A>G was the only mutation that Dr. Robert J. Desnick of Mount Sinai identified in my daughter’s original (2008) AIP diagnosis then again five and a half years later (2014) when he revoked that same diagnosis. Except, in the original diagnosis, he’d identified it as IVS10-31A>G; his subsequent revocation letter identified it as IVS10-31A>G (c.613-31A>G) and was accompanied with, “Initially this alteration was reported as pathogenic, resulting in [AIP]. However, review of literature and porphyria physician experts suggests that this alteration is a polymorphism. Furthermore, the alteration is now listed in NCBI, dbSNP as a single nucleotide variant (rs28990987) with a frequency of 0.5% in the general population, including about 46% among African-Americans, 58% among sub-Saharan Africans, and 0% among Caucasians. Based on this information, we report that [your daughter] is most likely not affected with [AIP].”23 With that, Dr. Desnick had opened Pandora’s Box into which I jumped and settled in for what I expected would be a long haul. And so it has been.

In time, a porph patient/friend with remarkable sleuthing abilities tracked rs28990987 to a medical journal article published by out-of-U.S. porphyria experts. I made contact with the authors and received via email the confirmation I’d half-expected, “single nucleotide polymorphism [SNP] marker rs28990987…is not [causal for AIP] but it is a sure Negroid (African) marker and may eventually be present in any particular AIP patients who has a Negroid ancestry, regardless of its physical appearance or geographic origin.”24

That same email included a medical opinion refuting 2014and 2018 Mount Sinai’s diagnostic conclusions regarding my daughter’s AIP. Based on lab results I’d shared with the porphyria experts, they provided the following summary, “The critical result for a diagnosis of AIP is the level of enzymatic activity of hydroxymethylbilane synthase, whether the patient is presenting an acute crisis or if never one has occurred. The person is nonetheless a carrier of one mutation capable of producing an acute crisis. A large proportion of carriers indeed never had one. But it is not mandatory. In the presence of typical symptoms, a low enzymatic activity is diagnostic. Even with absent U-BP (read paragraph above again). We are willing to contribute to the finding (or confirmation) of the actual molecular diagnosis of [her] ailment…).25Additionally, these experts recommended that “splicing mutations in intron 2 (IVS2+insG), intro 10 (IVS10-1G>T and intron 7 (IVS7+1G>A) be tried.”26

Because these porphyria experts had noted, “The person is nonetheless a carrier of one mutation capable of producing an acute crisis”27 and offered expert advice as to which mutations to “splice,” I was curious to see what exactly Dr. Desnick’s lab had found. So a few months after receiving that medical opinion (and offer), I requested all underlying/ supporting data for my daughter’s DNA testing results from Mount Sinai’s genetic laboratory. When that report arrived, I was surprised to see a dozen different acute porphyria variants (7 AIP, including c.613-31A>G with rs28990987; 2 HCP, and 3 VP) on Dr. Desnick’s “Revised Report.” All were classified as benign. I cross-checked and confirmed each variant with ClinVar). With the exception of rs28990987 (which was reported “not found” by ClinVar), none of the other variants listed on my daughter’s underlying/supporting data had appeared on any of Dr. Desnick/Mount Sinai’s previous communications.

The 2018 “Revised Report” held an unexpected (but welcome) surprise—a reference/source for the heredity information that supported the revocation of my daughter’s AIP dx but hadn’t appeared in is 2014 revocation letter. This time, four years later, it had. It said, “Previously, we reported that [your daughter] has Acute Intermittent Porphyria alteration, IVS10-31A>G. Initially, this alteration was reported as pathogenic, resulting in Acute Intermittent Porphyria (Puy et al., Am. J. Hum. Genet, 60:1371-1383, 1997). However, the Puy group subsequently reported that the lesion was benign as it was found in ~38% of a population of African and Afro-Caribbean ancestry (Robreau-Fraolini et al., Hum. Genet.,107:150-159, 2000). The frequency of this variant in various genome databases includes that this alteration is a common benign variant. The alteration is now listed in NCBI dbSNP as a single nucleotide variant (rs28990987) with a frequency of 4% of the general population, including about 43% among Africans, 2% among Latinos, and 0.2% among Caucasians.”28

This reflected changes from previous supportive heredity info, i.e. significant ↑ in “general population” (change from 0.5 to 4%) and slight ↑ among Caucasians (from 0 to 0.2%). However, the African–American and sub-Saharan identifiers were dropped altogether, while African (43%) and Latino (2%) were added. No reference (source) was provided for this heredity information. But it didn’t matter—I now knew that the “change” in variant classification had happened ~2000. This was concerning. My daughter’s AIP diagnosis had been granted near the end of 2008. The Robreau-Fraolini et al study had been published eight years before (2000). Were we to believe that Dr. Desnick of Mount Sinai was unaware of this alteration’s “reclassification”/“re-assignment” when he’d first identified it in my daughter’s DNA in 2008 and/or when he used it nearly six years later to yank that same diagnosis out from under her? Oddly, no mention of the rs28990987 alteration could be found in the Robreau-Fraolini study. However, disconcertingly, the study addressed splicing defect IVS10-1 G to T, explaining that “two common new intragenic polymorphism sites” had been identified, one “in intron 10, A/G dimorphism at position 7052 (A:0.56; G:0.44).”29

In the 2010 journal article my friend had tracked it to, rs28990987 was identified “rs28990987 (IVS10 7052 T>C) whose allele C is absent in Europeans, Asians and Venezuelan individuals, but has a frequency of 0.583 in Africans.”30 This was confounding. Could it be that VS10 7052 T>C is yet another identifier for ISV10-31A>G (c.613-31A>G) or might it be connected to intron 7 (IVS7+1G>A), which the out-of-U.S. porphyria experts suggested splicing?

To confuse the matter further, a 2011 study conducted by Dr. Desnick and Mount Sinai lab colleagues/staff comprised of seven patients diagnosed with AIP, VP or HCP came to my attention. Diagnosed meant the subjects had met the U-BP criterion. One study participant (H-AIP-1) was a 33 year old female with the IVS10-31A>G/+ mutation and the clinical status of “Symptomatic, on hemin therapy;” with U-ALA of 5.6 and U-PBG of 0.4.31 If, in 2000,  IVS10-31A>G (aka “rs28990987”—and if this is the correct identifier) had been found to be benign, why would the 2011 H-AIP-1 study subject with mutation IVS10-31A>G’s status have been “Symptomatic, on hemin”? And why was my daughter, allegedly also with mutation IVS10-31A>G (aka “rs28990987”) but whose body had yet to excrete the “gold standard” benefit from glucose/Panhematin® treatments for five and half years—until out of the blue, deemed to not have AIP at all?

Finally, if she “definitely does NOT have any porphyria,”32 as Dr. Desnick’s APF SAB colleague, Dr. Tishler then of Brigham and Women’s Hospital insisted in a 2015 letter to me, why is it her symptoms resumed with a vengeance when those Panhematin® treatments stopped—and why is they can also be relieved by IV glucose?

The well-presented 2002 Molecular and Biochemical Studies of Acute Intermittent Porphyrias in 196 Patients and Their Families pours more fuel on this fire. In Figure 1 of the study, titled “Exon/intron organization of the human PBGD gene and reported mutations responsible for AIP,” the mutation IVS10a͢͢͢͢͢→g appears beneath the heading W198X.33 Published two years after the Robreau-Fraolini et al study, it’s hard to believe that these and other highly-respected genetic/porphyria experts had not known the mutation had allegedly been reclassified to benign status.

Further, IVS10 (splicing defect) 613-31A→G also makes an appearance in a 2002 study published by Italian porphyria experts. Hematologically Important Mutations: Acute Intermittent Porphyria identified this and more than a hundred others in the “Mutations in the HMBS Gene Responsible for Acute Intermittent Porphyria” category Note: emphasis author-added].34

It doesn’t end there. Based on a study of three homozygous dominant AIP cases in Spain, the IPMDC authors wrote, “If it [the c.613-31A>G variant] were pathogenic, all homozygotes would be expected to have infantile- or juvenile-onset of homozygous dominant AIP, which is a severe neurodegenerative disorder with early demise.”35They continued, “Further support for its [c.613-31A>G] benign status is the finding  of individuals with a known HMBS pathogenic variant and markedly elevated ALA and/or PBG, who were also heterozygous or homozygous for c.613-31A>G, but without severe early-onset symptoms36 [Note: emphasis author-added] Question—if this “further supports” the variant’s benign status (and if benign means not causative), why did the subjects (esp. heterozygous) have markedly elevated ALA and/or PBG in this and in Dr. Desnick’s previously mentioned 2011 study? It is just incredulous to imply that all of these experts (and there probably are many others) were not aware that IVS10-31A>G had been “reclassified” to benign status.

Patient/Caregiver Commentary Re:  Direct-to-consumer testing and variant interpretation services

Generally speaking, some Americans can at times be curiously inquisitive about another’s background (heredity). As it happens, both of our children are adoptees with the same bio-birth mother so knew of their maternal heredity but craved knowledge of their paternal side. So we ordered DTC genetic testing for them as Christmas gifts—Ancentry.com for our son; 23andme for our daughter. The results provided what our kids’ longed to know—paternal heritages. 23andme confirmed that my daughter does have sub-Saharan genetics and after having been left desperately ill and completely demoralized following the revocation of her AIP dx, she gratefully embraced the small “sense of self” that 23andme had provided. Too, she was able to trace her paternal ancestral trail from sub-Saharan Africa to Spain to Puerto Rico to America.

However, when I asked her if she wanted to investigate 23andme’s “health risk” component, she adamantly declined, saying, “I don’t want to know anything else that’s wrong with me.” She’d been burned so badly that I respected her wishes and backed off. For a while. My initial skepticism, diminished by 23andme’s having matched sub-Saharan genetic heredity data to Dr. Desnick’s 2014 and 2018 Revised Reports, gave way to curiosity. After reviewing the out-of-US porphyria experts’ medical opinion, I asked for help from a trusted friend with experience in downloading Livewello to look into my daughter’s porphyria status. Alarmed by her findings and needing to see it myself, I downloaded the raw data to Livewello, located the Porphyria Profile template (ALAD, ALAS2, CPOX, FECH, HFE, HMBS, PPOX, UROD, UROS) and printed the entire report. I then entered each of the report’s porphyria variants into ClinVar and produced “Interpretation Reports” for each of the Livewello variants attributed to her, regardless of phenotype designation (-/-;-/+;+/-;+/+; NG). Not unexpectedly, ClinVar identified the majority of variants as “benign” or (a few) “likely benign.” Nonetheless, given the runaround we’d found ourselves enmeshed in regarding my daughter’s horrific medical condition vs her “benign” DNA results received from Dr. Desnick/Mount Sinai, the totality of what I learned from the 23andme/Livewello to ClinVar trail raised flags:

  • The clinical significance of one ALAD variant came up “Conflicting interpretation of pathogenicity; Likely benign; Pathogenic;”
  • The clinical significance of one CPOX variant came up “Pathogenic;”
  • The clinical significance of one FECH variant came up “Conflicting interpretation of pathogenicity;”
  • The clinical significance of one HFE variant came up “Pathogenic, other, risk factor;”
  • The clinical significance of a different HFE variant came up “Conflicting interpretation of pathogenicity, association, other, risk factor;”
  • Several variants (including HMBS rs28990987) were “not found in ClinVar” however:
  • The clinical significance of two different HMBS variants came up “Pathogenic;”
  • The clinical significance of one UROD variant came up “Pathogenic;”
  • The clinical significance of one UROS variant came up “Uncertain significance.”

Other than rs28990987, none of the 23andme/Livewello variants (acute, hepatic and cutaneous porphyrias) appeared on the underlying/supporting data I’d received from Mount Sinai. So the question was/is does my daughter actually have all the variants identified by Livewello? And if so, are the ones identified as pathogenic by ClinVar correct? Given the years of persistent, recurring symptoms (including but not limited to abdominal pain; nausea; vomiting; bowel dysregulation; extremity pain and weakness; anxiety; restlessness and severe convulsions), frequent low (extremely low) PBGD readings, and the “possible” biochemical evidence” (U-BP) intermittently excreted over the years (but not collected)—yes, she has porphyria. What other disease with a constellation of neurologically-based symptoms (excruciating abdominal, back and leg pain; progressive peripheral neuropathy; mental disturbances and convulsions) successfully responds to glucose infusions and resolves with Panhematin®?

The direct-to-consumer aspect of genetic testing companies like 23andMe, AncestryDNA, MyHeritage DNA, etc. is precisely what attracts people to such service offerings. All things considered, as far as education, experience, intelligence and the ability to voice concerns/questions to their physicians, contemporary patients are eons above those of generations’ past. This aptly describes patients and caregivers in our “missed diagnosed” community. Having had their porphyria diagnoses flatly denied (withheld) and/or revoked, the need to know why their illness worsened compelled (and still compels) “missed diagnosed” patients to seek DTC services—even some who’d also had DNA testing completed by one or more “certified labs.” So it is no wonder why “individuals who have negative biochemical test results for the AHPs have obtained their underlying DTC genotype data and used third-party companies to interrogate the SNPs in the heme biosynthetic genes.”37Many if not most of these patients compared results between the various tests (DTC and certified labs) and, not surprisingly, noted discrepancies. Indeed, many “interrogated” ClinVar (and/or similar databases) for DTC results and turned up clinical significance(s) of “benign,” “uncertain significance,” “not found” and “pathogenic.” Yet the certified lab (specifically Mount Sinai, Invitae) results mostly returned variants of benign status which conflicted with one (or more) DTC results. As one would imagine, this fueled (and fuels) patient skepticism. Suspicions of possible manipulation of “certified laboratory” results and/or data input is rampant.

Not only did I “interrogate” DTC generated genotype data, I “interrogated” Mount Sinai-provided genotype data as well. Why? Because it is my job as a mother to listen to my gut and intuition. My kid’s life is still on the line and no professional’s ego, feelings or agenda is above my doing anything within the law to help her. I, like every other mother/caregiver in this coalition, will never apologize to anyone for that.

Furthermore, supplying results directly to consumers appeals to patients. Unlike European guidelines of not sending reports directly to patients but rather to physicians/clinicians who may provide the patient with a copy,US federal HIPPA laws were enacted for that very purpose. Patients are entitled to receive medical reports pertaining to their health in order to make informed decisions—and physicians must comply with that request.  

Another DTC genetic testing aspect that appeals to patients is that the collection receptacles are anonymized. Consumers who go the DTC route sign an agreement stating that any raw data generated can be sold to third parties such as drug companies and universities for, essentially, “greater good” research. Scientists use the data to learn more about genetics and various conditions and diseases in hopes of learning more about diseases and to possibly find cures and treatments. Law enforcement can also obtain consumers’ DNA data via a court order.

Countless desperate “missed diagnosed” patients flocked to DTC genetic information services. Some shared the status of porphyria mutations identified by the companies they’d purchased data from. Apparently unnerved, APF addressed the issue in its March 2016 newsletter, “people unknowingly were turning to websites like 23andme and Livewello to find out if they had porphyria. Since many of the reports had genetic information that seemed similar to porphyria, people diagnosed themselves with the disease.”38 The non-profit gave “renowned geneticist and porphyria expert, Dr. Robert Desnick”39 a platform in that newsletter to address the matter. He noted, “It has come to our attention that some Porphyria patients have sent their DNA to 23andMe or to other commercial companies, and have gotten results suggesting that they have “DNA confirmed Porphyria.”40 We are concerned that results from companies other than DNA testing laboratories that have experience in diagnosing porphyrias may provide patients with misleading information. A major issue with DNA testing is whether a gene alteration (variant or mutation) is pathogenic (disease-causing) or benign (a change in the gene that does not cause or make one at-risk for the disease). For example, 23andMe does NOT do gene sequencing, but does determine if you have various gene alterations in the porphyria genes, all 57 of which are benign, and are not disease-causing but occur in a particular gene in which other lesions are in fact disease-causing. The benign lesions usually are identified by an “#rs” number. These benign changes are quite common but may lead a patient to believe that he/she has one or more porphyrias. They do not affect the heme biosynthetic enzymes, as they are not pathologic lesions. Of the gene lesions that cause disease, over 98% would be identified by gene sequencing as is done for all the Porphyrias at the Mount Sinai Laboratory and four Porphyrias at the Mayo Laboratory. The Mount Sinai Genetic Testing Laboratory provides Porphyria DNA testing for all eight Porphyrias, and has a full-time Porphyria Genetic Counselor…who is available to assist in arranging testing and interpreting the results. Typical time from receipt of sample to result is about two weeks. If the patient has “biochemical-positive” results and a DNA alteration cannot be found, there is a 1-2% chance that the patient has a “cryptic” mutation or a large deletion in the porphyria gene that is difficult to find by sequencing. The Mount Sinai Laboratory will do additional analyses to find the Porphyria gene lesion, if the patient has one.”41

It is true that 23andme doesn’t “do gene sequencing.” However, Livewello does—albeit not Sanger (or higher) quality. Disputing Dr. Desnick’s claim made in in his DTC opinion, at the time I’d downloaded my daughter’s raw data from 23andme, Livewello’s Porphyria Profile Report contained 111 (not 57) #rs numbers. A review of ClinVar results (based on #rs numbers) and subsequent communications with ClinVar personnel revealed that not all rs numbers are benign.

Evidently, leaks are common in the data world. While they’d signed the agreement that their anonymized raw data could be sold to third parties for the “greater good,” some patients were astonished to learn that their DTC genetic results had evidently been accessed by or possibly provided to “certified DNA labs.” These patients discovered that the underlying/supporting DNA test results they’d requested from the “certified clinical lab(s) that had produced the reports addressed some of their Livewello results. I was perplexed. My daughter’s 23andme raw data had been downloaded to Livewello too—months before I’d thought to request her underlying/supporting DNA test results data. Livewello had identified more than one pathogenic porphyria yet nothing about her Livewello variants appeared on her underlying/supporting “Revised Report.”

In sum, DTC genetic testing results provided our family the peace of mind that nothing else before had—heredity information corroborating the recollections of their birth mother and foster/adoptive agencies’ records. Maybe not verified by a certified high-brow lab, but certainly good enough at a time when our kids needed it most—particularly my daughter. As it turns out, her inherited porphyria(s) was/were a legacy from the birth father she will likely never meet.

Patient/Caregiver Commentary Re: ACMG and AMP guidelines for sequence variant classification

The IPMDC authors credit the American College of Medical Genetics (ACMG) and the Association for Molecular Pathology (AMP) for guidelines that “[provided] a framework”42 [for] variant classifications: pathogenic, likely pathogenic, uncertain significance, likely benign, or benign. However, reference was given to the Association for Clinical Genomic Science (ACGS) for the statement, “It has been noted that more focused guidance regarding the classification in specific genes is required as is the applicability of certain criteria may vary by disease and gene.”43Actually, this concept appeared in the Methods section of the ACMG/AMP May 2015 published paper, Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association of Molecular Pathology as, “We should also note that those working in specific disease groups should continue to develop more focused guidance regarding the classification of variants in specific genes given that applicability and weight assigned to certain criteria may vary by gene and disease.”44 Regardless of where it came from, this assertion likely inspired the “need” to “establish a disease-specific criteria and public database providing up-to-date information that will allow porphyria specialists to make informed decisions on the classification of variants in the AHP genes.”45

The authors put forth impressive efforts to convince readers of the alleged need for this database. However, a big picture perspective begs questioning such as, if acute porphyrias are considered so rare (less than 1 in 2000 in the European Union; <200,000 in the US) and now, “ultra-rare,” why is porphyria-specific genetic criteria so critical at this time? After all, the term “ultra-rare” surely doesn’t portend potential for rapid, substantial disease growth.

Theoretically a genetic database specific to a disease could be expected to be welcomed by patients and physicians. In reality, long years of miserable experiences have fueled skepticism for too many “a.p. missed diagnosis” patients/caregivers that this IPMDC IDDVP&BV endeavor is seen as just another tactic championed by US porphyria experts to keep the acute porphyria patient population within NIH rare disease boundaries.

With the exception of recognizing ACMG/AMP for producing “guidelines that take into account population, computational, functional, and segregation data”46which “provides a framework to enable classification of variants”47 the IPMDC authors essentially glossed over the well-established and respected collaboration’s mighty contributions to the worldwide genetic/genomic sequencing database endeavor. Anticipating an impending international flood of increasingly complex molecular diagnostic demands (for countless diseases), stakeholders of ACMG, AMP and CAP in 2013 convened a workshop to “revisit and revise the standards and guidelines for the interpretation of sequence variants.”48

The workshop participants considered a revised variant classification system and two potential scoring systems. While the majority supported a points based system to determine which category a given variant should be placed, in the end “the workgroup felt that the assignment of specific points for each criterion implied a quantitative level of understanding of each criterion that is currently not supported scientifically and [did] not take into account the complexity of interpreting genetic evidence.”49 Our “a.p. missed diagnosis” community applauds this decision. Though medically untrained we may be, we nonetheless recognize the critical importance of the experts’ staid commitment to maintaining scientific support in molecular diagnostics—especially where IEMs are concerned. An insightful patient/analyst colleague reminds us again of the oligogenic nature of AIP (and other acute porphyrias) and in referring to a source referenced in the IMPDC paper, ACGS Best Practice Guidelines for Variant Classification 2017 she notes, “of the 7000 rare diseases, nearly 5000 of these are claimed to be monogenic but low penetrance. This shouts that something is missing; either there is another, or several, genes involved or the penetrance is higher than claimed.”50 She continues, “The discovery of the ABCB6 gene’s influence on the severity of some proves that. Both CEP and EPP now include a variation on this, which is regularly included in genetic testing. There is no reason to believe that the situation does not apply to the other porphyrias.”51

The ACMG concurs, “Clinical molecular laboratories are increasingly detecting novel sequence variants in the course of testing patient specimens for a rapidly increasing number of genes associated with genetic disorders. While some phenotypes are associated with a single gene, many are associated with multiple genes.”52 The concept is not novel; applying it—or not to the acute porphyrias should be based on scientific evidence—never to fulfill a human-driven agenda. As does the ACMG statement re pathogenicity, “A variant should not be reported as pathogenic in one case and not pathogenic in another simply because the variant is not thought to explain disease in a given case. Pathogenicity should be determined by the entire body of evidence in aggregate, including all cases studied, arriving at a single conclusion…this approach will reduce the substantial number of variants being reported as “causative” of disease without having sufficient supporting evidence for that classification.”53

While the IPMDC touts its plans to validate “pathogenic variants in the heme biosynthesis genes causing the AHPs”54 and to “verify the published and currently unreported variants detected by expert porphyria laboratories in patients with the eight major porphyrias,”55 it is the last point, “based on their diagnostic biochemical findings,”56 that the “a.p. missed diagnosis” patient/caregiver community decries. Not a chance this group will support this experts-acknowledged highly fallible (as far as the urinary component is concerned) diagnostic method—especially since we are in total agreement with the ACMG when it comes to “entire body of evidence”—which has yet to be scientifically (not US Agenda-driven) determined. For those “a.p. missed diagnosis” patients with an established diagnosis, adhering to the method will likely result in revocation of that diagnosis, treatment plans ripped away and the patient’s (and his/her family’s) credibility and self-worth ruined. Such damage has been done over and over again for decades. That is why the IPMDC’s rationale for the IDDVP&BV falls flat with our group. I/we am/are here to speak for those who’ve been sentenced to a slow, hellish death—not to add to their anguish.

Patient/Caregiver Commentary Re: Formation of the International Porphyria Molecular Diagnostic Collaborative Database Information; Criteria for contributing laboratories; Genetic variant validation

It is not at all surprising to any in our “missed diagnosis” community that one of the authors (R.J.D), a US porphyria expert, proposed at the 2017 ICPP that this International Collaborative be launched.57

Given that several within our patient/caregiver community have reached over and beyond US borders to obtain additional information and/or second opinions (drawing ire and reprisals from US porphyria experts), this particular IPDMC author no doubt expected that inviting the European contingency to partner in an “international” porphyria collaborative effort would shut us up once and for all. It won’t. This is not just “sour grapes;” lives are at stake.

IPMDC authors allege that “[p]orphyria experts from countries worldwide indicated their support of this International Collaborative, including the European Porphyria Network (EPNET) and the US Porphyrias Consortium.”58 It is the latter’s endorsement of the collaborative effort that fuels cynicism about a US agenda-driven “need” for this IPDMC. Table 4 appears to be proof pudding to support that cynicism.

The IPMDC paper also states that “contributing laboratories will be expected to participate in the quality assurance program of the European Molecular Genetics Quality Network (EMQN) and in the EPNET External Quality Assessment Scheme for the porphyrias or other similar quality assurance program.”59  Why the International Collaborative selected these particular laboratory quality assurance criteria makes sense—at least for northern Europe—because by all accounts northern Europe has the highest prevalence of AIP-affected phenotypes most likely to excrete first-line urinary “biochemical evidence.” Nonetheless, that doesn’t mean that “a.p. missed diagnosis” patients don’t exist in those areas. They do. Atypical they may be, these patients deserve answers and appropriate medical care, too.

Perhaps because US was largely settled by European immigrants, Scandinavians being among the earliest, that made sense in this country, too—generations ago.US porphyria experts evidently adopted European guidelines, largely based on Swedish Porphyria (AIP) to diagnose the acute porphyrias. However, with APF’s founding, several generations had passed and potential patients that didn’t “fit the diagnostic mold” (aka “negative” U-BP) evidently began to approach the patient advocacy organization for help. One would think someone with a scientific perspective would have wanted to investigate the “anomaly.” But sadly that didn’t (or wouldn’t) happen. American porphyria experts chose to adhere to a diagnostic protocol that has yet to be documented as “supported scientifically” (as is evidently required by the ACMG/AMP/CAP).60

EPNET’s guidelines appeal to US porphyria experts because many EU porphyria experts reference increased urinary excretion of PBG and more precisely because, “[p]orphyrin biochemistry diagnostic of a specific AHP can be used within the Association for Clinical Genomic Science (ACGS) guidelines as strong evidence toward pathogenicity, as it is an aspect of the disease that is measurable and is pathognomonic of a defect in one of the AHPs.”61 This supports our belief that US porphyria experts expect the agenda they established nearly forty years ago to hold steady.

However, that agenda could well be compromised or even thwarted by the European Porphyria Initiative’s (EPI), which in its 2005 “Platform to Develop a Common Approach to the Management of the Porphyrias and to Promote Research in the Field” acknowledged, “In almost every European country at least one porphyria diagnostic and advisory centre exists; however, these centres often do not collaborate and may even be in competition with each other. This approach goes against the progression of knowledge and the drive within Europe to centralize data on rare diseases.” 62 A review of EPNET’s “Clinical features of an acute neurovisceral attack of porphyria” lists ten features—darkened urine is not among them.63

Patient/Caregiver Commentary Re: Methods for Variant Validation: Porphyrin precursor measurements; Enzyme assays; RNA analysis; In silco analysis

Since the time of Hippocrates, “darkened” urine excreted during attacks time has been a hallmark of extreme sickness. 2,000+ miles to the north and many generations later, Dr. Jan Waldenström developed a curiosity about reddish urine-evacuation holes surrounding farm houses in northern Sweden, applied his physician/scientist faculties—and ultimately identified Swedish Porphyria.

Given the AIP founder populations in Europe, it makes layman’s sense that that continent (particularly northern Europe and even more particularly, the Scandinavian countries as mentioned previously) would have the highest prevalence of AIP—and therefore also the highest ratios of patients who excrete the hallmark darkened urine. Indeed, Sweden reports that 100% of AIP patients excrete elevated porphyrin precursors.64Sweden’s neighbors, Finland and Norway respectively reported that 89% of patients had/have “[d]ark or red urine” as a clinical feature65 and 64% of patients exhibited “[d]ark/reddish urine.”66 Whether these statistics represent occurrence during inaugural attacks, subsequent attacks or both was not specified.

Via its partnership with Alnylam Pharmaceuticals, the US entered the “international” AHP “attack symptoms” stats arena in 2015/2017. Results of Alnylam’s 2015 “Patient-reported Attack Symptoms” screening questionnaire of 31 symptoms revealed that “Change in urine color” was reported at ~78%. Two years later (2017) “Change in urine color” registered at ~82%. It should be noted that while the US had the highest number of study subjects enrolled in Alnylam’s “Explore” study, participants from twelve other countries (Italy, France, Bulgaria, Germany, UK, Poland, Switzerland, Czech Rep, Finland, Netherlands, Spain and Norway) also took part in the study.67 To our knowledge, no such statistics have ever been published strictly for USA’s acute porphyria patient population.

Nonetheless, it is evident that not all AIP patients excrete porphyrin precursors with every attack—inaugural or successive. Way back in 1939, Dr. Jan Waldenström reported such an occurrence, “I have been able to observe a case where porphyrins could be detected neither in urine nor bile during an attack…Two brothers of the patient suffer from typical a.p…Porphyrins and red pigment, however, were found in the urine at a later date, when the patient showed no abdominal symptoms…The diagnosis: porphyria without porphyrins and chromogen was discussed. It has now been proved.”68 He also noted that the porphyrins and red pigment were found in the urine at a later date, when the patient showed no abdominal symptoms—which some in our “missed diagnosed” community as well as “expert-confirmed” acute porphyria patients report has happened.

Several decades after Dr. Waldenström witnessed the AIP attack with no visible porphyrins/red pigment phenomenon, an American teen began experiencing painful, sometimes debilitating symptoms (abdominal pain, breathing difficulty, arm and leg weakness) which continued to appear and disappear in mysterious fashion for ten long years. Standard lab tests yielded no clues. This individual occasionally noticed “strange colored” urine (although she doesn’t clarify what age that had been noticed) which was attributed to menses. She visited multiple doctors who, when unable to find biochemical explanations for her condition, minimized or dismissed her concerns entirely. She was given (mis)diagnoses with deprecating labels such as over-anxious, hypochondriac, postpartum depression, possible manic depression, etc. Ten years later, still suffering, she was prescribed Dilantin for “minor seizure activity” which sparked a life-threatening attack for which she was hospitalized. While in the hospital, she was catheterized and dark, purple-red colored urine began to spill into the urine bag. Blood and urine samples were collected and sent to NIH for testing; AIP was diagnosed. She was transferred to NIH (Washington, D.C.) A physician later confirmed that Dilantin had caused the AIP attack. She was treated with Panhematin®, survived, and eventually improved enough to, with a friend, co-found the American Porphyria Foundation.69

 Today this woman is APF’s director. Her 2004 book opens with the statement, “I was only seventeen years old when I suffered my first attack of Porphyria.”70How much time had passed from the time of her first porphyria attack till APF was established was not disclosed but it is nonetheless obvious that AIP knowledge and technology had advanced significantly from Dr. Waldenström’s 1939 observation. The point to be made here is that more than twenty-two years after APF had been established, the co-founder wrote the book that essentially acknowledged that what she’d struggled with for ten long years beginning at age seventeen had been porphyria. Yet the same recognition (that such symptoms are porphyria-based) for patients with the debilitating, life-altering symptoms (abdominal pain, breathing difficulty, arm and leg weakness) that appeared and disappeared in mysterious fashion without biochemical proof (U-BP) would not be acknowledged by APF and its SAB as porphyria.

Because these patients were effectively abandoned by APF, opportunities to more thoroughly investigate acute porphyria were lost. We submit, had the APF director not taken that Dilantin, attributed to having triggered the life-threatening AIP attack she suffered, and had Panhematin® not been effective, APF might not have happened—not as or when it did, anyway.

As it is, the (at the time) future APF co-founder appears to have been designated as the Index Case of the entire US AIP patient population for all time. This was good for her, as well as the APF SAB team. But as it turned out, not for the US advancement of acute porphyria studies—nor for the multitude of “misdiagnosed” patients who came after and were shoved into a never ending, gruesome Groundhog Day scenario like the APF director herself had suffered from age seventeen to about twenty seven.

Oddly, nine years after her book w published, recollection of the APF director’s first attack of porphyria changed. In the 4th quarter, 2013 APF newsletter, she wrote, “I remember being so afraid when I had my first attack of AIP. I was in terrible pain and so sick I was sent on an air ambulance to the NIH in Washington, DC.”71 However according to her book, the attack described happened years after her inaugural attack of Porphyria at age seventeen.72 Perhaps confusion or “brain fog” (AIP symptoms) caused her to disremember? Probably not. Adherence to the porphyria agenda—perhaps this “recollection” was meant to coincide with and lend support to the Alnylam Pharmaceuticals article introducing impending clinical trials of ALN-AS1 that appeared in the same newsletter? Probably so. Alnylam, like the company/companies) that produces/produced Panhematin®, used U-BP to test the efficacy of their specific treatment/therapy. That meant acute porphyria patients who did not produce U-BP were of no use to the APF/pharmaceutical partner team(s) in clinical trials. This apparently has been the basis of decades worth of “a.p. missed diagnosis” patients/caregivers complaints about APF’s “cherry-picking” of study subjects. This is also likely why the “a.p. missed diagnosis” AHP patient population has continued a steady expansion while “expert-confirmed” AHP patient population maintains a different type of “steady.”

To that end, revocation of a patient’s acute porphyria diagnosis was also documented by the APF director in her book. She wrote, “there are people who are taking Panhematin® but clearly do not have Porphyria…Eventually, after discussing the tests with [the patient] at length, she [the patient] requested that [her tests] be redone…Although the results were the same, one of the physicians reviewing the tests knew how to interpret them correctly and was convinced from the results that she did not have Porphyria. Nonetheless, he ordered a 24-hour urine, plus blood and stool tests to be sent to a Porphyria center. When [the patient’s] test results were returned, her ALA and PBG levels were within the normal range…Considering the biochemistry and the symptoms, it was clear that the woman did not have Porphyria. However, since she became a bit confused when she did not feel well and had been told in the past that she had Porphyria, she insisted that she had the disease regardless of the test results…The patient’s physician [stopped the Panhematin® treatments]…I am not sure what happened in the end, but I felt sorry for her because she was hanging on to a misdiagnosis and would then miss the true problem.”73 The US “agenda” was in play. The ill-fated patient was left to her own devices. “Misdiagnosed” is the operative word for those who approach(ed) APF having been diagnosed with porphyria by a doctor/specialist not on the non-profit’s scientific advisory board.

Our ever-expanding patient/caregiver community’s dilemma is that “massive amounts of porphyrin precursors excreted during attacks” is just not true for every patient. This does not mean that none of these patients hasn’t ever excreted odd-colored urine—indeed some have. So why weren’t they diagnosed? Many reasons: no awareness of AHP; didn’t mention “it” (colored urine) to physician(s); “it” was attributed to “something else” (for females, generally menses); sample was not collected; when became aware, “it” was not the dark, purplish, port wine color so often referred to by experts  but various gradations of pink, orange or brown; urine retention during attacks; collection process was compromised; sample was “mishandled,” “dropped,” “lost,” “mis-identified,” “mis-directed,” “not fresh,” “too old,” etc.

Some patients had been diagnosed with an acute porphyria by a physician who took an interest in their case, thought for him/herself and did his/her own “homework” (a scarcity in US where increasing bureaucracy and legalities have impinged on physicians’ ability to practice qualitatively)—and worked with the patient to develop effective treatment programs. But sometimes, circumstances changed; the patient moved—or the diagnosing doctor moved, left practice, died. When the patient sought a “new” physician for medical assistance, s/he was inevitably “re-tested” but this time didn’t meet the quantitative measures (established by APF et al). As a result, they were left in limbo. Some contacted APF directly for help in locating a physician who might help them and were inevitably referred to an APF/SAB-connected physician. The vast majority came away devastated—and disillusioned with the US porphyria-expert group.

Some time ago, a patient (who didn’t meet U-BP requirements but nonetheless had been receiving Panhematin® treatments) reported to some in the patient/caregiver community that his/her Mount Sinai DNA test results had been returned with a cryptic notation—the identification of a mutation with potential PBG retention qualities. Meaning there was a biological reason why the patient didn’t excrete U-BP. The patient shared that, under Dr. Desnick’s direction, his/her blood was being “checked” on a regular basis. Not surprisingly, this information ran rampant through the “a.p. missed diagnosis” patient/caregiver community. Unfortunately, said patient expressed fear that his/her treatments might be curtailed and essentially cut off communications with those in our group with who he/she’d been in touch.

Patient/Caregiver Commentary Re: Enzyme assays

            Due to the inheritance of faulty gene mutations,the substantive evidence most often provided as the reason for acute porphyria symptomatology by porphyria experts is deficient enzyme activity. In Molecular aspects of the inherited porphyrias, Sass and Kappa’s noted, “the enzymatic defect at every subsequent step [of the biosynthetic pathway] leads to tissue accumulation and excessive excretion of porphyrins and/or their precursors…”74Twelve years later, porphyria experts in Spain noted, “AIP [and the other AHPs are] metabolic disease[s] of haem synthesis, whose haem precursors may accumulate in the body.”75NORD agreed with that statement, “This enzyme deficiency can result in the accumulation of porphyrin precursors in the body.”76 And Merck Manual’s online Professional Version, edited in part by an APF SAB member, chimed in with “These [enzyme] deficiencies allow heme precursors to accumulate, causing toxicity.”77 We took such statements to mean that it was possible (perhaps probable) that not all heme precursors “spewed out” from the heme biosynthetic pathway left some patients’ bodies via urine excretion; some stayed in the body. To our non-medically trained minds, that they were “toxic” explained the severe neurological symptoms that befalls the patients among us. It’s a theory that merits more thorough scientific investigation.

Since the IPMDC authors tossed out the first pitch about erythrocyte HMBS activity, we’ll follow that lead. The IPMDC paper states “Measurements of erythrocyte HMBS activity have been used in the past [Note: emphasis author-added]to help confirm the diagnosis of AIP.”78 The reference for that statement was a 2002 source. Oddly, nine years after that 2002 source had been published, the 2011 published edition of Nelson Textbook of Pediatrics’ Chapter 85, titled  “The Porphyrias” co-authored by Karl E. Anderson, Chul Lee, Manisha Balwani and Robert Desnick noted, “Erythrocyte PBGD activity is decreased in most AIP patients and helps confirm the diagnosis in a patient with high PBG.”79 Something is amiss. The 2019 version of the Nelson Textbook of Pediatrics is not yet available in hard cover; it will be interesting to see if the same statement appears in that version. With its most recent website re-vamp, the reference to PBGD testing for AIP “latency” disappeared from the APF website’s DIAGNOSTIC TESTING FOR THE ACUTE PORPHYRIAS – CLARIFICATION OF TESTING RESULTS section.

Porphyria experts (at least those in US and Europe) have known for decades that PBGD activity is decreased in the majority of AIP patients. Even the APF-favored Porphyrias Consortium, on the Rare Disease Network website, acknowledged that (although they referred to it as “HMBS activity in RBCs Decreased in ~90% of cases).80

Prior to the era of DNA diagnostics, CRIM analysis was relied on by many porphyria experts to differentiate subtypes of AIP, which were classified based on PBGD enzyme activity. Sassa and Kappas identified three AIP subtypes and determined that in one, Type II, the erythrocyte PBGD measurement is normal. Yet the APF director has claimed on several occasions that she’s never heard of acute porphyria “sub-types.” After nearly forty years at the helm of the organization during which the widely respected Dr. Sassa had served for a time on the APF scientific advisory board?

At the time, Sassa and Kappas also noted that more than “100 mutations of the PBGD activity have been described.”81 It is obvious that these US porphyria experts worked comfortably in the genetics field.

Patient/Caregiver Commentary Re: RNA analysis

            According to an extensive study (UK) of 467 acute porphyria patients, Sanger sequencing evidently did identify over 98% if HMBS, CPOX and PPOX variants. But not ALAD, which brings up the point—if ALAD is never tested for, it is no wonder why so few patients have actually been identified. It is the only acute porphyria that doesn’t appear on Mount Sinai’s DNA testing requisition form and “a.p. missed diagnosis” patient/caregiver community participants from out-of-US have indicated the similar. Nonetheless, according to EPNET’s Specialist Porphyria Laboratory Table, testing for ALAD gene is available in Denmark, France, Italy, Spain, Sweden, Switzerland, The Netherlands, UK.82 Research indicates that the highly competitive, ever-growing intelligence of the DNA testing industry offers an improvement (albeit a very costly one) to Sanger sequencing.

Patient/Caregiver Commentary Re: In silico analysis

            Interesting. IPDWC authors cite, “It should be noted that current prediction accuracy plateaus at approximately 80% and many programs have low specificity, resulting in overprediction of genetic variants as pathogenic” and attribute the statement to five and seven year old sources.83 Actually, ACMG’s more recent (2015) paper states, “Most

[in silco algorithms]

tend to have low specificity, resulting in overprediction of missense changes as deleterious, and are not as reliable at predicting missense variants with a milder effect.”84AMCG professionals agree that in silco analysis should not be used as the sole source of evidence to make clinical assertions.

Patient/Caregiver Commentary Re: OVERLOOKED/UNADDRESSED Relevant Topics:

Powerhouse PBGD (ad CPOX, PPOX too?); Heme deficiency=Acute Porphyria Trigger; Beyond urine—acute porphyria biomarkers; Blood; “Latent” vs. “Asymptomatic” vs. “Misdiagnosed”

  • Powerhouse PBGD (and CPOX, PPOX too)?

From the first look I had of the results from my daughter’s lab tests ordered by a newly- minted neurologist who’d “heard of this thing called porphyria in med school,” I’ve focused on PBGD results. My daughter was deathly ill but her urine test results were “normal” (“porphyrin profile, 24 hr” was “Creatinine C.714 L”  “Uroporphrin 1.8 L.”64); her PBGD level was “Indeterminate”—6.9 L vs “Expected range >7.0.” Knowing absolutely nothing about AIP at that point, I hadn’t realized the neurologist had ordered the wrong urine test. But it mattered not; mother’s intuition told me, “It’s in the blood—follow that PBGD thing.” A few days later, another trip to the ER resulted in a “brown” urine sample, identified as such on the ER discharge paper. By then I’d read some about AIP and asked that the urine sample be sent to be tested for AIP. My request was ignored. Less than two weeks later, blood tests were drawn and urine samples taken again. Her PBGD had decreased to 5.3 (expected range >7.0). In addition to “textbook” AIP symptoms, she’d been struggling with almost daily periods of convulsions, breathing difficulties, increasing periods of grave physical, neurological and cognitive complications. ER visits were required multiple times a week—sometimes daily. This cycle went on for weeks—until, fearing for her life and being that she was an adoptee, I insisted on DNA testing. Having found APF’s website, I read about DNA testing being the preferred diagnostic method for porphyria and that Mount Sinai was to place to go. So I began making calls. I had no intention of stopping until I’d secured DNA testing for my child. Only three acute porphyria genetic tests were available through Mount Sinai—actually four if one counted the three-acute-porphyria option which is the one I selected. I followed the directions provided by MS’s genetic counselor, inserted a prayer card with the blood sample into a sturdy box, forked over the fee and sent the precious package off to Mount Sinai. Weeks later, the “good news/bad news” call came. My daughter had been diagnosed as having AIP. 

The relief was amazing. It didn’t last long. The rest of the story is documented in a book my daughter and I wrote about the hell that childhood-onset AIP wreaked on her young life—and on our family.

Following the aggressive treatment protocol that a Swedish/US transplanted AIP specialist who’d been referred to us by the mother of a young-adult woman with acute porphyria, my daughter’s live had been saved and she’d  been doing relatively well for five and half years. Then out of the blue, Dr. Robert J. Desnick, PhD, MD, Director, Mount Sinai Genetic Testing Laboratory inexplicably revoked her AIP diagnosis. She has steadily declined physically, neurologically and mentally since. That “PBGD thing” at the forefront of my mind, I requested the test be included with every “new” doctor’s blood test orders. Sure enough, her PBGD levels definitely correlated to her AIP presentations. The weaker she became, the more symptoms she displayed and the lower her PBGD levels turned out to be. Though they probably thought I was a nutty, over-protective mother who wouldn’t “cut the apron strings,” carrying my daughter’s binders of medical records to every appointment, a few benevolent hematologists responded to my pleas and ordered IV glucose and/or Panhematin® for her. Although I couldn’t get any of them to order PBGD tests after she’d received Panhematin® (even a few days or a week after), it was evident that hematin was beneficial. In every instance, she’d gone from being a “droopy” to young adult able to stand up and think for herself again—for a while.

I knew I’d found a reliable biomarker that helped identify my daughter’s AIP activity. However, because PBGD measurement was not acknowledged by APF (US “porphyria experts”), local and regional doctors ignored my repeated insistence that it was an effective barometer.

A 1976 medical article gave me hope, “Measurement of the activity of uroporphyrinogen I synthase activity provides an excellent laboratory aid in the diagnosis of acute intermittent porphyria, particularly in those patients who are asymptomatic or in whom the disease is not biochemically manifested by porphyrin precursor excretion.”85 [Note: Emphasis author-added] But no one connected to the US porphyria advocacy foundation would accede this “old” article.  With no way to find or contact the authors, I swallowed my angst yet again.

Then I happened upon an exciting 2007 Japanese study, written the year before my daughter overtly presented with AIP symptoms that confirmed I was on to something. It stated, “The [PBGD] activity normalizes as the patient improves, suggesting that this enzyme is a more sensitive monitor for acute intermittent porphyria attacks than the urinary parameters currently used for its diagnosis”86 [and] PBG-D is a good indicator to predict or detect the AIP attack before its onset.”87 It also stated, “it is known that AIP patients show an abnormal urinary profile of ALA, PBG, UP and PBG-D and that this profile shows wide variations from status to status within the same subject.”88 The paper concluded with, “Presently PBG-D testing is performed for the diagnosis of chronic or acute AIP. We propose that monthly range PBG-D monitoring is crucial for prediction of the acute phase in AIP patients by using the negative deviation of PBG-D from the mean value as a clinical benchmark to predict and prevent AIP attacks. Physicians treating porphyric patients should use monthly testing schedules to estimate the potential risk of an AIP attack and to establish opportune heme therapy.”89 Had I come across this awesome paper years earlier, perhaps our family might have relocated to Japan, might have even met Dr. Sassa himself and we would have avoided the torturous US porphyria agenda debacle entirely. A cursory review of ICPP lists of abstracts showed no indication that this very beneficial information ended up on an international porphyria experts’ platform which is truly unfortunate.

My daughter’s PBGD lab results undoubtedly contributed to the (out-of-US) porphyria expert teams’ 2018 finding because they noted, “The critical result for a diagnosis of AIP is the level of enzymatic activity of hydroxymethylbilane synthase, whether the patient is presenting an acute crisis or if never one has occurred. The person is nonetheless a carrier of one mutation capable of producing an acute crisis. A large proportion of carriers indeed never had one. But it is not mandatory. In the presence of typical symptoms, a low enzymatic activity is diagnostic. Even with absent U-BP (read paragraph above again).”90  I realized that the porphyria expert team that had submitted a professional opinion on my daughter’s case had corroborated the Japanese porphyria experts’ eleven year old study, even if they had been unfamiliar with it. They’d also validated the approach taken nine years earlier by the kind, compassionate and AIP knowledgeable Swedish/US transplanted pediatric hematologist/oncologist/AIP specialist who’d saved my daughter’s life after she/we’d been set adrift by APF/Dr. Desnick following her November, 2008 DNA diagnosis. I wondered why our US porphyria experts, surely as intelligent as any of these physician/scientists, refused to show interest in any AIP diagnostic method that is “more sensitive” than U-BP and why they lacked the compassion shown by experts born, bred and medically trained outside the US.

  • Heme deficiency=Trigger

Dr. Cecil Watson’s New York Times obituary remembered him as “chief researcher in the discovery of hematin, the most effective treatment of the disease porphyria, an inherited disorder of the liver.”91Dr. Watson’s unique understanding and interest in “the many biosynthetic intermediates and degradation products of heme which are eliminated in human excreta”92 resulted in diagnostic and treatment discoveries that are still relied on by porphyria experts.

With coworker Dr. Samuel Schwartz, he developed a qualitative method for detecting porphobilinogen in urine—still used to identify “patients who carry the genetic traits of hepatic porphyrias associated with neurologic lesions.”93 The Watson-Schwartz test was quickly embraced by US and European porphryria experts, essentially cementing its position in the acute porphyrias diagnostic protocol. But it was “long after retirement from academic responsibilities [that Dr. Watson] had the “intellectual satisfaction of discovering a highly effective and often life-saving therapy for a disease which had preoccupied him for over forty years—the successful treatment of acute [porphyria] attacks [by infusing] hematin.”94

This was by no means easily achieved and Dr. Watson’s lab was not the only one working to “elucidate the mechanism and regulation of heme synthesis in the liver.  Contributions were also made by many other laboratories in [US] and Great Britain. But it was Cecil who eventually put it all together when he recognized that porphyric attacks are associated with severe heme depletion in the liver.”95 [Note: Emphasis is author-added.]

Built on years of witnessing my daughter’s AIP presentations, reviewing lab tests and speaking with countless medical professionals and “a.p. missed diagnosis” patients and caregivers, I developed a theory about heme deficiency’s role in acute porphyria activity with PBGD being a sort of “barometer”—at least for my daughter. But nothing about any such connection could be found in any US porphyria experts’ APF-produced materials or in any of their published papers/documents. Certainly, “heme deficiency” was mentioned in several papers, often with APF SAB member Dr. Herbert Bonkovsky’s name appearing as author or co-author and usually about hematin infusions with references to the free heme pool.

For instance, in Porphyrin and heme metabolism and the porphyrias, Bonkovsky et al states that hematin infusion “repletes a critical regulatory heme pool in hepatocytes—which leads to downregulation of hepatic ALA synthesis, which is a biochemical hallmark of all forms of porphyria in relapse.”96

Dr. Watson’s heme depletion finding was explained in the Textbook of Peripheral Neuropathy as, “Cytochrome inducers like barbiturates increase the synthesis activity of hepatic cytochrome as much as  40- to 50- fold; this increases the incorporation of intracellular heme into hepatic cytochromes, leading to the depletion of the reserve of heme.”97

A few months later, Dr. Bonkovsky released another paper with a different research team; it didn’t take a rocket scientist to figure out that Heme status affects human hepatic messenger RNA and micoRNA expression was connected to Alnylam’s development of a new drug (ALN-AS1) which targeted ALAS-1 or that APF was wholly involved in the matter. At the time I had more interest in learning about study team’s objective “to characterize…the comparative effects of heme excess vs heme deficiency in human hepatocytes,”98 however, this paper did give credence to my theory about heme deficiency contributing to acute porphyria affected-patients’ performance. While it was good to learn more detail about the toxic effect of excess heme, it was the statement, “[a] deficiency of hepatic heme is well-known to be associated with disease phenotypes, especially the acute porphyrias in relapse”96that provided the answer I and others sought. Still, the “in relapse” part niggled my brain as did the ending, “partial defects in genes and enzymes of the heme synthesis, which with other genetic and environmental factors, lead to a critical deficiency in the regulatory heme pool of hepatocytes and hence to uncontrolled and marked up-regulation of hepatic ALA synthase-1, which normally is the rate-controlling enzyme of heme synthesis.”99 It would be beneficial to specifically know the effects “partial defects in genes and enzymes of heme synthesis” have in heme depletion—without additional triggering effects.

Approximately a year and a half after the release of Dr. Bonkovsky’s Heme status affects human hepatic messenger RNA and micoRNA expression paper, Alnylam Pharmaceuticals expressed an interest in the heme deficiency issue. However, based on comments made during an Alnylam Roundtable session by Dr. Karl Anderson concerning heme deficiency, it doesn’t appear that the US porphyria experts had then or have now any interest in pursuing it [heme deficiency]. During the roundtable session, a slide titled “Pathophysiology of AIP” stated that ALAS1 is induced by “depletion of ‘free’ home pool”—and “ALAS1 induction [is] accentuated by partial deficiency of PBGD [which] limits heme supply to the regulatory “free” heme pool.”100

The next slide, also titled “Pathophysiology of AIP” contained one bullet point, “Neurologic manifestations,” beneath which read, “Heme deficiency→hemoprotein dysfunction?? and beneath that, “e.g. vasospasm due to NOS deficiency???”101 During the Q&A session, the Alnylam executive conducting the session said/asked Dr. Anderson to, “Explain the potential of heme deficiency in targeting ALS-1. Do you see that in patients that might have heme deficiency treatment with ALN-AS1 might exacerbate that deficiency?102 Dr. Anderson responded, “I think the evidence of heme deficiency and the acute porphyrias is pretty weak. But it might be possible looking to animal model to see if any, in the brain, for example, if MRI changes occur that are similar to what’s been described in humans. But I think people agree that the best hypothesis is that intermediates in the pathway, particularly ALA may be responsible. The problem is that that’s not really proven, but most of the evidence points towards that, we know it’s something from the liver. And so because transplantation cures the disease, so it would be something in the liver, coming from the liver that cause the heme efficiency say in the—in the nervous system. And that’s rather kind of a stretch.”103

A “a.p. missed diagnosis” caregiver of two children with HCP (with a porphyria expert’s professional opinion to support her) disputes Dr. Anderson’s statement that heme deficiency is “rather kind of a stretch.” This is her story:

In a family of more than 10 sufferers of HCP, an Australian mother has 2 children (youngest and oldest) with HCP. At age three, the oldest child (F) began exhibiting HCP symptoms. A paternal family member, who happens to be a physician in paediatrics/genetics/metabolics, confided that porphyria was in the family. After thorough testing this physician’s opinion was that porphyria was the best explanation for the child’s symptoms, despite the literature excluding the possibility of children having attacks before puberty. She explained that in rare diseases, little is known about them and that the literature can often be incomplete, especially in metabolic diseases. She has stated that as porphyria is a genetic metabolic disease it would be more likely to be active from birth and that family accounts have reported active disease from a very young age. This information proved of little help when seeking a diagnosis for the children due to the lack of insight from porphyria experts in their state. The younger child (M), dx with epilepsy and a brain disorder at a very early age began exhibiting porphyria symptoms due to unsafe epilepsy medications. The child’s neurologist insisted that genetic and biological testing be done on all three children in the family, previously refused by the porphyria specialist in their state due to the assumption that children do not have acute attacks. All 3 children were tested, the two who were suffering symptoms came back with positive DNA, the stool biomarker of HCP (Copro III:I reversed) and the male child also had high urinary PBG due to years of taking unsafe epilepsy medications since his birth. The female was 16 and the male child was 7 at the time. Because the younger child excreted U-BP, he was considered in an acute attack and removal of the offending epilepsy medications proved to stop the symptoms. No treatment was offered or received by the porphyria expert but the child is frequently placed on glucose IV by doctors at his regular hospital in order to avoid attacks. The older child, continuing to suffer severe symptoms and attacks, did not excrete first-line U-BP and so was denied treatment—for eighteen years. Having left school, unable to eat or sleep, often being taken to emergency via ambulance, she was left to suffer due to a lack of high urine PBG, despite her having seen a multitude of specialists over more than a decade who ruled out common causes for her symptoms, despite her family history of porphyria and even despite the DNA result. In 2016, the child/young woman became deathly ill. The mother sought contact with an Australian porphyria expert in another state who confirmed that her daughter was indeed suffering from porphyria, citing the DNA result combined with the stool ratio indicating HCP plus symptoms and triggers synonymous with an acute attack of porphyria. He began treating the young woman with glucose/Normosang (the European/Australian version of Panhematin®) treatments. Her condition has improved considerably. Previously in a wheelchair, she is now walking, but she remains chronic, needing numerous treatments with heme infusions per year. She currently has another excellent specialist in her state who regularly tests her heme levels and organizes treatment when heme levels are depleted and symptoms worsen. She also has been found to have high urinary ALA during most attacks –something never tested previously when urinary PBG was assumed to be the only relevant indicator. She has never had high U-PBG yet her doctors are now well aware that it is not a good indicator of acute attacks in her and she receives regular Normosang as she needs it. It is her specialist’s opinion that she has been heme deficient for years and will need many years of treatment before her body recovers from years of medical neglect.104

Another mother’s straight-A chemistry major high school age daughter began suffering with symptoms during twelfth grade senior finals that forced her first ER visit. As her health progressively worsened, her parents made the rounds of every conceivable doctor and specialist they could find or were referred to. Medications made the daughter sicker yet she was offered antidepressants over 25 times while her actual serious and life threatening symptoms of tachycardia 224 bpm, labile hypertension 200/100, and stomach pain were discounted. She was accused of being on drugs, pregnant, lying or crazy. “How do you lie about a 195 heart rate when the monitor clearly shows it?” the parents wondered. After a time, porphyria was mentioned and testing started. However, proving one has porphyria in the US is almost harder than having the disease. Her clinical history was “textbook” porphyria including rare signs and symptoms like temporary vision loss. Except for U-BP, everything fit—HCP was highly suspected. Multiple excreta testing were ordered. HCP fit, except she hadn’t excreted U-BP so treatment is not available to her. DTC genetic testing leaned toward HCP. With no ability to do HCP enzyme testing in the US [according to EPNET’s website, US does not provide full molecular services (enzyme assays)],105 the parents took their daughter to France seeking professional opinions and enzyme assays from porphyria experts there. Her daughter’s HCP enzyme level was reported at 292 which when compared to a diagnosed, de-identified study patient (data provided in published medical journal paper) whose reported level was 300—in “compound heterozygous HCP.”106 Close but no cigar. As with my daughter’s dx revocation—and so many other hapless patients whose diagnoses have been withheld or revoked, no U-BP means no diagnosis. No diagnosis means no treatment. No diagnosis means loss of credibility. No diagnosis means not being counted. In the US, not being counted means the US acute porphyria patient pool remains within US-agenda expected parameters. The family returned to the US, still seeking answers. APF reprisal was typical and this time posted on a public Facebook forum which met with ready response from “a.p. missed diagnosis” community members:

    “UPDATE ON ACUTE PORPHYRIA TESTING: FRENCH PORPHYRIA CENTER (CFP) A US individual seeking acute porphyria testing has posted widespread misinformation about the French Porphyria Center (CFP) and their diagnostic and testing capabilities. Due to this plethora of misinformation, the Director of the CPF [name] informed the APF that they will no longer accept US patients at their facilities except for diagnosed patients, who are presymptomatic or symptomatic, and are living or traveling in France. The French will certainly care for these patients just as US experts care for French patients traveling or living in the US. This decision was made after great concern that some of this same misinformation was attributed to him [Director of CPF] and his well-respected facility.

    “The APF, the USA experts, the CPF and the other European Porphyria Centers have worked together diligently to offer accurate data regarding diagnosis and proper testing, including data about enzyme testing. In the past, certain enzyme deficiencies were measured to help determine the type of porphyria, but now DNA is used to determine pathogenic mutations. The enzyme deficiency test can still be useful in research and when people have positive biochemistry, but their DNA is cryptic. If you have testing concerns, call the APF or seen the APF website.

   “porphyria is serious diseases, ppl cant tout their nonsense science with a bunch of scientific words but no factual evidence. now scientists are mad…it is bizarre to think that the apf has anything to do with diagnosis or treatments. we only publish what the scientists tell us

   “and it is important where a person gets their medical info…not patient-generated medical info that is different from personal experience which is so great to share…personal experience is not medical info from drs…ppl should not change that…or alter what a dr said. or think porphyria experts who have devoted their lives to patients dont know what they are talking about…that is ridiculous.

   “its super important to get info from experts/science based…there is also an issue re certain mutations that ppl think are disease causing because a number of them have the same mutation. instead, this same mutation appears is widespread in the population is not disease causing.

   “another thing that is confusion is that ppl think that since their mutation has not seen yet, they think they may have porph…instead, they do know the gene is a porph gene…like pbgd for aip…but it will have a lot of different family mutations.”107

Response from Caregiver:

   “This is very sad for the people who have porphyria who can’t get a diagnosis in the US because they are not excreting high levels of PBG or have a DNA diagnosis. If only APF would acknowledge that many with porphyria are not obtaining a diagnosis and treatment and broaden their information about thorough testing for a complex disease people wouldn’t feel the need to travel outside of the US to get treatment. So many desperate people in excruciating pain…it breaks my heart. There are many academic papers showing no elevations in PBG in porphyria and genetic testing is in its very early stages. Every geneticist will tell you this. To rely on either one means diagnoses can be missed. I find it abhorrent that the APF feels the need to control people’s choices regarding diagnosis. This is a situation created by APF; desperate people take desperate measures. Scientists are not gods. Much is still to be learned about the mechanisms of porphyria and the APF’s goals should be in helping people not in controlling people and slandering those who are trying to help [a] family member stay alive while fighting for a diagnosis. There is much to be done regarding testing in porphyria and the APF doesn’t seem to be doing anything about it. It’s a dire situation that is ruining lives.

   “And let’s not forget that university educated, academically minded, research-experienced people can also be parents and sufferers of porphyria. My family has many Drs and one, a metabolic geneticist who first diagnosed my [child’s] symptoms at the age of 6 as being porphyria, does not agree with using the PBG test to diagnose an attack and determine treatment. Her advice was find someone who is willing to do comprehensive testing that is specific to HCP. The PBG test is not enough. She also suggested contacting researchers as new findings are coming out about rare diseases every day. I don’t think patronising people is the way to go. We are not all idiots in tin foil hats. My [child] does have chronic attacks of porphyria and DOES NOT HAVE HIGH PBG! Thankfully, [s/he] now gets treatment DESPITE all of the misinformation from so-called experts.”108

The parent who was lambasted by APF post re the “French CPF” had this to say, “Upon our return from France, I posted on FB that [my daughter’s] enzyme test results showed more deficiency than another patient who had been diagnosed and whose case had been written up in a research paper by that same center. The APF director bashed the test. I pointed out that it was done at a French porphyria center by the director (who is doing the Alnylam drug trial ) and she said, “I’m contacting the French.” And she did. My daughter has been very sick with six hospitalizations consistent with porphyria attacks since our return.”109

That makes three young women, two of whom have suffered for years (one nearly for the whole of her life) and one whose life has been more recently similarly shafted, yet all were dismissed by porphyria experts because they didn’t achieve the diagnostic urinary “gold standard.” Two eventually received treatment with glucose/Panhematin® and remarkably well to the modality. In a callous and highly suspicious manner, one’s diagnosis (my daughter’s) was revoked. Without treatment, the third young woman’s health has severely deteriorated, her enzyme deficiency wholly dismissed by experts. The intent of including these reports/responses is to reflect the urgency of need and dismissive manner that US porphyria experts respond—from the top down, and in unison. Our “a.p. missed diagnosis” patient community includes toddler to octogenarian patients and is comprised of caring, intelligent, well-researched patients and caregivers. We must, for the greater good of acute porphyria patients everywhere and to come, continue to speak out and share our knowledge. Acute porphyria won’t stop. It’s in the genes of an uncounted number of people on this planet. Acute porphyria shouldn’t be allowed to continue to bankrupt the lives and finances of individuals, families, societies, private and single payer insurance sources.

Recalling the (at the time) future APF co-founder’s report of having suffered for ten years before ultimately taking the dose of Dilantin that incited the life-threating attack that ultimately produced the AIP diagnosis, I wondered if perhaps she, too, had been “heme deficient” for all of those years. There are case studies of patients who’d ingested Dilantin with no untoward effects, which substantiates another great physician/scientist’s finding—Sir Archibald Garrod’s concept of chemical individuality.

Unfortunately, instead of US porphyria experts exhibiting even a modicum of interest, all three cases drew interference and retaliatory acts from APF leadership and/or associates. That being said, and knowing that other individuals who’ve presented clinical acute porphyria symptoms without excreting “gold standard” U-BP had/have received treatment with glucose and/or Panhematin® therapies, successfully mitigating and/or resolving their symptoms too, it seems reasonable enough evidence to encourage launching a thorough scientific study to determine the role that heme deficiency plays (alone or in concert with the gamut of triggers generally noted as inducers) in triggering acute porphyria activity.

It has been nearly five years since the Alnylam/Dr. Anderson Roundtable Q&A interchange—nothing seems to have changed with regard to US interest in heme deficiency. Based on observations made over more than eleven years of caring for my porphyric daughter, hundreds of attacks and heaven knows how many glucose and/or Panhematin® treatments she has had, I (along with the foregoing mom/caregivers and patients who know the benefits of hematin treatments) submit that severe heme deficiency in and of itself can be an attack trigger. And we are confident that enzyme assay (PBGD for my daughter and CPOX for the young woman whose parents sought French experts’ help) appears to be a suitable warning signal that heme levels are falling into danger status.

However, my (and others’) online posts concerning enzyme monitoring, heme deficiency or any other topic not APF-endorsed were (and still are) routinely denounced by the patient-advocacy organization. In providing information which confirmed experiences and/or provided scientific reasoning behind acute porphyria presentations exhibited by many “a.p. missed diagnosis” patients from the wealth of information available by worldwide porphyria experts, we’d clearly stepped over the APF protectionism of “only posting and publishing what [its] scientific advisory board of experts says.”110 

To that end, APF has gone so far as to amend its various public communications to counter attempts to share experiences and/or information from other sources outside of APF’s SAB’s provisions. For example, after I posted info online about the PBGD/attack connection, an APF website section (apparently no longer available) titled “Misinterpretation of Test Results” appeared. In typical fashion of minimizing “a.p. missed diagnosis” patients it stated, “Incorrect diagnoses of Porphyria can occur in patients having minimal abnormalities in laboratory tests, such as small elevations in urinary porphyrins or porphyrin precursors that in fact have little or no diagnostic significance. Incorrect diagnoses are less likely if reliance is placed on a few first-line tests in most clinical situations as described above. Overuse and over-interpretation of minor abnormalities in results of second-line tests, including erythrocyte PBGD, other enzyme assays, and fractionation of urinary and fecal porphyrias, account for many incorrect diagnoses of Porphyria.”111

To that we question when and why the Watson-Schwartz test went from a being qualitative to a quantitative acute porphyria testing tool. When my son was diagnosed with Type 1 diabetes (via first-line urine test then second blood testing to arrive at a diagnosis), I’d asked the endocrinologist , “How bad is [his diabetes] that he needs to test eight time a day?” S/he replied, “All diabetes is bad. It doesn’t matter how often one has to test. It’s all bad.” Surely, the same can be said about acute porphyria. Studies have shown that PBG excretion levels vary between patients and even within each patient; there does not appear to be any correlation to the level of pain/acute porphyria symptomatology. As with diabetes—all acute porphyrias are “bad” and should not be gauged solely on presence of U-BP.

When porphyria experts from different countries provide information that disputes US “findings,” or provide assistance that US would/could not concerning intelligent young women who (as the APF co-founder did decades ago) know they are very sick, not faking and not mentally ill, it is well past time for unbiased, authentic science to take over. It was apparent to many in the “a.p. missed diagnosis” patient/caregiver population that APF website “changes” were intended to discredit, disparage and silence those who refuse to fall in line with the nonprofit’s agenda. Having been blacklisted by this group (like the Australian mother before me—APF’s tentacles reach far and wide—and many others before me), I began challenging the unconscionable revocation of my daughter’s AIP diagnosis. Shortly thereafter, APF posted a link on an open Facebook porphyria forum page to a paper titled Feigning Acute Porphyria. The four authors were University of Texas Health Science Center at Houston; the lead author earned her medical degree from University of Texas Medical Branch—where Dr. Karl Anderson, chair of APF’s SAB runs a Porphyrias Consortium Porphyria Center. Although no acknowledgement or thanks to him are proffered in the paper, given the relationship between the two medical entities and the fact that one-third of the paper’s references are attributed to him, it’s reasonable to assume that Dr. Anderson’s AIP “expertise’ was extended to the UTHC psychiatrists’ research, writing and/or reviewing the text of this paper.

The paper reviews the case of a man who’d presented to a “sister hospital” of UTHCD with complaints of a “porphyria attack” and request[ed] opiate analgesics.” He had no medical documentation to support the diagnosis of AIP he alleged to have. He was evaluated by a “multidisciplinary psychiatry service and found to have ‘irritable mood, no suicidal ideation, no psychosis, no manic behaviors, was future-oriented and looking forward to receiving housing assistance and free pain medication.’” He was discharged from the sister hospital with a diagnosis of “adjustment reaction with anxiety (he’d recently moved to Texas from New York but later stated he’d moved from Virginia), nonopiate medication and [with a] follow-up hematology appointment.”112Upon being discharged from UTHCD, he went directly to UYHSC’s ER complaining of severe abdominal pain and stating he’d go home and ‘shoot myself if the pain doesn’t go away.’113 “In addition to suicidal ideations, he complained of depressed mood, decreased sleep, anhedonia, poor energy, nausea, vomiting, abdominal pain and homicidal ideations toward his landlord.”114 His vital signs, including sodium were in normal range; his abdominal exam, bowel sounds, motor strength unremarkable and his abdomen not distended. However, even as he acknowledged being anxious he “calmly described his intentions to end his life if [his pain was not adequately controlled]. ”  He also told the nursing staff that he would go and get a gun and ‘kill you all’ if he were discharged to home. He later stated that he was only frustrated we would not give him the medicine he needed to treat his porphyria.”115

Evidently, the ER “obtained medical records from the hospital where a significant portion of [the patient’s] AIP treatment occurred.”116 While initial diagnosis records were not available, accounts of a reported AIP flare with postprandial vomiting and twenty-five lb weight loss were obtained. “Although his qualitative [U-PBG] was negative, he was started on IV hemin 350 mg intravenously every two weeks. He also received morphine and fentanyl transdermal patch as needed for pain.” He’d been treated with hemin in two more occasions, but was “poorly compliant with follow-up appointments.” Subsequently, [the patient] presented with abdominal pain for which he was treated with IV hydromorphone despite two negative qualitative PBGs and negative 24-hr quantitative porphyrins. He had two more negative qualitative PBG tests in 2006 and one more 24-hr quantitative porphyrin test In 2009 he was evaluated for abdominal pain [in the ED] and had a normal porphyrin profile at that time. In total, his urine has been tested on 11 different dates likely secondary to nine different AIP episodes to diagnose [AIP] and each test has been negative. No genetic testing was ever received.” From that point forward, the patient “failed to keep any of the outpatient hematology clinic appointments. A month later he appeared at the ED with complaints of acute abdominal pain; “his vital signs were all within normal limits. He was discharged with three more outpatient hematology appointments, which he did not” keep.117 He then moved to Texas where the AIP cycle started again.

The Feigning Acute Porphyria paper states, “While feigning symptoms for secondary gain is common for some illnesses such as chronic pain, the presentation appears unique”118and “We found one other study with a similar presentation, in Polish.”119

Posting the link to this paper was a cheap shot aimed at “a.p. missed diagnosis” caregivers, our daughters and every other patient whose symptoms have been dismissed, minimized and ignored as well as those who’ve died from lack of appropriate medical treatment  because his/her acute porphyria was neither acknowledged nor treated.

Actually, many “missed-diagnosis” acute porphyria patients/caregivers identified with various aspects of the patient’s state of mind and body and thought it absolutely reflective of the highly skeptical attitude and indifference US medical professionals have about acute porphyria. Many “a.p. missed diagnosis” patients have had similar experiences themselves and caregivers have observed similar in those they care for. The consensus of these untrained porphyria experts was that the patient was not feigning anything, rather what happened to him is consistent with the treatment not only they but many “expert-confirmed” acute porphyria patients report they’ve been confronted with by medical professionals. It aptly demonstrated how the medical staff  are simply not equipped to handle the multi-dimensional aspects of acute porphyria nor the individuality of each patient. Neither did any of the professionals (previous or at the time the documented events) understand effective treatment—providing at minimum, IV glucose or if needed IV heme regimen until the patient’s liver is satiated enough to function well.

None of us missed the jab intended by APF’s posting of Feigning Acute Porphyria. Clearly conceived and written by highly skeptical medical professionals, the article points out many things that generations of “missed diagnosed” patients understand/understood only too well because they repeatedly experience/experienced escalating untreated acute porphyria.

The paragraph, “Clinicians should consider this diagnosis in all adults with unexplained symptoms seen in acute porphyrias especially if the patient presents with severe abdominal pain with or without constipation, muscle weakness, hyponatremia, hypertension, tachycardia, and dark or reddish urine,”120 begins appropriately enough. However, it ends on a note which, from the “missed diagnosed” patient/caregiver perspective is based on US porphyria experts’ deficient foundational information which then perpetuates medical practitioners throughout the US erroneous interpretation of the acute porphyrias’ confoundedly varied yet oddly similar presentations, diagnosis and treatment protocols.

This in turn unfortunately sustains the US porphyria experts’ Agenda—and upholds EU’s (more understandable) apparent diagnostic confirmation bias.

Assuming that the patients of the “a.p. missed diagnosis” communities “want” to have acute porphyria is a wholly inappropriate deduction made by people of intelligence who don’t actually have the complete medical knowledge they claim to have earned. This is not surprising because there doesn’t appear to be one US porphyria expert/physician who suffers with an acute porphyria or has cared for a loved one 24/7 who has acute porphyria. The Swedish doctor who saved my daughter’s life came from the “region of Sweden with the highest prevalence of AIP.” She knew AIP. She knew that glucose and hematin treatment needed to be done “until” (until the liver is satiated—and that the treatment is not meant to be taken like aspirin for a headache). She knew that AIP patients can and do sometimes present as though they have mental illness. She knew what to do when the 12 year old bedraggled youngster with exhausted parents walked into her office.  She speculated that my daughter “may not produce U-BP until late teens or early adulthood.” Unlike the US experts who’d effectively abandoned my daughter, she knew AIP.

From a “missed diagnosed” patient perspective, the Feigning Acute Porphyria patient’s presentation is heart breaking-ly familiar. Parts of it were reminiscent of my daughter’s AIP attack presentations on occasion. From our book, Purple Canary, “Once again, blood was drawn and a urine sample taken…She was given 650 milligrams of Tylenol every 4 hours and put on a drip with 5 milligrams of oxycodone hydrochloride. When asked what level her pain was on a scale of zero to ten, ten being the worst, she readily rated it a ten. Hours later, the ED report noted, “…pain still a 10 out of 10, post oxycodone. Pain is still constant.” Still early in her ordeal (pre-diagnosis), she was politely responsive to the medical personnel’s questions and submitted to their prodding and pushing tests. The records reported, “Child laying on bed, conversive [sic] and interactive,” [yet her abdominal pain was raging]. When the ED doctor decided to discharge her “[she] began sobbing and begged to stay in the hospital.” Alarmed, I took up her appeal. She was admitted, received an IV drip through the night and was discharged the next day with an appointment for a follow-up appointment with her GP. At that meeting, we were given an order for another porphyria blood test and an order for a thoracic/lumbar x-ray. 121 Subsequent recurrent pre-dx AIP episodes/attacks earned her the erroneous diagnosis of conversion disorder.

The Feigning Acute Porphyria patient’s affect also was reminiscent of a patient who has suffered with acute porphyria for decades and shared one of his stories. His mother (passed) had porphyria (type unknown). Post-HCP diagnosis, he said during a particularly severe attack he’d behaved “bizarrely,” which ended with him being arrested and committed to a psychiatric ward. There he was given “a lot of medications” that did nothing or mostly exacerbated his illness.122

That the patient in Feigning Acute Porphyria avoided hematology appointments identified with “a.p. missed diagnosis” patients, one who shared, “I can understand stopping hematology appointments. I stopped mine…they were worthless. Vital signs are always within normal limits for me aside from sometimes being tachycardic, which they do not care about. An acute porphyria attack is a weird thing for a grown man to just make up and go into a hospital to try to get help with. He knew what he needed and like we all do, tried to get help and being anxious and talking about ending his life if pain wasn’t controlled sounds pretty normal for a porph attack to me. The fact that he had records of prior attacks being treated says a lot. We all know it ain’t easy to get heme! He was probably functioning better after some heme treatments, tried to be optimistic and thought he was in remission, was stressed by the move and found himself in this awful situation.123

 “This sounds a lot like my [brother]. Very self-sabotaging. Makes statements that he’s fine but then threatening to kill himself due to pain. At first I thought [this was a story] about my [brother]. Very similar except he does have positive tests on blood.”124

“An endocrinologist I saw a few years ago espoused the philosophy of “treat the patient, not the lab work”. I forget what the term is, but if you are a physician groping for a diagnosis, and try something [resulting] in the patient [getting] better or well, you conclude that you treated the right thing. It’s a method of functionally diagnosing someone. If it walks like a duck, quacks like a duck it’s probably a duck (even with negative lab work), treat it like a duck (as long as the risks of doing harm are factored in).125

In other words, “missed diagnosis’ patient/caregivers have been there, done that. If nothing else, heme deficiency likely exacerbates the effects of other triggering (endogenous and /or exogenous) factors in acute porphyria patients. This, in fact, was Dr. Watson’s finding in 1977: “[t]here is compelling, indirect evidence of hepatic heme deficiency due to the respective genetic errors of the three inducible hepatic porphyrias, [AIP, VP and HCP]…[the] induction is enhanced by exogenous inducers such as barbiturate, estrogens and other “porphyrinogenic” chemicals and factors, including glucose deprivation.”126

  • Beyond urine—acute porphyria biomarkers

For years, maybe decades, the fallibility of urinary biochemical proof (U-BP) has been acknowledged from around the world by various porphyria experts (except in the US), yet as far as diagnostics are concerned, many of not most contemporary porphyria experts still turn to first-line urinary test results to determine if a diagnosis of acute porphyria will be pursued. The “a.p. missed diagnosis” patient/caregiver community understands that as darkened urine (ultimately supplanted by U-BP) has been a hallmark of AIP’s presence since Hippocrates’ time.

Nonetheless, in spite of having been part of the Swedish team to report that 100% of Swedish AIP patients excrete U-BP, in the September 7, 2017 Alnylam Roundtable, Dr. Eliane Sardh of Sweden nonetheless recognized that “there are several unmet needs and areas of improvement in [the]field of acute hepatic porphyria. To that, she added, “We need better biomarkers for the disease [acute hepatic porphyria] since ALA and PBG probably are just surrogate markers, and the specific levels of porphyrin precursors do not correlate to the disease severity or the risk for a patient to become recurrent.”127 That statement resounded (and still resounds) throughout the “mixed diagnosis” patient/caregiver community.

The next year, porphyria experts in neighboring Norway published results of a comprehensive study, Lifestyle factors including diet and biochemical biomarkers in acute intermittent porphyria: Results from a case-control study in northern Norway. Interestingly, study subjects consisted of symptomatic and asymptomatic patients. The objective of the study was to measure the effects of various triggering factors and diet on porphyria patient’s biochemicals (in urine, serum and plasma) and compare the results achieved from symptomatic and asymptomatic patients. Triggering agents studied included diet, nutritional supplements, physical energy expended, emotional stress, medications, alcohol, smoking, present and chronic diseases and surgeries prior to the start of the study. A total of thirty-four biomarker levels were measured and recorded including urinary ALA, PBG, total porphryins, cholesterol, triglycerides, hemoglobin, ferritin, iron, potassium, magnesium, phosphate, sodium, cortisol, epinephrine and others. Given that most, if not all, “missed diagnosed” patients rely on simple sugars as part of DIY treatment regimens, I found it interesting that the report noted “U-ALA correlated significantly and negatively with S-pre-albumin and sugar/candies intake.”128In other words, it works. “a.p. missed diagnosis” patients heartily endorse it. Besides the acute porphyrias, not many (if any, besides hypoglycemia) diseases are relieved or are resolved with sugar intake.

Dutch porphyria experts had also recognized the need for better biomarkers and developed “an enzyme assay for plasma [ALA] and [PBG] which is a more sensitive test for AIP than urine ALA and PBG analysis.”129 They also found that the combination of plasma ALA and PBG, and fluorescence scanning could be used as a screening test for AIP, VP and HCP the assays had been assessed in a “large group of subjects characterized for AIP, VP and HCP at the DNA level.”130 Notably, none of the “patients had acute porphyria complaints at analysis.”131 Further, the Dutch porphryria scientists noted that “[one] family had combined HCP and VP mutations” and “All patients who had previously had an acute porphyric attack had abnormal plasma ALA, PBG or fluorescence results in the asymptomatic period.”132

The acute porphyria “a.p. missed diagnosis” patient/caregiver are excited about the promise that Dutch porphyria experts appear to be within striking distance of “breaking the code” of the too-long-endured U-BP acute porphyria diagnostic hallmark.

Before any of these studies or comments had been made by out-of-US porphyria experts, the US Porphyrias Consortium had launched an NIH-sponsored clinical trial titled Acute Porphyrias: Biomarkers for Disease Activity and Response to Treatment. The study start date was scheduled for January 2014 though it wasn’t posted until October 2016 with the estimated study completion date slated for December 2021. The estimated enrollment was 50 “well documented” AIP, HCP and VP symptomatic and asymptomatic patients. US porphyria experts expected to measure “[e]xpression of heme biosynthetic and heat and stress response genes in potential biomarkers” for metabolites in blood, urine and stool samples.133

All study subjects had been “expert-confirmed,” meaning they’d been granted the diagnosis of acute porphyria based on U-BP. The breakout of AIP, HCP and VP subjects was not disclosed, nor was the ratio of asymptomatic vs symptomatic patients. The last update was posted on July 25, 2018. As of this writing, no outcome measures have been posted and with a completion date of December 2020, obviously, no study results are available.

US porphyria experts’ commitment to U-BP being the “gold standard” to diagnose the acute porphyrias remains steadfast. That being said, a relatively recent “maypole ribbon” contribution was provided by a gentle, intelligent and resourceful “a.p. missed diagnosis” acute porphyria patient in the form of a discovery that would surely make Dr. Cecil Watson and Dr. Freidrich Meyer Betz darn proud of his efforts and findings. It is the basis for the perhaps the most telling section in this response and follows.

  • Blood

The porphyria world owes a huge debt of gratitude to Dr. Watson whose “insatiable curiosity stimulated countless medical students to search for the why of clinical phenomena observed at the bedside.”134 However, even as he is heralded for discovering hematin and the infusion of same to successfully treat afflicted patients, for whatever reason, it appears Dr. Watson, with a PhD in hematology and pathology—and virtually every acute porphyria expert before and since neglected the importance of a critical part of the acute porphyria diagnostic/treatment puzzle. That “part” is the end product of the heme biosynthetic and bone marrow pathway mechanisms known as the “fluid of life”135—blood. To be sure, blood components (porphyrins, precursors, enzymes, particularly as in PBGD being used to determine that AIP is allegedly “latent” even as patients with “negative U-BP” are suffering with clinical symptoms equal to or worse than “expert confirmed” patients’ misery) have been mentioned throughout porphyria history. However, knowing that inherited mutated genes results in deficient enzymes that cause dysfunction in the heme biosynthetic pathway, why porphyria experts before, since and including Dr. Watson leapfrogged over blood testing (aggregate and cell characteristics) in acute porphyria diagnostics and treatment to concentrate on urine remains a mystery to us. Even the Japanese, who noted, “[e]ventually, they [blood cells] enter circulating blood and are excreted in urine and feces.”136 So, what becomes of those who aren’t excreted in urine and feces? What are the characteristics of those “enzyme deficient” blood cells? So many questions; too few answers. Not medically trained doctors/scientists, we nonetheless know that blood cells are continuously made and destroyed and that when, for acute porphyrics, the demand for new blood cell production dramatically escalates, all hell can break loose. 

Awash in the misery of debilitated physical, neurological and emotional health and weary of the decades-long erroneous insistence emanating from US porphyria experts that U-BP is the diagnostic gold standard for acute porphyria, the previously mentioned resourceful patient decided to take it upon himself to at long last prove that his illness was not “latent.” During his lifetime, this man has lost five family members to porphyria, including his mother who after twenty-five exhausting years of fighting, succumbed to pain-wracking AIP—sadly, on her son’s birthday in 2010. Having spent the better part of his youth working hard to help his father pay for his mother’s medications and other medical care, he himself began presenting with the “family disease” in 2007. Nine years after his mother’s passing, he describes his financially and emotionally bankrupt father as “still numb.” Now twelve years later he believes that HCP, not AIP controls his life; doctors weren’t able to tell the difference when his mother was suffering. He remembers, “they used her like a guinea pig; they kept trying everything possible to control her seizures and pain. With all the different doctor changes, she would forget what medications she had taken. Because each doctor wanted to start over from scratch, I began to keep a list of safe and unsafe medications. Once we learned of the APF back in the early ‘90s, I shared the list with them and told them we should start [a safe/unsafe drug list]. As far as getting any closer to APF we stopped at around 1995. I am so disheartened after all these years, APF and the US porphyria expert community has hardly done anything but push Panhematin® which killed the   woman [who’d] told us about APF and [Panhematin®]. I’d found her [porphyria patient] through the internet in about 1992 and we had contact until around 1994. Then it stopped; her son finally contacted me the next year to say she’d been given two doses of Panhematin® within four hours which had killed her. Tragic news. My mother and his mother, both nearly the same age, talked a lot on the phone like we do here and compared notes.  It did help both women and I wish it had not turned out as it did.” 137

For too long, like his mother before him, this man’s house has been his prison; his body his tormenting jailer. With the exception of his father, his family is “all dead.” Friends are long gone, save for those he’s connected with through the online “a.p. missed diagnosis” patient/caregiver community. With plenty of time to reflect on the past and dreary pain-filled present he said, “What this disease does to the body is really horrible. Each day is a challenge. It

[porphyria]

rolls through families over and over. I’m so sick of it. It’s just one endless tragedy after another rippling into the future of an entire family spreading out. It’s really bad struggling to fight when you are sick inside. You so want to just give up. So few care anymore about solving problems and mask them with pain medications. It is sad. This is America; we are supposed to overcome. [Regarding this disease, we] aren’t anymore.”138

Weary that “sitting around just waiting to die isn’t good for the coming generations,” he made the decision to “do everything I can to help turn the page to find answers for anyone with this strange disease.” With that, he remembered that before ‘I even considered I had porphyria, I’d paid someone who’d been studying blood his whole life to look at mine.” That’s when his interest in monitoring his own blood began. Then about two+ years ago, his porphyria raging, he with met someone who, “did a live microscopy of my blood with a scope. He told me that my white blood cells were not attacking the viruses and being very dormant.”139 Interest renewed, he purchased his own digital microscope and began to periodically monitor his own blood cell activity during and outside of attacks—something no doctor or expert had ever suggested be done for his mother or himself. What he’s found is forehead-smacking—strangely misshapen blood cells.

Occasionally, others in our patient/caregiver community had shared information of reports of misshapen blood cells that had been shrugged off by hematologists, internists, etc. Before she was DNA diagnosed with AIP, my daughter’s hematologist informed us that her red blood cells were oddly-misshapen, “but I don’t know why.” Other patients described similar reports—one whose blood cells at the time of collection were lemon-shaped (sharp on both ends). She shared the memory, “the doctor who showed me my lemon shaped red blood cells, a world-renowned MD and HMD, seemed extremely taken aback by the appearance of my blood and remarked that I must be anemic, but I’m not. Not in the traditional sense anyway. He seemed very upset and shocked by what he saw, so much so that he showed me and I’ve never forgotten it.”140 She said she’d learned from an “expert-confirmed” AIP patient that the individual had seen a physician decades earlier who, when told s/he’d been diagnosed with AIP, had quipped “Ah, Caucasian Sickle Cell!” The expert-confirmed patient also shared s/he’d recently been asked by APF to write a paper about that encounter so it could be presented during a conference call between APF and a Sickle Cell organization “to discuss our mutual problem of extreme pain.”141

The following article was published in APF’s 1st quarter 2019 newsletter, titled, Sickle Cell Disease and Acute Porphyria:

“APF was asked by the government Pain Task Force to participate in a conference call with the Sickle Cell Organization to discuss our mutual problem of extreme pain. Sickle cell disease is an inherited blood disorder marked by flawed hemoglobin. Sickle cell, like the acute porphyrias, is an excruciating group of diseases that involve heme. Normally, hemoglobin allows red blood cells to carry oxygen from your lungs to all parts of your body. Normal red blood cells are smooth, rounded, flexible and can flow freely. In Sickle Cell disease, when these red blood cells lose their oxygen, they become rigid, sticky and misshapen, like a sickle, and live only 10 days as opposed to the normal 120 days. These sickle-shaped cells obstruct capillaries and restrict blood flow to an organ resulting in pain and other serious damage. The crises are extremely painful and often require pain management with opioids.”142

The article prompted the a bit more research and the following short comparison of similarities by our “a.p. missed diagnosis” patient/caregiver “investigating blood team” of the two conditions:

Sickle Cell Disease                                          Acute Hepatic Porphyria

Inherited                                                         Inherited

Molecular disease                                            Molecular disease

Involves hemoglobin—oxygen                       Involves hemoglobin—oxygen transporters transporters of the body                                    of the body               

Abnormal hemoglobin protein identified       Hemoglobin studies unknown (or unreported)

  (1948)                       

RBCs lose their oxygen; “de-oxygenated,”    Documented problematic oxygen-heme binding

 they become rigid, sticky & misshapen         No data re RBC characteristics after heme

                                                                        biosynthetic pathway

RBCs live only 10 days as opposed to 120    Unknown (or unreported)

Sickle cell shape obstruct capillaries and        Condition/shape/volume unknown (or unreported)

    restrict blood flow to organ(s)                    Porphyrin/precursor shapes unreported

    resulting in pain/ other serious damage       Resulting damage to organs, etc. unknown

Crises are extremely painful; often require     Chronicity and crises are extremely painful;

      pain management with opioids.                            require pain management with opioids.

Drug developed to prevent SCD (1995)        No drugs to prevent AHP

While it is remarkable that Sickle Cell Disease (first characterized in the US in 1910) and the Acute Porphyrias (first publicized case ~1899) have several similarities, it is mind-blowingly sobering to see in “black and white” that information about acute porphyrias’ blood cell characteristics in this day and age is so severely lacking. Given that Dr. Waldenström, “father of AIP,” was considered to be one of the giants of hematology and that Dr. Watson’s “pioneering scientific work [was on] the metabolism of hemoglobin, porphyrins and bile pigments,”143it seems odd that the resulting product of the acute porphyrias—blood—hasn’t been granted the respect it surely deserves. Other than to use it to deem AIP’s latency (erroneously as it turns out in some cases), why scientists were smitten with shiny objects (aka excreted) metabolites that for generations have been given preference time and again over the blood cells that had been churned through the heme biosynthetic pathway and entered the circulating blood versus those that had been “spewed out of” the pathway is staggering.

Intriguingly, the APF co-founder/director wrote multiple times throughout her book of having blood drawn before, during and after the life-threatening attack that precipitated her AIP diagnosis. She recalled a time, evidently about 20 years after that life-altering event when unrelenting porphyria pain sent her back to her internist where she was informed that, “my blood was not as oxygenated as it should be.”144 She was admitted to the hospital where she learned that “[medication] had compromised my breathing. In addition, my feet were terribly swollen, and I was having difficulty urinating….these symptoms paled in comparison to the tremendous pain…I lay in bed for days on end almost out of my mind with pain. The IV of morphine did not make a dent in the agony. The doctors had to be extremely careful as my oxygen level with dangerously low and could decrease even more from [medication] use.”145 Which raises an obvious question, why had she not been administered supplemental oxygen—even at very low levels? It is highly unlikely that this had not been reported to APF SAB members; the APF co-founder writes that Dr. Anderson (SAB chair) intervened and “assured

[the attending doctor]

that I had endured 20 years of intermittent pain and almost never asked for prescription drugs [she had asked for morphine].”146 So we know that the APF SAB chair had some involvement—yet didn’t think that arterial blood gas analysis might be an informative measure to determine influencing acute porphyria activity? Or, most likely, the US porphyria Agenda had taken precedence. Oxygen deficiency can be a very real problem for acute porphyria patients. In my ‘mom’ opinion, it seems most likely in concert with heme deficiency and can be assuaged with supplemental oxygen. In fact, supplemental oxygen alone has been used by some “a.p. missed diagnosis” acute porphyria patients to relieve symptoms and/or to head off attacks

Because she’d continued to have intermittent breathing problems/respiratory distress, I’d asked my daughter’s various doctor(s) to get an arterial blood gas baseline then to monitor it during AIP problems. My requests were dismissed.

It is telling that APF’s scientific advisory board (SAB) has long been weighted to MD gastroenterologists and MD hepatologists and (very) light on MD hematologists, MD biochemists, MD endocrinologists, MD  neurologists, MD pathologists,  MD pediatricians—to the point of non-existence of the several latter specialties. So it is not surprising that only four papers by-lined by APF/SAB members addressing the blood/acute porphyria connection turned up in a search. Though vintage, Blood Volume and Bilirubin Production in Acute Intermittent Porphyria is by far the most informative for sleuthing patients/caregivers. While the focus was on bilirubin production, it also provided some snippets that “a.p. missed diagnosis” patients/caregivers might share with their own physicians/hematologists who are generally appreciative of receiving this type of information, if only for a “starting point:”

  • “[m]ean blood volume in thirteen AIP patients was 80 per cent of normal;
  • “the total blood volume and total red-cell volume in AIP patients were significantly reduced from normal values, whether compared as an entire group or by sex;
  • “bilirubin is a product of heme degradation;
  • “changes in the bilirubin production rate closely paralleled changes in the red-cell volume;
  • “effective erythropoiesis is frequently decreased in patients with AIP;
  • “the decrease (of erythropoiesis) is of variable magnitude and will not be detected by routine hematologic studies since the hematocrit is not reduced.”147

Ironically, this thoroughly focused paper on blood components relating to acute intermittent porphyria paper was based on AIP patients selected because they had “[demonstrated] increased urinary excretion of porphobilinogen (PBG) which was measured by the method of Marver et al.”148 No investigation of blood characteristics was even considered. However, the point about decrease in erythropoiesis not being revealed in hematocrit readings is important and raises the question—can that be tracked, and if so, how?

The only other paper with an APF/SAB member by-line that actually addressed blood components in acute porphyria was the more recent (2013) Heme status affects human hepatic messenger RNA and microRNA expression, researched and published by APF/SAB member Dr. Bonkovsky and research team. However, the apparent reason for that research, which was supported by a grant from NIH/NIDDK, was to assist Alnylam/APF in achieving success for its product, Givosiran.

The last two papers’ titles allude to providing information pertaining to blood regarding the acute porphyrias. In actuality, the focus of both Neurovisceral Porphyrias: What a Hematologist Needs to Know by Dr. Bonkovsky and research team and What Hematologists Need to Know About Acute Hepatic Porphyria by Dr. Balwani is the “US-obligatory” enzyme deficiencies, biosynthetic pathway (blood building process) agenda with emphasis on urinary output and heme pool repletion with hematin. To be fair, Neurovisceral Porphyrias: What a Hematologist Needs to Know did address erythrocyte PBG and plasma porphyrin levels as “second-line testing” to be done “If the [urinary] porphobilinogen level is increased….”149 However, his discussion of erythrocyte PBGD and AIP was probably more than a hematologist would expect—and less than what s/he really needed/wanted: “Worthy of emphasis is that about 10% of patients with AIP have normal erythrocytic PBG deaminase levels. There is a single gene encoding PBG deaminase, but erythroid cells utilize different promoters and transcriptional sites than hepatocytes and other cells. As a result, the erythrocyte enzyme lacks the amino terminal residues encoded by exon 1. Therefore, in the 10% or so of patients with AIP who have mutations in exon 1, erythrocytic PBG deaminase activities are entirely normal. Another limitation is that there is a large range of variation in activity of the enzyme, and there is an overlap between normal and carriers of the deficiency.” 150

Interestingly, Dr. Bonkovsky noted in the Heme status affects human hepatic messenger RNA and microRNA expression paper that he had been led to “to develop heme as a potential therapy for acute porphyria in relapse.”151 This apparently was a reference to case thirty or so years earlier in his career when he worked for the NIH Public Health Service under Dr. Tshudy, who would go on to become an inaugural member of APF’s SAB. The case bears sharing here as an analysis of the case had been documented in the paper, Repression of the Overproduction of Porphyrin Precursors in Acute Intermittent Porphyria by Intravenous Infusion of Hematin which describes how the patient presented at the NIH Clinical Center in late February 1971 with an attack that had started earlier in that month. By report, at the time she was excreting “a large amount of PBG.”152 For the next month or so various treatments (medication, high carb diet, insulin, supplements) were tried with no improvement until the patient’s condition “slowly but inexorably” deteriorated; “she became bedridden and totally incapable of self-care.”153

By April (a month and half after admittance), due to continued deterioration (dysphagia, inability to clear broncho-pulmonary secretions) a tracheostomy was performed and continuous ventilation provided. Intravenous hematin was started in mid-April, 250 mg amounts were given twice daily three days in a row; one of those days, two doses were given, “in part subcutaneously. There was no apparent clinical response.” Within a day or two, the patient developed “acute gastric bleeding;” a gastrectomy was performed which was followed by “severe renal failure.” In response, peritoneal dialysis was done; the patient “became totally anuric [unable to pass urine]…[then] became comatose and developed opisthotonus. Hematin was resumed “on May 7, again, without clinical response…[t]he patient died on May 29 [almost 3 weeks later], of profound central nervous system failure attributed to acute porphyria and uremia.”154 Unfortunately, it appears that a scientist mindset appears to have overridden the physician’s creed throughout this poor woman’s final AIP battle.

Forty-four years after the scientific review of the case had been released to the medical world, APF’s 1st quarter 2015 newsletter featured an article authored by Dr. Bonkovsky about the case, titled DR. BONKOVSKY CREATES HEMATIN.

The APF SAB member recounted his perspective of the NIH team’s three month long attempt to battle AIP in 1971. Having only been associated with NIH’s Public Health Service for a year or so at the time, Dr. Bonkovsky’s account definitely leaned toward the scientist side of the equation. His report of that account states that [a month and a half after the patient had been admitted and after numerous therapies had been tried to improve her condition] he’d “proposed to Dr. Tschudy and other senior leaders of our Branch that we should try giving her heme intravenously, in hopes that some of it would find its way into her liver cells and perhaps other cells that were deficient in heme and were over-producing ALA and PBG….”155

            His proposal to Dr. Tschudy questions his understanding at the time that a “revved-up” HBP mechanism, not the liver and other cells, was responsible for the “over-produc[tion]” of porphyrins/precursors. Nonetheless, I do applaud the first part of that thought, “some of it [heme] would find its way into her liver cells and perhaps other cells that were deficient in heme,” as that had been my thinking for so long—not just repleting the heme pool—but replacing cells (porphyrins and precursors) with donated, “normal” blood cells.

In any event, that is when Dr. Bonkovsky’s APF newsletter recount of the 1971 case turned to a scientist’s enthusiasm of “creating heme.” The NIH is a hospital dedicated to clinical research; it is highly unlikely that Dr. Bonkovsky worked alone but more than likely was one of a team of interns, residents and others in this endeavor. That being said, his perspective of the fatal 1971 case’s hematin story follows:  

“Accordingly, I obtained several pints of outdated blood from the blood bank of the NIH clinical center, and I set out to purify and crystallize hemin chloride from these units of blood. The purification involved several steps, including eventual crystallization of the product from boiling acetic acid. I worked all day and all night, and by the next morning, I had beautiful, extensively washed and purified crystals of the desired product. The final yield was about 1,000 mg of hemin chloride. Of course, we had no real idea of what the right dose would be for patients with AIP, but, based upon the results in rats, we believed that 3-5 mg per kilogram body weight would be reasonable. Our patient weighed about 60 kg, so we decided to administer 250 mg every 12 hours in our initial study. The next challenge was to redissolve these crystals in an aqueous solution, suitable for administration to humans. Hemin is not very soluble at physiologic pH [7.4], but it is soluble at high pH. I decided to dissolve the precious crystals into a solution of 1% sodium carbonate, which has a pH of about 10-11. I was able thus to dissolve the 250 mg [about 10 ounces] of hemin in 25 mL of the sodium carbonate. Heme at this pH is actually in the form of hydroxy-heme, with OH – anions replacing the Cl – ions, and this form of heme had been named hematin by Hans Fischer, MD, PhD, the outstanding pioneering German chemist, who had won the Nobel Prize for chemistry in 1930 for his work on pyrroles, porphyrins, and the chemical synthesis of heme. Thus was hematin for human use first born.”156

Actually, Dr. Watson happened to have worked with and learned directly from the highly venerated organic chemist Dr. Hans Fischer whose studies of hemoglobin fueled synthesis of hemin.157 However, it was Dr. Cecil Watson who is rightfully recognized for developing hematin.158 Dr. Bonkovksy continued, “After dissolution, the pH was adjusted downward slowly and carefully with hydrochloric acid to a final pH of 7.5, and the final solutions were put into brown vials for immediate administration. We felt the latter was important because it was known that hematin in aqueous solutions undergoes rapid ‘aging’ reactions, with formation of polymers and degradation products that may not have the desired therapeutic effect and that also may cause adverse effects. The biochemical effects of the first four infusions, 250 mg given every twelve hours, on April 13 and 15, 1971, were dramatic, with marked decreases in urinary and serum ALA and PBG. Unfortunately, in this woman who had been severely ill for months and, by now, was totally paralyzed, we did not observe clinical improvement. Nevertheless, it seemed worthwhile to treat her with additional doses of hematin. Thus, for the next several weeks, I spent all day and most of the night, purifying, crystallizing, and preparing hemin chloride for further infusions. We gave several more infusions of hematin to the patient during the next month or so, with further strongly positive effects of decreasing levels of ALA and PBG, both in the serum and in the cerebrospinal fluid. (By this time, due to the ravages of AIP with severe systemic arterial hypertension, acute on chronic renal disease, and superimposed sepsis, the patient had developed severe kidney failure and had stopped making urine. We reported these findings, so that other physicians and scientists around the world could benefit from our experience and could further test the effects of hematin earlier in the course of acute porphyric attacks. I finished my two-year appointment at NIH in June, 1971.”159

Note: “severe systemic arterial hypertension” is emphasized by this author to call attention to the need to identify de-oxygenation during acute porphyria activity—and to the need to recognize one of the most basic (and critical) efficacious components of acute porphyria treatments.

Five years later after that 1971 ill-fated AIP battle, three of Dr. Bonkovksy’s co-authors of Repression of the Overproduction of Porphyrin Precursors in Acute Intermittent Porphyria by Intravenous Infusion of Hematin (Bosssenmaier, Cardinal, Watson @ Abbott-Northeastern Hospital, Minnesota) published another case of “a young woman with acute porphyria in profound relapse.” This time, earlier intravenous infusions had resulted in “remission of symptoms and rapid recovery to the point “that she was able to leave the hospital in less than a month.”160 Interestingly, this team completed “[s]erial studies of serum and urinary levels of porphryin precursors and serum level of hematin provided highly important information about the effect of hematin on acute porphyria.”161 [Note: Emphasis author-added.] At least adding serum testing to the mix was a start. The scientists published a paper about this hematin success, Hemin Treatment of Acute Porphyria: Early Remission of an Almost Fatal Relapse.

Six years passed between that experience and APF’s founding. Dr. Bonkovsky makes note of other physician-scientists, particularly [those] in Minneapolis and explains how they came to use hematin early in attacks of AIP with excellent results. To that end, it is fairly obvious that the APF scientific advisory board of porphyria experts had knowledge of this and other successful reports so one is left to wonder if the reference to serum testing was intentionally overlooked—and why, with knowledge of the APF co-founder’s bout with “dangerously low oxygen level” arterial blood gas investigation hadn’t been moved up on the acute porphyria diagnostic—or treatment—scale.

The most recent of those four papers by an APF/SAB member (actually it is an interview with Dr. Manisha Balwani of Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences, and the journal Hematology & Oncology about hematology aspects relating to the acute porphyrias. Coordinated eleven years after the publication of Dr. Bonkovsky’s Neurovisceral Porphyrias: What a Hematologist Needs to Know paper, Dr. Balwani’s interview What Hematologists Need to Know About Acute Hepatic Porphyria, too, pushed the heme biosynthetic pathway agenda through and through. With the exception of the mention of “half-normal” enzyme activity and Panhematin® treatment, no blood components or measurements were discussed. Not being a hematologist, but having spent many hours over years as a “a.p. missed diagnosis” acute porphyria patient’s caregiver in the company of hematologists, I surmise they would probably have preferred learning more about the blood effects of AHPs.

The Caucasian Sickle Cell conversation with “expert-confirmed” acute porphyria patient and the APF article reverberated with the “a.p. missed diagnosis” patient’s recollection of her own “lemon-shaped” cells and other patients/caregivers’ reports of “weird blood” lab reports. Theorizing that Sickle Cell Disease and Acute Porphyrias might have more in common than excruciating pain, she and the aforementioned amateur lab analysist/patient put their heads together and another theory brewed. What if those genetically-based enzyme deficiencies, blamed for heme biosynthetic pathway dysfunction in the acute porphyrias similarly resulted in impaired blood cells?  Wouldn’t that cause pain?

For your review, following are several samples (albeit not “certified lab” approved) of this not-professionally-trained scientist’s own blood cells photographed on a digital microscope. Note the remarkably-odd shapes, positions and distributions of blood cells. Given the IEM nature of acute porphyrias who’s to know if taken in the same sequence at different days/times would show similar—or worse characteristics? He submitted several photos (in no particular order, time and/or date not identified) of his own blood samples for review:

Desperation motivated (and still motivates) this individual to “test on myself until I can find an answer to solve this [missed diagnoses] problem. I feel I am getting closer and with God’s help and a few others in this group, I think I can.” With the death of his mother and other bio-family members’ ever present in his mind, his commitment is unambiguous, “It just depends on His will and what strength I have each day to get up to fight again. I may die doing it but at least we can know more and my sacrifice won’t go unnoticed in this Godforsaken world.”162

This gentle man has never experienced the benefit of infused Panhematin® as my daughter and others have so he has not been able to “check” his blood samples before and after such treatments—as surely he would. And yes, we are aware that Panhematin® has had involvement with deadly effects on true acute porphyria heroes—unintended human guinea pigs. Dr. Watson and Dr. Bonkovsky bore witness to such, but evidentially neither thought to investigate the before/after blood effects. The question is, are some of these blood cells misshapen because of acute porphyria, or are they the product of another (others) condition(s)? Seems coincidental that the report of misshapen cells from patients (through their doctor) is purely coincidental.

Given my daughter’s experiences and my observations, my theory about Panhematin® is that it works because donated “normal” blood cells (that is, fully formed with adequate oxygenation and other components) replete the heme pool. That acute porphyria blood cannot be guaranteed to be “normal” at all times is probably the reason why, generally speaking, porphyria-patients aren’t preferred blood donors.

Thanks to my having just read Rachel Carson’s Silent Spring chapter about cellular oxidation and my having a medical article on hand in the hospital about the AIP heme/oxygen binding “problem,” my daughter and I long ago also performed an (unintended) experiment.

It happened in the hospital when my daughter was being administered Panhematin® but her severe attack wasn’t seeming to be responding as had always happened previously With only a short time left to go of the Panhematin® treatment, I finished reading the chapter, showed the attending doctor the paragraph I was reading and the medical article and begged him to administer supplemental oxygen to her immediately. He complied. The supplemental O2 switch on through the remaining IV glucose post hydration, my daughter responded famously. We left the hospital within 15 minutes of the post-treatment IV glucose finishing, her walking upright, with good eye contact, appropriate response to conversation and without the usual after-hemin complaints of severe aches and pains. I then shared the experience, the Silent Spring chapter and the medical info with her hematologist. From that point forward, supplemental oxygen (via face mask) during IV glucose w/ ½ NS + 10q KCL/L at 150 ml/hr and/or IV Panhematin® treatments became the norm. The supplemental oxygen suggestion has benefited other “a.p. missed diagnosis” patients, for which we (and they) are thankful.

Perhaps if all those decades ago the porphyria experts had thought to check the APF co-founders blood before, during and after her life-threatening attack instead of focusing solely on U-BP, the non-profit patient advocacy and physician education organization APF would have followed a different path and truly would today be able to say with integrity, “dedicated to improving the health and well-being of all individuals and families impacted by Porphyria.”163 [Note: Emphasis author-added/intended.]

 Surely, building on these findings and theories presented herein, trained, interested and porphryria experts—absent the US-agenda will be encouraged to at long last take leaps beyond Dr. Cecil Watson’s marvelous discoveries. Doing so just might turn the long-held acute porphyria diagnostic “gold standard” into “fool’s gold.”

•     “Latent” vs. “Asymptomatic” vs. “Misdiagnosed

When asked to describe what acute porphyria is to them; “missed diagnosed” patients/caregivers replies included: “severely lacking quality of life;” “a living hell;” “a life shredder;”  “never being believed—by anyone;” “like being in a weird ‘Alice in Wonderland;’” “not understood;” “doctors acting like I’m crazy;” “excruciating, mind-bending pain, and more pain, vomiting, heart racing like crazy, not being able to breathe, brutal, just brutal;” “like wrangling unicorns;” “horrible;” “praying that the next attack won’t be my last—but will be the one when I finally pee pbgs;” “ERs, hospitalizations, no answers, no help, no interest;” “being told over and over that everything is normal—but I know it isn’t;” “being treated like or talked to like you’re a hypochondriac, a junkie or mentally ill;”  “being treated with contempt by doctors, families;” “involuntary commitment to psyche wards—the worst;”  “very isolating, very scary and very, very painful;” “seeing umpteen doctors who just don’t give a f-ck, don’t give a shit, don’t listen, don’t believe you, just don’t care;” “losing friends, jobs, life, self;” “the experts say that acute porphyria can become chronic. What they (experts) don’t get is that acute porphyria chronicity develops early—especially when left untreated. They just really don’t know what it’s all about, do they?”164 According to one discerning non-U.S. porphyria specialist, “Porphyria is as bad as cancer.”165Yet when it comes to receiving adequate attention, acute porphyria doesn’t seem to be on any medical/agency radar. As long as information like the following is sanctioned by European porphyria experts, it won’t be: “It is important to know that ~80% of people who have changes in their Porphyria genes (called mutations) never have symptoms of the acute Porphyrias. These people are said to have ‘latent acute Porphyria.’”166  “If urine ALA and PBG are normal during an attack, it essentially rules out an acute porphyria.” 167

The foregoing represents an undisputable disconnect between “missed diagnosed” patients and porphyria experts’ understanding of latent and asymptomatic. The most recent (2012) medical dictionary defines “latent” as, “[n]ot manifest, dormant, but potentially discernible” and “asymptomatic” as “[w]ithout symptoms, or producing no symptoms.”168

At one point or another, both terms have been applied to my daughter and many if not most (or all) of those in the “missed diagnosed” patient/caregiver community. Clearly, all US and most EU porphyria experts consider “negative” U-BP (not making the grade) to be an indication that a patient’s acute porphyria status is dormant, completely dismissing the “potential discernable” aspect of the definition. Similarly the “asymptomatic” has been applied to too many patients whose horrific suffering is routinely minimized, as IPDMC authors did when writing, “symptoms and signs may mimic other, more common conditions…”169 or in denying that what they suffer (often requiring ED, clinic or hospital admittance) are not attacks because the patient didn’t excrete, collect or test positive for U-BP.

APF’S co-founder did exactly that in an email response to me following Facebook communication she’d had with my daughter after her diagnosis had been revoked in which the girl’s obvious distress had been evident. The APF director stated ,  “I feel badly for you as you are back at square one…you might want to contact the best of the experts in Europe [because I’d already communicated with a Swedish porphyria expert at which Dr. Desnick obviously took offense] and ask them about [your daughter’s] situation…It is so hard. As I mentioned to her with 7000 rare diseases, it can be very difficult to obtain a diagnosis. We have several patients in the same situation with DNA but no attacks.”170[Note: “no attacks” is intentionally author-emphasized.] She essentially said my daughter did not have porphyria attacks. Remembering that the APF co-founder had described experiencing debilitating “Porphyria” activity and attacks for years before ingesting the Dilantin that prompted the attack that produced U-BP in her memoir, I was more than dismayed. But we weren’t alone. This individual’s contemptuous comments had been heard before—by patients that the APF co-founder/director and/or SAB members had dismissed as having been “misdiagnosed.” Many, if not most of these patients had attacks—but no (or low) U-BP.

Patients who’ve approached the APF for help, reporting they’d been “fine,” “normal” until “the symptoms” inexplicably struck and included excreting “weird, darkened urine (collected, tested and met U-BP parameters) were welcomed with open arms into the non-profit’s fold. So, too, were the ones who reported they’d taken (or been given) medication(s) that resulted in worsening symptoms—and excretion of “weird, darkened urine” that had been collected and tested positive for porphyria. However, others reported a more concerning case history—“sick [sometimes] since I was born” or “since I can remember,” “no doctor could find answers,” “horrific childhood,” “sick all the time,” etc. These seldom included mention of odd-colored urine and if it did, the color range noted was wide—from pink-ish to orange-ish to cola-colored—and generally were not collected or tested. But while the patient reported ongoing “sickness,” massive quantities of excreted U-BP

[and collected]

was elusive. Those were/are the ones dismissed. What resulted was a divide between the patient groups—one that grew wider, deeper and more acrimonious as the years passed.

A few years ago, “expert-confirmed” AHP patients began approaching the closed “a.p. missed diagnosis” patient/caregiver online forums. Many were simply curious, not understanding why someone who didn’t excrete U-BP would even think they had porphyria. Some came with a purpose—to push the APF agenda (thinking they were doing the closed forum participants a favor).  More than a few came to bully, some through private messaging, and did incomprehensible damage to people who’d already been damaged by the APF “machine;” they were met with blazing, protectionism responses. More recently, some “expert-confirmed” AHP patients, apparently realizing that individuals within the “a.p. missed diagnosis” patients/caregivers communities provide helpful ideas, tips and information based on experience generally (but not always) centered on communications with their own clinicians (if they have them) be it MDs, NDs, ODs, etc. and/or research obtained from the wealth of information published by porphyria experts throughout the world, have begun to do likewise.

SUMMARY—Questions Galore, Still

 Every single “a.p. missed diagnosis” patient’s story deserves to be told to and/or read by porphyria experts. These patients are survivors. Wrenched out of society by a wretched illness that refuses to show itself within the highly fallible, narrow guidelines set by experts whose refrain is “that’s the gold standard,” each has become a self-researching, self-study subject by necessity. Enmeshed in pain, despair, fear and destitution each uses his/her own body’s reactivity to guide him/her through each and every day and night. Carrying the burden of society, family, self-loathing, each bears his/her angst and discovers all he/she is able concerning acute porphyria(s), the body and their own seemingly ever-changing physical/neurological responses in order to attempt self-treatment so they could live. another. pain-filled. day. another. woeful. week. another. depressing. month. another. miserable. Year—all the while remembering and mourning the life he/she lost. For these hapless patients, most days end up being experimental undertakings.

 “a.p. missed diagnosis” patients didn’t get to live because of APF and its SAB’s paltry agenda-driven studies and medical information; they lived (and survive) in spite of APF et al’s indifference and not-infrequent interference. These patients (and their caregivers, if they have them) do the best because they’ve fought (and continue to fight) to know the most. Scorned by the US non-profit “dedicated to improving the health and well-being of all individuals and families impacted by Porphyria,”170 we lean on each other’s compassion and sharing of experiences—and  information provided in porphyria studies from the truly worldwide porphyria expert community.

To that end, the “a.p. missed diagnosis” community offers kudos and thanks in particular to porphyria experts in Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Colombia, Czech Republic, Denmark, Finland, France, Germany, India, Israel, Italy, Japan, Nepal, The Netherlands, Norway, Poland, Romania, Russia, Saudi Arabia, Singapore, Slovakia, South Africa, Spain, Sri Lanka, Sweden, Switzerland, United Kingdom and early United States (pre-1980s), Venezuela and so many more for publishing useful, explanatory research findings.

Porphyria experts in these countries have served as the “a.p. missed diagnosis” community’s de facto doctors—and has helped (and still helps) patients/caregivers navigate pain-drenched and perilous existences.  Among the points that the “missed-diagnosis” patient/caregiver community find irritating is that many, if not most, US reports, speeches, etc. about acute porphyria inevitably include statistics (prevalence, incidence, symptoms, etc.) from European sources—about Europe. Never any US statistics—or information beyond what APF’s experts “say.” To that point, is a 2017 report from Cancer Therapy Advisor written by a member of APF’s SAB. Interestingly, though the obligatory US portrayal of the heme biosynthetic pathway was included, CRIM subtypes were discussed. I found the next sentence to be typical of APF SAB communications, “The occurrence of type II explains why only ~95% of all AIP subjects have decreased erythrocyte PBGD activity.”171 Note, the emphasis on “only” was author-added because 95% is a significant number; it is misappropriate to attach “only” to it—particularly where genetics are concerned. Besides, it doesn’t match the ~90% reported in the Porphyrias Consortium’s Rare Disease Network chart as HMBS activity in RBCs mentioned on page 17 of this response. 5% is a considerable difference and we have figured out that the 90 or 95% number plays better with keeping the US-Agenda going. We believe the number (or percentage) of AIP patients with normal (or perhaps, increased) PBGD erythrocyte is only ~5% should be the accurate portrayal.

As noted at the beginning of this response document, the reason this “a.p. missed diagnosis” population exists—at least in the US—appears to be to insure that the acute porphyrias stay within the parameters of NIH’s rare disease category. This helps achieve/maintain FDA orphan drug status for the medications APF has partnered with pharmaceutical companies to treat acute porphyrias. This thinking quite likely began with the APF/Abbott Laboratories’ Panhematin® partnership and carried through to the current APF/Mount Sinai/Alnylam partnership. This was all but confirmed in Alnylam Pharmaceuticals’ Q2 2018 Results’ Earning Call (August 2, 2018) during an interchange between an Alnylam executive and an investor analyst. To wit: the analyst asked Alnylam about the “potential opportunity” that is a “patient queue that’s building”172 [re Givosiran]. The Alnylam executive replied, “…let me emphasize that porphyria will remain an ultra-rare disease, we believe, and our key is, within an ultra-rare, frankly, to find everybody…we’ve been working with the porphyria network to strengthen the next set of physicians that are coming up and looking for the disease, younger, kind of, more aggressive types that are going out to the community to educate and we’ve seen good uptake with that.”173

The latter part of that response alludes to APF’s Protect the Future program which, according to APF’s website, as of this date comprises eighteen (18) PTF doctors. This is concerning. Several current APF SAB members actually worked with/for porphyria experts from an era of integrity, honesty and absolute credibility—a few of whom were also members of APF/s SAB at various (and relatively short) times. Unfortunately, what the “a.p. missed diagnosis” patient/caregiver community sees happening is manipulation of these younger/ “newer” doctors’ thought processes and/or discouraging inclinations to research anything outside the “US Acute Porphyria Agenda.” This, of course, defeats the purpose of performing traditional clinical research in concert with practicing patient-centered medicine. Combined with the nineteen (19) scientific advisory board members, that’s thirty-seven (37) physicians putting emphasis on the heme biosynthetic process of building red cells and being taught that Panhematin® is the rescuer to treat acute porphyrias. My daughter and the Australian woman’s daughter can attest to that. They can also attest to Panhematin® efficacy as a panacea for heme deficiency. However, while it is true many lives have been saved thanks to Panhematin®, the drug has also had its problems. In our opinion, continuing to put together research studies about Panhematin® (which may include APF PTF doctor/researchers’ participation) as APF SAB chair, Dr. Karl Anderson is planning yet another (Panhematin® Prevention Study)—without in-depth research on the full range of acute porphyria patients’ biomarkers, including enzyme assays (HMBS, CPOX, PPOX, etc.) and patient’s blood characteristics is pure folly and in our opinion, only being done with the intent to insure the US Acute Porphyria Agenda endures.

Perhaps one of the better quotes said about the acute porphyrias that the “a.p. missed diagnosis” patient/caregiver community can relate to and endorse was stated by Dr. Balwani in her interview with Clinical Advances in Hematology & Oncology, “One important thing to note is that no sign or symptom is universal and presentations are often atypical.”174And yet, presentations “atypical” from the “gold standard” isn’t accepted in US porphyria experts’ agenda—in which APF PTF doctors receive their “training.”

The acute porphyrias continue to take tremendous financial toll on people, families, communities and societies. As quintessential physician/scientist Dr. Sardh of Sweden said a couple of years ago in an Alnylam Roundtable Session, “We still have very limited knowledge of the pathophysiology of the disorder as well as the natural history.”175 This, coming from Sweden—AIP epicenter, no less—where surely, there must be some Swedes who, like the one Dr. Waldenström observed so long ago sometimes don’t excrete U-BP but do exhibit a.p. activity or attack symptoms. It is to be noted that the venerable Dr. Waldenström did not disregard or comment that the patient was thought be “feigning” acute porphyria as heard too often in the US. If nothing else, APF has succeeded in spreading the word that acute porphyria is RARE. Unfortunately, many physicians and specialists are inclined to put RARE conditions into the too-hard basket.

Many patients in our “a.p. missed diagnosis” communities have serious illnesses in addition to acute porphyria. It is an extremely delicate balance to manage but most agree that knowing what they are dealing with and keeping the acute porphyria aspect of their illness contained as best can be done (especially when working with medical providers for treatment, i.e. surgery/medications, of the other illnesses) makes a huge difference in their quality of life.

They’ve come to know their individual body’s extreme sensitivities to chemicals, even certain medications that APF labels “safe” including vaccinations, “shots” e.g. tetanus, flu, etc., alcohol/preservatives used in injectable meds; foods (natural and added chemicals); anything that contains a sulfur ion; meds that are known to reduce cellular oxygen (heparin), supplements (like vitamin Bs, C, D, E, glycine, niacin, magnesium, melatonin, folic acid)—even in minuscule amounts, stress, exercise, toxins—again, even in the minutest amounts, including plastics/rubber in medical devices and the dreaded scented products. For the most part, they live by NAPOS’ porphyria drug list and have learned to dose-down everything to start, even in the safest of meds. Vials, ultra-mini tablets, sublingual applications—to survive, they essentially live Dr. Archibald Garrod’s chemical individuality concept every single day. Dangerous? Perhaps, but what choice did/do they have?

If one wants to know the devastation that untreated acute porphyria has on the human body, “missed diagnosis” patients are sources just waiting to be tapped—most are eager to submit to DNA and other acute porphyria testing—without a US or Alnylam bias.

This paper, in response to the IPMDC announcement was prepared with the intent of sharing findings from our community and to appeal to the greater worldwide porphyria expert community to review—and God willing, to act on them. For consideration, we’ve offer the following concerns and suggestions for the worldwide porphyria expert assemblage’s consideration:

  1. overall, US “a.p. missed diagnosis” patient/caregivers report dissatisfaction with diagnostic test report results received from “certified” laboratories and express concern about possible manipulation of testing results (DNA, U-BP, F-BP, enzyme assay (PBGS, HMBS, CPOX, PPOX));
  2. deeper investigation and resolution of the oligogenetic nature* of the acute porphyrias and what impact that may have on symptom presentation, testing, treatment modalities is warranted;
  3. investigation and resolution that a “retention” or “inhibitor” gene or genes may indeed contribute to the silencing of PBG excretion;
  4. efficacy of PBGS, PBGD, CPOX, and PPOX enzymes as biomarkers to gauge acute porph activity/attack and need for treatment;
  5. to that end, getting a better understanding of HCP, VP, and ALAD prevalence and while recognizing that each case is unique, identifying nuances (similarities) for each of these acute porphyria manifestations is imperative;
  6. deeper investigation and resolution of porphyrin/precursor whereabouts for those that make it through the heme biosynthetic pathway mechanism and 1) enter the blood stream, 2) are lodged in tissue/organs, 3) are spewed out during the process and are excreted in urine/feces, 4) any other possible destination;
  7. recognition of heme deficiency and the role it plays in triggering attacks—alone and/or in conjunction with other triggers;
  8. or those patients who agree; either consider periodic infusions (some patients do weekly) and/or early use of IV glucose as treatment (with appropriate Na and K supplementation) and with supplemental oxygen administered during the infusion (may reduce need for expensive hematin);
  9. for those patients who agree; use of IV hematin as treatment (with appropriate Na and K supplementation)—until the liver is satiated—and with supplemental oxygen administered during the infusion;
  10. investigate the misshapen blood theory put forth by the “a.p. missed diagnosis” patients—and its role in the “porphyrin/precursor whereabouts;
  11. with a scientific mindset, research Sickle Cell Disease/Acute Porphyria (and/or other IEMs) similarities. Successful treatments for other IEMs have happened in the past. There may be something to take away from treatments developed for these other IEMs (especially in comparison to SCD re potential de-oxygenation).

*To be fair, at one time the Porphyrias Consortium did address the possibility of “additional genes” in an answer to a FAQ “general question” presented on the Rare Disease Network site (printed out 6/2011). The question, “What is “latent” porphyria? If my doctor told me that I have “latent” porphyria, does this mean I will never have any symptoms?”176 The Porphyrias Consortium answer to that is lengthy, but included, “There may also be additional factors, including additional genes, that modify the symptoms.”177 Note: as of 7/13/2019 this site can’t be reached.

CONCLUSION—Attention: European participants of the International Porphyria Molecular Diagnostic Collaborative and the Worldwide Porphyrin and Porphyrias Experts Assemblage: Proceed with caution.

It is extremely concerning to the “a.p. missed diagnosis” community that the International Porphyria Molecular Diagnostic Collaborative intends to use the May 10, 2019 paper to support its position at the 2019 ICPP in Milan’s roundtable session to establish a definition for acute porphyria attacks. While it all seems appealing, it is imperative that the reason for creating “an evidence-based database of verified pathogenic and benign variants for the porphyrias” have a scientific base—not a US agenda-driven base. This agenda must be recognized and curtailed for it is the antithesis of precision medicine.             

The IPMDC paper’s Disclosure section is revealing—more than a dozen connections between Alnylam and co-authors of that paper; many of whom are also involved with Alnylam’s ENVISION (Givosiran) clinical trials. These relationships as well as Alnylam sponsorships of websites and paid attendance for various individuals to pricey conferences, meetings, etc. smacks of conflicts of interest. As one insightful “a.p. missed diagnosis” patient noted about the IPMDC paper, “This publication does nothing to show me that they care about all patients. If you’re in the perfect presentation club, you are placed on the pedestal as a martyr for the cause. If not, then you are a usurper who must be punished.” 178 Regarding the IPMDC author who proposed International Collaborative, s/he had this to say, “[This individual] has the most to gain.”179

In my/our “a.p. missed diagnosis” opinion, what the IPMDC is doing (unintentionally by some participants, but most certainly deliberately by others) is nothing more than the continuation of my daughter’s ten year IVS10-31A>G/APF/Desnick/Mount Sinai nightmare, as well as the denigration of a particular CPOX patient/caregiver mom duo and of a certain PPOX patient.

At the present time, for my daughter, PBGD, heme deficiency and genetic influence/expression remains a jumbled mess still within that US Pandora’s box Dr. Desnick opened five years ago. As if to demonstrate our “missed-diagnosis” patient/caregiver theory that not all porphyrins/precursors excess resulting from “dysfunction” of a revved-up heme biosynthetic pathway are excreted out of the body through urine and/or feces but rather, remain the body, my daughter, suffering with intermittent convulsions and fainting episodes, severe ongoing kidney and abdominal pain and other acute porphyria symptoms, recently reported that a personal hygiene product removed from her body during menses was purple.

We believe that it wasn’t coincidence that any of these variants appeared in IPMDC’s paper—they were selected because they represent patients and/or caregivers targeted for silencing by the US porphyria powers that be. No doubt the variants highlighted in the IPMC paper are the ones planned to “pilot” IPMDC’s program—if it hasn’t already happened.

Our community includes toddler to octogenarian patients and is comprised of caring, intelligent, well-researched patients and caregivers. Lives have been torpedoed—shattered beyond all recognition. The souls of our daughters, mothers, sons, fathers and too many other loved ones have been destroyed. No doctor or scientist has the right to do that—to anyone—and get away with it. Besides pain, degradation and desperation, many in the “a.p. missed diagnosis” patient community feel exploited, victimized and/or traumatized which they attribute to medical maleficence. Most are extremely dissatisfied with their quality of life. Try as they might, many of these once vibrant, brilliant individuals have lost their grasp of Nietzsche’s, “If you have a way to live, you can bear almost any how.” Attempting to keep them from suicide or joining The Final Exit network180 (an American 501 nonprofit right to die which holds that mentally competent adults who suffer from terminal illnesses, intractable pain, or irreversible physical conditions have a right to voluntarily end their lives) is a daily heartrending reality for those who care. With the right diagnosis and treatment, though not irreversible, the condition could be made manageable. Two mothers have done it for their daughters. More than one patient did it for herself.  Suicide needn’t be the answer. God will call them when they have fulfilled their purpose on this earth.

The US may have the loudest group of “a.p. missed diagnosis” patients but our closed online forums increase weekly with patients/caregivers from around the world desperately seeking assistance, knowledge, help, understanding. We must, for the greater good of acute porphyria patients everywhere (and those up-and-coming) continue to speak out. Acute porphyria won’t stop. It’s in the genes of untold numbers of people on this planet. Acute porphyria shouldn’t be permitted to continue to bankrupt the lives and finances of individuals, families, societies, private and single payer insurance sources. The intelligence of physicians (GP and/or specialists) who attempt to help members of our community should not be affronted by the arrogance of “experts” whose logic and research trails seem to defy scientific reasoning.

Of course, changing “a.p. missed diagnosis” patients to active status will blow porphyria statistics right out of the water—for a while. Long-term, gaining better, more accurate knowledge of the true, full acute porphyria pathophysiology will have favorable impacts not only for patients but for families, communities, and societies for eons to come. For one, reducing or eliminating the need for multiple medical testing to go on ad nauseam and at great expense. Developing more cost effective treatments for another. Returning people to the work force. Testing infants at birth and monitoring throughout the lifetime. So many positive possibilities to replace so much despair and cost. That’s what precision medicine, personalized medicine, and/or genomic medicine—aka as patient-centered care is meant to do, isn’t it?

Thank you all for the time and patience granted to reading this patient/caregiver perspective prepared work. We hope it will guide you toward Sir William Osler’s professional commitment, “The good physician cares for the disease; the great physician cares for the patient.”  

###

FOOTNOTES/REFERENCES

1.         New York State Rare Disease Alliance; nysrda.com

2.         Reilly MD, JD, P.; Orphan: The Quest to Save Children with Rare Genetic Disorders: Cold Spring Harbor Laboratory Press; 2015; 313.

3.         Brown, D.; https://www.goodreads.com/quotes/488064-sometimes-a-change-of-perspective-is-all-it-takes-to

4.         Chen, B. et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 1.

5.         Ibid.

6.         Brookes, A.; email response to author; May 10, 2018.

7. Zimmer, C.; She Has Her Mother’s Laugh: The Powers, Perversions ad Potential of Heredity, New York, 2018; 133.

8.         Young, E.; The Atlantic: What If (Almost) Every Gene Affects (Almost) Everything?; Global Genes; June 25, 2017; https://globalgenes.org/2017/06/25/the-atlantic-what-if-almost-every-gene-affects-almost-everything/

9.         Anonymous “missed diagnosis” patient contributor.

10.       Chen, B. et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 1.

11.       Ibid, 1-2.

12.       APF; 1st Quarter, 2013 Newsletter; Testing and Latent Porphyria; 6. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/1st%20Quarter%202013%20News%20Letter%20part%202_2.pdf

13.       Ibid.

14.       APF: 2nd Quarter, 2013 Newsletter; International Porphyria Congress; 4. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/2nd%20Quarter%202013%20News%20Letter.pdf

15.       APF: 2nd Quarter, 2013 Newsletter; Exciting New AIP Treatment in Development; 7. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/2nd%20Quarter%202013%20News%20Letter.pdf

16.       Daniell, W. et al; Environmental Chemical Exposures and Disturbances of Heme Synthesis; Environmental Health Perspectives 105, Supplement 1; February 1997; 3. http://www/herc.org//news/mcsarticles/daniell-full.html

17.       Chen, B et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 3.

18.       Ibid.

19.       Desnick, Dr. R.J.; Mount Sinai; original AIP diagnosis communication; November 25, 2008; author’s personal health records.

20.       Wright, CF. et al; Genomic variant sharing: a position statement; Wellcome Open Research 2019; Last updated Feb 5, 2019; 6.          

21. Chen, B et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 4.

21.       Ibid.

22.       Ibid.

23.       Desnick, Dr. R.J.; Mount Sinai; revoked diagnosis letter and revised report; June 12, 2014; author’s personal health records.

24.       Porphyria experts’ identity withheld; Index Case Medical Opinion; February, 2018; personal health records.

25.       Ibid.

26.       Ibid.

27.       Ibid.

28.       Desnick, Dr. R.J., Mount Sinai; underlying DNA revised report; May 9, 2018; author’s personal health records.

29.       Robreau-Fraolini, AM et al; Porphobilinogen deaminase gene in African and Afro-Caribbean ethnic groups: mutations causing acute intermittent porphyria and specific intragenic polymorphisms; Human Genetics 2000 Aug; 107(2):150-9; 157.

30.       To protect porphyria experts from potential harassment, author chooses to withhold this resource info.

31.       Zhang, J. et al; A LC–MS/MS method for the specific, sensitive, and simultaneous quantification of 5-aminolevulinic acid and porphobilinogen; J Chromatogr B Analyt Technol Biomed Life Sci. 2011 Aug 15; 879(24): 2389–2396; 16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269068/

32.       Tishler, P.V.; Letter to author on Brigham and Women’s Hospital letterhead, June 4, 2015.

33.       Kauppinen, Fraunberg; Molecular and Biochemical Studies of Acute Intermittent Porphyria in 196 Patients and Their Families; Molecular Diagnostics and Genetics; November 2002, 3. http://clinchem.aaccjnls.org/content/48/11/1891.long

34.       Cappellini et al; Hematologically Important Mutations: Acute Intermittent Porphyria; Blood Cells, Molecules and Diseases; Jan/Feb 2002; Table 1.

35.       Chen, B et al; International Porphyria Molecular Diagnostic Collaborative: an evidence-based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 4.

36.       Ibid.

37.       Ibid.

38.       Desnick R.; SELF DIAGNOSIS: THE GOOD AND BAD; APF March 2016 Newsletter. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/Newsletter%20March%202016%201st%20qtr.pdf

39.       Ibid.

40.       Ibid.

41.       Ibid.

42.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 5.

43. Ibid

44.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, March 2015.

45.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 5.

46.       Ibid.

47.       Ibid.

48.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine; March 2015; 1.

49.       Ibid, 2.

50.       Anonymous “missed diagnosis” patient.

51.       Ibid.

52.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, May 2015; 1.

53.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, March 2015; 7.

54. Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 5.

55.       Ibid.

57.       Ibid.

58.       Ibid.

58.       Ibid, 6.

59.       Ibid.

60.       Richards et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, March 2015 and May 2015.       

61.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 6.

62. Deybach, J.-CH. et al; European Porphyria Initiative (EPI): A Platform to Develop a Common Approach to the Management of Porphyrias and to Promote Research in the Field; Physiological Research; April 25, 2005; 2.

63. EPNET “The Porphyrias” @ https://porphyria.eu/en/content/porphyrias

64.       Harper, P., Sardh, E.; Management of acute intermittent porphyria; Expert Opinion on Orphan Drugs; April 2014; 353. [https://www.researchgate.net/publication/263245362_management_of_acute_intermittent_porphyria]

65.       Mustajok, S.; Table 2.2.; Molecular Genetics of Acute Intermittent Porphyria in Finland thesis; Helsingin yliopiston verkkojulkaisut;1999. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/mustajoki/index.html

66.       Myketun, M. et al; Porphyrias in Norway; Tidsskriftet; Issue 8, April 29, 2014; Table 2.  https//tidsskriftet.no/en/2014/04/porphyrias-norway.

67.       Alnylam EXPLORE presentation; Natural History Study 12-Month Study Enrollment and Follow-Up; April 2017; 3. https://www.alnylam.com/wp-content/uploads/2017/06/ICPP-2017-EXPLORE-Presentation-Capella.pdf

68.       Waldenström, J.; Neurological Symptoms Caused by Socalled Acute Porphyria; Acta Psychiatrica Scandinavica; June 1939

69.       Lyon Howe, D.; Porphyria: A Lyon’s Share of Trouble; Howerite, Inc.; 2004.

70.       Ibid, 2.

71.       Lyon, D.; Lyon’s Share; APF 4th Quarter 2013 Newsletter; 3. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/APF%20Newsletter%204th%20Quarter%202013%20part%202.pdf

72.       Lyon Howe, D.; Porphyria: A Lyon’s Share of Trouble; Howerite, Inc.; 2004; 20-24

73.       Ibid, 195-197.

74.       Kappas, Sassa; Molecular aspects of the inherited porphyrias; Journal of Internal Medicine 2000; 247:169-178; 169. https://www.ncbi.nlm.nih.gov/pubmed/10692079

75.       García-Diz, L. et al; Assessing nutritional status of acute intermittent porphyria patients; Eur J Clin Invest. 2012 Sep;42(9):943-52; 1. https://www.ncbi.nlm.nih.gov/pubmed/22519672

76.       Anderson, Badminton; NORD; Acute Intermittent Porphyria, 2019 version; 1. https://rarediseases.org/rare-diseases/acute-intermittent-porphyria/

77.       Bonkovsky, Rudnick; Overview of Porphyrias; Merck Manual’s online Professional 2019 Version. https://www.merckmanuals.com/professional/endocrine-and-metabolic-disorders/porphyrias/overview-of-porphyrias

78.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 7.

79.       Anderson, K., et al; Nelson Textbook of PEDIATRICS; Chapter 85 The Porphyrias; 517.

80.       Porphyrias Consortium; Acute porphyrias; Table 2.; undated. https://www.rarediseasesnetwork.org/cms/porphyrias/Healthcare_Professionals/diagnosis

80.       Sassa, Kappas; Molecular aspects of the inherited porphyrias; Journal of Internal Medicine 2000; 247: 169-178; 172.

82.       EPNET; European Porphyria Network; Specialist porphyria laboratory table. https://porphyria.eu/en/content/specialist-porphyria-laboratory-table

83.       Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence –based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 8.

84.       Richards, S., et al; Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and the Association for Molecular Pathology; Genetics in Medicine, May 2015. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544753/

85.       Peterson, LR. et al; Erythrocyte uroporphynogen I synthase activity in diagnosis of acute intermittent porphyria; Clin Chem, 1976 Nov; 22(11): 1835-40. https://www.ncbi.nlm.nih.gov/pubmed/976654

            86.       Tanaka, H. et al; Long-Term Follow-up of Erythrocyte Porphobilinogen Deaminase Activity in a Patient With Acute Intermittent Porphryria: The Relationship between The Enzyme Activity and Abdominal Pain Attacks; Bulletin of the Osaka Medical College 53 (3); June 18, 2007; 155.

87.       Ibid, 159.

88.       Ibid, 156.

89.       Ibid, 159.

90.       This author chooses to protect the identities of these porphyria experts.

91.       New York Times archives; Obituary; Dr. Watson was the chief researcher in the discovery of hematin.; APRIL 14, 1983.

92.       Schmid, R; The National Academies Press Open Book; Biographical Memoirs V.65; Chapter: 19. Cecil James Watson; May 31,1901-April 11, 1983; 9.

93.       Ibid, 10.

94.       Ibid, 2.

95.       Ibid, 10.

96.       Bonkovsky, H., et al; Porphyrin and heme metabolism and the porphyrias; Comprehensive Physiology; Jan 3, 2013 (1) 365-401; https://www.ncbi.nlm.nih.gov/pubmed/23720291

97.       Abou-Zeid, A., Donofrio, P.; Texbook of Peripheral Neuropathy  Chapter 21, Porphyric Neuropathies; Porphyrins & Porphyria Diagnosis; April 2012; 289. https://books.google.com/books?isbn=1936287102

98.       Bonkovsky, H., et al; Heme status affects human hepatic messenger RNA and microRNA expression; World Journal of Gastroenterology; March 14, 2013; 3.

99.       Ibid, 8.

100.     Alnylam; RNAi Roundtable: ALN-AS1 for the Treatment of Hepatic Porphyrias; August 21, 2014; slide #19.

101.     Ibid, slide #20.

102.     Alnylam Phamaceuticals RNAi Roundtable Transcript Q&A; August 21, 2014; 17. http://www.alnylam.com/web/assets/082114Alnylam.pdf

103.     Ibid.

104.     Anonymous “missed diagnosis” caregiver 1 report.

105.     Anonymous “missed diagnosis” caregiver 2 report.

106.     Ibid.

107.     APF director; Porphyria Sucks FB posts ~5/13/2018.

108.     Anonymous “missed diagnosis” caregiver 1; Porphyria Sucks FB posts ~5/13/2018.

109.     Anonymous “missed diagnosis” caregiver 2 response.

110.     APF director; FB post; 9/16/2016, 10:02 pm.

111.     APF website; MISINTERPRETATION OF TEST RESULTS ~4/20/2019. https://porphyriafoundation.org//patients/abpit-porphyria/testing-porphyria/misinterpretatio

112.     Elkhatib, R. et al; Feigning Acute Intermittent Porphyria; Case Reports in Psychiatry; 2014:152821.  [https://www.hindawi.com/journals/crips/2014/152821/]

113.     Ibid.

114.     Ibid.

115.     Ibid.

116.     Ibid.

117.     Ibid.

118.     Ibid.

119.     Ibid.

120.     Ibid.

121.     Gould, J and J; Purple Canary: The Girl Who Was Allergic to School, The True Story of How School Chemicals Unleashed a “Rare” Illness That Devastated a Young Girl’s Life; 2016.

122.     “Expert confirmed” acute porphyria (HCP) patient, anonymity respected.

123.     “Missed diagnosis” acute porphyria patient, anonymity respected.

124.     “Missed diagnosis” acute porphyria patient/caregiver, anonymity respected.

125.     “Missed diagnosis” acute porphyria patient, anonymity respected.

126.     Watson, et al; Postulated deficiency of hepatic heme and repair by hematin infusions in the “inducible” hepatic porphryias; Proceedings of the National Academy of Sciences of the United States of America; National Academy of Sciences   May, 1977; Vol 74. No.5; 2218. https://www.jstor.org/stable/67179?seq=1#page_scan_tab_contents

127.     Sardh, E.; Alnylam RNAi Roundtable: Givosiran, in development for the treatment of acute hepatic porphyrias; Transcript; 9/7/2017; 4.

128.     Storjord, E. et al; Lifestyle factors including diet and biochemical biomarkers in acute intermittent porphyria: Results from a case-control study in northern Norway; Molecular Genetics and Metabolism; December 2018. https://www.sciencedirect.com/science/article/pii/S1096719218305286?via%3Dihub

129.     Wilson, Edixhoven, Koole, de Rooij; EPNET, European Porphyria Network; The Diagnosis of Acute Hepatic Porphyria by Plasma, ALA, PBG, Fluorescence Scanning and Enzyme Assays, Using DNA Analysis as Reference; 2018; 1.

130.     Ibid.

131.     Ibid.

132.     Ibid, 2.

133.     NIH Clinical Trials; Acute Porphyrias: Biomarkers for Disease Activity and Response to Treatment; October 17, 2016.  https://clinicaltrials.gov/ct2/show/NCT02935400

134.     Schmid, R.; Biographical Memoirs: V.64 (1994), Chaper 19: Cecil James Watson; The National Academic Press OpenBook; 2. https://www/nap.edu/read/4548/chapter/20

135.     NIH; National Cancer Institute; Seer Training Modules; Blood. https://training.seer.cancer.gov/anatomy/cardiovascular/blood/

136.     Tanaka, H. et al; Long-Term Follow-up of Erthrocyte Porphobilinogen Deaminase Activity in a Patient With Acute Intermittent Porphryria: The Relationship between The Enzyme Activity and Abdominal Pain Attacks; Bulletin of the Osaka Medical College 53 (3); June 18, 2007; 158.

137.     “Missed diagnosis” acute porphyria patient, anonymity requested.

138.     Ibid.

139.     Ibid.

140.     “Missed diagnosis” acute porphyria patient, anonymity requested.

141.     Ibid.

142.     APF; Newsletter; 1st Quarter 2019; Sickle Cell Disease and Acute Porphyria; 3. https://porphyriafoundation.org/sites/default/files/2019-05/APF-Newsletter-1Q2019_v1.pdf

143.     Schmid, R.; Biographical Memoirs: V.64 (1994), Chapter 19: Cecil James Watson; The National Academic Press OpenBook; 2. https://www/nap.edu/read/4548/chapter/20

144.     Lyon Howe, D.; Porphyria: A Lyon’s Share of Trouble; Howerite, Inc.; 2004; 172.

145.     Ibid.

146.     Ibid, 173.

147.     Bloomer, J. et al; Blood Volume and Bilirubin Production in Acute Intermittent Porphyria; The New England Journal of Medicine; January 7, 1971; 284:17-20

148.     Ibid.

149.     Bonkovsky, H.; Neurovisceral Porphryias: What a Hematologist Needs to Know; Hematology; 2005.

150.     Ibid.

151.     Bonkovsky, et al; Heme status affects human hepatic messenger RNA and microRNA expression; World Journal of Gastroenterology; 2013 Mar 14; 19(10); 1593–1601.

152.     Bonkovsky et al; Repression of the Overproduction of Porphyrin Precursors in Acute Intermittent Porphyria by Intravenous Infusions of Hematin; PNAS, Vol. 68, No. 11; November 1, 1971; 2725.

153.     Ibid.

154.     Ibid, 2726.

155.     APF; DR. BONKOVSKY CREATES HEMATIN; 1st quarter 2015 Newsletter, 5. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/Newsletter%20March%202015.pdf

156.     Ibid.

157.     Hans Fischer; Encyclopedia of World Biography; The Gale Group Inc. https://www.encyclopedia.com/people/history/historians-miscellaneous-biographies/hans-fischer; https://www.thefamouspeople.com/profiles/hans-fischer-7254.php

158.     New York Times archives; Obituary; Dr. Watson was the chief researcher in the discovery of hematin.; APRIL 14, 1983.

159.     APF; DR. BONKOVSKY CREATES HEMATIN; 1st quarter 2015 Newsletter, 6. https://www.porphyriafoundation.org/apf/assets/file/public/newsletters/Newsletter%20March%202015.pdf

150.     Peterson, A. et al; Hematin Treatment of Acute Porphyria: Early Remission of an Almost Fatal Relapse; JAMA The Journal of the American Medical Association 235(5):520-2 · March 1976. https://www.researchgate.net/publication/22209063_Hematin_Treatment_of_Acute_Porphyria_Early_Remission_of_an_Almost_Fatal_Relapse

161.     Ibid.

162.     “Missed diagnosis” acute porphyria patient, anonymity respected.

163.     APF; website landing page. https://porphyriafoundation.org/

164.     “Missed diagnosis” acute porphyria patients, anonymity respected.

165.     Out-of-US porphyria expert—as told to a long-suffering “missed diagnosis” patient.

166.     APF website; https://www.porphyriafoundation.org/content/diagnostic-testing-acute-porphyrias-clarification-testing-results/?page=13

167.     The Porphyrias Consortium; Diagnosis of the Porphyrias; undated; https://www.rarediseasesnetwork.org/cms/porphyrias/Healthcare_Professionals/diagnosis

168.     Farlex Partner Medical Dictionary © Farlex 2012 https://medical-dictionary.thefreedictionary.com/asymptomatic; https://medical-dictionary.thefreedictionary.com/latent

169.     Chen, et al; International Porphyria Molecular Diagnostic Collaborative: an evidence–based database of verified pathogenic and benign variants for the porphyrias; Genetics in Medicine; May 10, 2019; 2.

170.     APF director; email correspondence to author 1/14/15.

171.     APF; website landing page. https://porphyriafoundation.org/

172.     Bonkovsky, H.; Acute Porphyrias; Gastroenterology/Hepatology; Cancer Therapy Advisor; Decision Support in Medicine, LLC.; 2013, 2017; 4.

173.     Alnylam Pharmaceuticals (ALNY) Q2 2018 Results-Earnings Call Transcript; August 2, 2018; 23. https://seekingalpha.com/article/4194126-alnylam-pharmaceuticals-alny-q2-2018-results-earnings-call-transcript

174. Balwani, M.; What Hematologists Need to Know About Acute Hepatic Porphyria; Clinical Advances in Hematology & Oncology; November 2016 – Volume 14, Issue 11; 3. https://www.hematologyandoncology.net/archives/november-2016/what-hematologists-need-to-know-about-acute-hepatic-porphyria/

175.     Sardh, E.; Alnylam RNAi Roundtable: Givosiran, in development for the treatment of acute hepatic porphyrias; Transcript; 9/7/2017; 4.

176.     Porphyrias Consortium; Patients and Families; Frequently Asked Questions, General Questions. http://rarediseasenetwork.epi.usf.edu/porphyria/patients/learnmore/FAQ.htm

177.     Ibid.

178.     “Missed diagnosis” acute porphyria patient, anonymity respected.

179.     Ibid.

9.     Ibid.


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