FEAR-RIDDEN, FRUSTRATED, FORGOTTEN and FED-UP:
Patients with Atypical Acute Porphyria Presentation Stuck in Urinary Diagnostic Quagmire
Caregiver/patient perspective by parent/advocate/author of Purple Canary
©J. Gould, 1st Quarter, 2017
My daughter developed an odd combination of recurrent debilitating physical, neurological and psychiatric symptoms at age eleven. More than a year later, DNA testing confirmed that she had the mutant gene associated with Acute Intermittent Porphyria (AIP), a rare inborn error of metabolism that can disturb heme (blood) production and wreak havoc on the central nervous system (CNS). However, because her body did not generate the urinary biochemical proof that porphyria experts insist signifies AIP attacks, a few months later they refused to endorse the diagnosis. This was in spite of the fact she frequently suffered severe, sometimes life-threatening attacks that were relieved only by known AIP treatments—infusions of glucose and/or an orphan drug (biologic) known as Panhematin. Over time, I asked experts associated with the US “go-to” organization for all things porphyria why it was that urinary biochemical excretions alone were relied on to diagnose AIP attacks, why her DNA diagnosis had essentially been dismissed, and why clinical symptoms were not even considered? The answers I received were vague and, in my opinion, frustratingly insufficient. Nonetheless I persevered in my quest to get answers to help my daughter by expanding my research to the Internet.
Then, hoping to create awareness that AIP can and does present in childhood, I wrote Purple Canary. It wasn’t until I’d nearly finished writing the book that I discovered closed Facebook forums frequented by porphyria-affected patients, many (if not most) with atypical acute porphyria presentation, and caregivers. I quickly felt I’d landed in familiar territory because, like my daughter, these patients had been unceremoniously dumped into “undiagnosed,” “questionable,” or, more likely, “latent” or “asymptomatic” porphyria categories. As such, very few were (and still are) unable to maintain societal connections or to find medical personnel interested, willing and/or able to put puzzle pieces together to try and help them. Without expert support, they are often labeled attention- or drug-seeking, hypochondriacs or mentally ill by medical (particularly ER or ED) personnel. Unfortunately, most doctors know little or nothing about the acute porphyrias. Sadly, some just don’t believe that porphyria exists. A limited number of doctors actually put porphyria on a patient’s differential diagnosis list but, intimidated by the disorder’s complexities, end up following the experts’ lead because “they are the experts.” This does nothing to help the plight of suffering patients whose urinary excretions during severe attacks do not match DNA results or who have family members with known acute porphyria; it only compounds their misery. As with my daughter, I refer to these patients as having atypical AIP presentation. That is, atypical (uncharacteristic) from the more readily identified “Swedish Porphyria presentation.” This thinking was based on a case that Swedish doctor/scientist Jan Waldenstrom witnessed in 1939, “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.”[i] I reasoned that my daughter’s AIP presentation, like the case Dr. Waldenstrom described, was more like the patient’s than the brothers’ and therefore, “atypical.”
Terribly sick, frustrated and anguished about their plight, the suffering of these patients is no less horrendous or debilitating than those who receive an expert-approved diagnosis. However, lacking the diagnosis, they are essentially set adrift and left to their own devices. Most endure horrific chronic symptoms, potentially life-threatening attacks and debilitating, long-term neurological effects. All the while, they seek to capture the Holy Grail of AIP diagnosis—very high levels of urinary PBG excreted during an attack. They steadfastly cling to the hope that the next attack might generate enough urinary PBG to finally make them eligible for medical recognition. One patient shares, “I have been in constant attacks for about nine weeks. I had more tests yesterday so am waiting for results. I tell doctors I will be dead waiting for results. [My doctor] wanted me to have some urine tests. He was angry because I didn’t do what he had wanted last attack so I thought I had better get this in before he dumps me as a patient. But I have been too sick to make it to the lab. What difference does it matter? I asked him who cares about the numbers when I have every symptom, almost died a few times and my father died of porphyria. I honestly feel like my body can’t take much more of this.”[ii] These forums routinely carry such stories. The level of intelligence, research, compassion and sharing of knowledge and experiences by individuals within these groups is remarkable even as despair runs high. Forum administrators and contributors who are walking the same, difficult road (sometimes for years or decades) try their best to help “newbies” understand that they are neither “weird” nor alone.
For many years I believed that with its abundance of porphyria experts the American Porphyria Foundation (APF) offered mastery of what are perhaps the most maligned diseases known to medicine. However, my thinking on that changed. Why? First and foremost, because I witnessed for myself how a patient (my daughter) whose biochemical AIP results didn’t match DNA testing had been essentially dismissed by this patient support group. And how, as a parent attempting to advocate for more information, I was routinely given the run-around while my child’s health deteriorated to the point that I sought medical assistance from a non-APF porphyria expert. Thankfully I did. The result was a life-saving intervention that was met with disinterest by APF professionals and experts.
Next, I learned from members of the closed forums that before it’d happened to my daughter and me, other atypical acute presentation patients and/or caregivers had been similarly shut down by professional, medical and scientific individuals associated with this organization.
Last was the grating reticence of the group’s professionals to engage in deeper discussion when asked for further explanation about information produced/published by the group’s experts and its unwillingness to provide corroboration or refutation about information presented by patients and/or caregivers obtained from other expert sources (domestic or foreign). Evidence to the latter point surfaced when I located a 2003 Swedish article (Acute intermittent porphyria in childhood: a population-based study) and sent it to the attention of the APF admin and scientific groups. I never received indication that they might have already been aware of its presence or that my correspondence had even been received. However, just last year I happened upon an article, Clinically Important Features of Porphyria and Heme Metabolism and the Porphyrias that contained information about AIP in childhood. What I read reminded me of the 2003 Swedish article so I checked the reference list and sure enough found that the 2003 Swedish article had been credited. However, critical information from that article had been omitted.[iii] Interestingly, the same APF expert I’d asked directly in 2009 (six years after the Swedish article’s publication) if it was possible that children did not always produce urinary biochemical “proof” of AIP activity was listed as co-author of that 2014 article. Apparently, he was familiar with it.
Having posed what I thought were rational questions to various APF-connected professionals over the years to which I’d received no or lackluster answers, I became suspicious of motives. The clincher came when the APF executive director posted on the group’s open Facebook page, “APF only posts and publishes what our scientific advisory board of experts says,”[iv] confirming what I and so many others had long suspected. Unfortunately, so doing contributes to the belief that a worldwide wealth of scientifically-proved knowledge and experiences are left unshared with those who might benefit. Ostrich behavior does not imbue confidence.
In the early ’80s, Desiree Lyon Howe and her porphyric friend shared a vision and saw it through and Ms. Lyon Howe continued to build the organization after her friend’s death. I understand why plenty of patients and caregivers sing APF’s praises. After all, these patients received answers, validation, support and treatment when desperately ill. But each need only thank their own bodies for the fact that the biological process had been set up since birth (actually since conception) to produce AIP urinary biochemical proof when triggered just so.
For all the modern scientific advances having been and being made, as far as the acute porphyrias go, holes with life-threatening implications remain. Since its release about a year ago, it is clear that Purple Canary resonates with the porphyria patient community. It is because of my daughter’s and so many other acute porphyria patients’ suffering that my research and advocacy continues. This paper’s intent is to present findings that I as a parent advocate have made in hopes of contributing to unraveling the AIP diagnostic and treatment insufficiency roadblock that has long stonewalled this particular patient community. To that end, I read Orphan: The Quest to Save Children with Rare Genetic Disorders written by Philip Reilly, MD, JD. Early in his book, Reilly states that he wrote the book “to convey a message of hope.”[v] As a parent of a now young-adult child with the mutant gene associated with a rare disease, I offer kudos to author Reilly because he does that and so much more. I’m neither a doctor nor a scientist. I am a “just” a parent/advocate who hopes that holes will be start to be filled once unbiased medical and/or scientific entities conduct and document in-depth analyses of the full pathophysiology (including the performance of blood components from creation (erythropoietin) through liver biosynthetic pathway activity and elimination—if indeed they are all eliminated) of typical and atypical acute porphyria presentations. This is further discussed on page 8.
Uroscopy – In ancient times, a practice known as uroscopy (visually examining excreted urine) became de rigueur to diagnose ailments. In fact, Hippocrates (460-377 BC), heralded as the founder of modern medicine, is said to have been the original uroscopist.[vi] He is credited for having been the first to identify the blood/liver disease that centuries later came to be known as porphyria. In direct contrast to the school of medicine teachings of the time that the human body was a compilation of isolated parts to be treated individually, Hippocrates believed the body functioned as one unified organism and treated each patient “as one, coherent, integrated whole.”[vii]
About fifteen hundred years after Hippocrates identified a disease based on the color of a patient’s urine, in a land far from his domain, the Swedes made a connection between patients who suffered recurrent, unexplained bouts of severe physical, neurological and/or psychiatric distress and red urine holes found in the snow surrounding their homes. Eventually, the peculiar illness was found to be an inherited condition and given a name—acute intermittent porphyria (AIP). When seen outside the Scandinavian country, the odd disease with its puzzling array of symptoms accompanied by dark red and/or reddish-purplish color urine came to be known as “Swedish Porphyria.” Somewhere along the way the Swedish identifier apparently became passé. Today, AIP is found in all races and on every continent. Although uroscopy is not a specialty most modern day physicians claim as an area of expertise, the practice can still serve as a preliminary indicator for certain diseases, particularly the porphyrias. This is because darkened urine can be an early indicator of a porphyria’s presence. Following Sweden’s lead, AIP diagnostic techniques in the US moved from uroscopy to chemical analysis of the urine (urinalysis) to blood/enzyme analysis to DNA analysis, a still-evolving science. However, the US diagnostic practice of analyzing urine to confirm AIP has been given diagnostic precedence over genetic markers and/or blood (enzyme) tests. And therein is the problem for a sizeable number of individuals with known familial porphyria and/or DNA confirmation of the mutant gene. Though they suffer with incapacitating physical, neurological and sometimes, psychiatric symptoms that make their lives a living hell, urinary biochemical proof of AIP’s manifestation remains elusive.
US AIP Presentation: Swedish vs. Atypical AIP Presentation – Due to the AIP founder effect (many cases derived from a single lineage[viii]) that characterizes Sweden’s population, the world has long looked to the Scandinavian country as the leader for all things AIP. As well it should. The base of knowledge and experience acquired and/or developed over centuries by the Swedes concerning AIP symptomology; precipitating factors (triggers); long term complications and treatment options are priceless and of extraordinary import. However, I’ve come to believe (erroneously or not) that relying on classic “red urine holes in the snow” Swedish Porphyria presentation to definitively diagnose modern day US AIP overlooks certain points. For one thing, while maintaining a somewhat steady upward trajectory, Sweden’s population base has for the most part remained cloistered with migration to the country largely attributed to familial connectedness.[ix] Therefore AIP genes in that region have remained homogenous, resulting in AIP characteristics that have remained within certain margins for generations. But the relatively recent influx of refugees into Sweden may portend a change in future margins.
America’s genetic pool is not by any stretch of the imagination like Sweden’s. The population of the world’s melting pot results from centuries of inter-mixing immigrants (Swedes being among the earliest[x]), native peoples, enslaved peoples brought into this country and transients from all regions of the world (Scandinavians being the first[xi]). Amazon.com recently released a map showing America’s history-based diversity based on genetic data from analyzing 770,000 tubes of saliva submitted to the company from Americans.[xii] Obviously, AIP (and other porphryia) genes hitched rides in the livers of some of these people. As a result, our twenty-first century population likely contains an unfathomable number of variant gene mutations. In that way, while not as dramatic as US, other countries like Canada, Australia and UK share a similarity to the US.
It seems preposterous that porphyria experts will not entertain the idea that AIP in this and other countries is not going to always mimic classic Swedish Porphyria presentation. And, given our country’s intention to remain a nation made up of and welcoming to immigrants and transients, it seems likely that deviations in US AIP gene expression will continue.
Nonetheless, the world should continue to pay homage to and rely on what has been learned and generously shared by Swedish scientists, researchers and physicians. The country has long-maintained a national porphyria registry comprised of people who have inherited the mutated HMBS (a/k/a PBGD) gene. Between that country’s gene homogeneity and access to its DNA registry, AIP activity can be relatively easy to identify there. Yet when a patient appears to be in AIP distress, the Swedes still rely on biochemical testing to determine the presence of AIP-connected metabolites (i.e. ALA and PBG) during attacks. However, if doing so does not provide conclusive evidence and “[i]f there is no registered family history,”[xiii] Swedish experts conduct “genetic analysis [which is] more time-consuming…[because i]dentification of the affected gene is made with the help of slightly less reliable measurements, including enzyme activity in the blood and the level of PBG in the urine.”[xiv] Unfortunately, I’ve never been able to determine what level of PBG constitutes AIP activity in Sweden. Nonetheless, Swedish doctors maintain a “better safe than sorry approach” and provide treatment to such patients.
But this is the United States, not Sweden where no nationwide porphyria registry exists. As such, “[d]etection and accurate diagnosis of the porphyrias [continues to be] bedeviled by confusion and controversy for many reasons, including their comparative rarity and their variability in both the clinical and biochemical expression.”[xv] For many acute porphyric patients, caregivers, and the medical personnel who try to help them, Robert Day’s assertion is as true today as when he noted it in 1984. While US experts would undoubtedly disagree with the thirty-three year old statement, the number of patients with symptom presentation, bio-family AIP history and/or DNA-confirmed AIP gene inheritance but without “biochemical expression” has continued for generations. At the same time, the number of patients whose AIP can be biochemically confirmed remains small—perhaps the reason why a recent APF assertion stated that AIP is ultra-rare. Treatment for expert-confirmed patients is available through (and endorsed by) APF and its Porphyria Consortium and alliances between that group and pharmaceutical companies continue to be eagerly sought. However, those who present with severe AIP symptoms but don’t produce high levels of urinary biochemicals are not even considered to have AIP, so treatment is withheld. Frighteningly, these patients are not advised to avoid acute porphyria triggers—even those who’ve been confirmed to have the AIP mutant gene.
Yes, patients whose systems generate high urinary biochemical markers during attacks, especially those with dark red/purple color change could rightfully be compared to the “red hole in the snow” presentation and therefore be considered to have Swedish Porphyria presentation. Swedish Porphyria presentation will of course maintain a position in the overall world’s populace. However, as physical distance from “AIP ground-zero” (Sweden) widens and generational time and dilution of international genetic pools continue, it appears that position will understandably remain miniscule. Still, as said at the beginning of this paper, Swedish doctor Waldenstrom witnessed atypical acute porphyria first hand seventy-eight years ago.[xvi] This paper will show that cases of atypical acute porphyria still occur—not only in Sweden but in the US, Canada, UK, Australia, and other countries.
Low or Absent PBGs = No Treatment in US, UK, Australia and other countries – Because most US doctors adhere to porphyria experts’ position of withholding treatment unless and until high level urinary biochemical proof of an AIP attack is achieved, current and future lives are at risk. A couple of years ago I turned to a Swedish expert to ask about the withholding treatment for patients who don’t present with high levels of urinary biochemical “proof” which may or may not be associated with “darkened” (e.g. red, purple) urine during AIP attack. The expert responded that my question was valid and had been discussed among Swedish experts too. He also noted, “Our firm standpoint is that it is not possible to exclude activation of acute porphyria or a current attack only on grounds of absence of red urine, or because tests for U-PBG show to be normal…Normal precursor excretion during the acute attack is probably unusual and not in accordance with the current biochemical model of acute porphyria, but should all the same on grounds of probably reliable clinical reporting, be taken as in fact occasionally occurring…The unresolved question is whether there may also be phases during the attack where neither precursor concentration is elevated, and we think it must for the time be kept open…Still, it is not possible to exclude the possibility of attacks of acute porphyria devoid of the usual biochemical markers for the condition.”[xvii] He concluded, “The outcome depends on the differential diagnostic skill of the doctor and in unresolvable cases will [be a] better safe than sorry strategy help to avoid unfortunate outcomes.”[xviii] So, though occasionally occurring (in patients DNA-proven to have AIP) Swedish experts acknowledge and accept normal precursor excretion and/or normal precursor concentration levels during acute attack. I wondered, too, if ALA neurotoxicity might in patients with atypical acute porphyria presentations somehow impact PBG development and/or performance through the biochannels?
It wasn’t long before I heard that I’d been accused of “starting an international incident” so wasn’t too surprised when the Swedish expert contacted me to say he had not been aware that my question about PBG excretion in acute porphyria could in any way be controversial. Honestly, when I’d asked it, neither had I. But I’m glad it did because when I connected that “unresolvable cases” seen in Sweden for which a better safe than sorry strategy to avoid unfortunate outcomes was taken were essentially the same as atypical or undiagnosable cases” that are routinely dismissed by US experts and tossed aside, I knew the topic needed further exploration. It was clear to me that Purple Canary would create controversy and I felt that would be good for the whole of the porphyria community.
Diagnostic Lag Time: Latent/Asymptomatic AIP? In 2015, APF scientific advisory board (SAB) member Dr. Robert J. Desnick stated that the typical AIP diagnosis from first symptoms takes about ten years.[xix] He further said that there are many people who have the gene but aren’t symptomatic, yet have what he termed “vague…like neuropathic pain and progressive neuropathy”[xx] symptoms. He then acknowledged this has yet to be studied. I submit that as far as my daughter and many, many other cases are concerned, both Dr. Desnick’s and the APF’s position of labeling these patients as “aren’t symptomatic” is mistaken. Following are two cases I offer to debate the latent or asymptomatic label attached to diagnostic lag time:
Case 1: In her book, Porphyria, A Lyon’s Share of Trouble, the APF co-founder and executive director described her first attack as a teenager in great detail. She told of suffering horrendous abdominal pain at 17 that developed into a pattern of monthly attacks, yet her symptoms routinely did not match test results. She went from doctor to doctor but having received the label of hypochondriac was essentially ignored—for about ten years. Then a family friend who happened to be a physician offered help. Again, tests came back negative but this doctor had also noted the “slight seizure activity” that plagued her and decided to treat her with Dilantin. Doing so precipitated a full-blown, life-threatening attack during which she was catheterized and purple-red color of port wine urine was excreted.[xxi] AIP was diagnosed. There was no mention of her having noticed any coloration change in her urine during the prior ten-year period. It should be noted that in the APF sponsored Porphyria, The Movie Ms. Lyon Howe remembered her urine color at that time as being the “color of Coca Cola”[xxii]—the same color that many atypical acute porphyrics have reported but never achieved the diagnosis.
Now, should Ms. Lyon-Howe’s torment during the ten year period prior to being diagnosed with AIP be considered latent or asymptomatic? Should the many individuals who have been denied a diagnosis consider taking Dilantin or similar medication in hopes that urinary “proof” might finally happen? My answer to both questions is, “Of course not!” In point of fact, Ms. Lyon-Howe’s biochemical levels were not disclosed so only she and her doctors know what her PBG diagnostic level was at the time and if she in fact would have “made the grade” in contemporary times.
Case 2: This case occurred more recently (2015) and is referenced in an APF scientific advisory board (SAB) member co-authored article. It describes a 32-year-old woman who’d sought medical help for intermittent bouts of nausea and abdominal pains she’d suffered for six years with. Except for anemia and elevated coproporphyins, a lengthy medical evaluation revealed nothing. The patient was referred to another facility for presumed acute porphyria. Urine samples had been collected but results had not yet been received which meant the porphyria diagnosis was conditional, pending receipt of the biochemical (ALA & PBG) results. However, the patient’s condition worsened so much so that administration of daily treatments of intravenous hemin was started. By the third infusion (three days), the patient’s pain and nausea had improved significantly. Following another two days of infusions, “resolution of her symptoms was nearly at hand and the patient was discharged to outpatient follow-up.” When the patient’s urine samples test results were returned, it was noted the PBG level taken before heme treatment had registered 2 mg/g.[xxiii]
What is pertinent here is that the patient was in obvious distress and the decision was made to administer hemin in spite of not yet having the benefit of urinary biochemical results. As with Ms. Howe’s condition, should this 32-year-old patient’s acute porphyria be considered to have been latent for the 6 years before presenting to this medical team? Since her resulting U-PBG level was in the normal range,[xxiv] did the medical team err in administering five days’ worth of hemin to resolve her symptoms? Once again, my answer to both questions is, “Of course not!” This appears to be the Swedish experts’ “better safe than sorry approach” having been successfully utilized by an American doctor whose differential diagnosis skills were on target.
Both of these patients presented to medical personnel when in physical and neurological distress and ultimately ended up receiving appropriate treatment. Still, far too many others suffer with the same, severe recurrent symptoms, sometimes for decades—multiples of Ms. Lyon-Howe’s ten year and Case 2’s six year pre-diagnostic timeframes. Yet, sight unseen, most of them have been (and continue to be) denied investigation of AIP activity based solely on porphyria experts’ onerous and confusing criteria.
The AIP Equation – In my non-medical, mom-mind, some time ago, I consolidated the AIP equation into three inexorably linked components: 1) genetics, 2) blood, 3) liver. In mid-year 2016, just prior to Purple Canary’s publication, I noted the APF’s scientific advisory board (SAB) was comprised of fifteen experts. Seven were gastroenterology or liver specialists, two were geneticists, and oddly, for a rare illness that is largely treated by hematologists—only one hematologist. The remaining board members were associated with dermatology which made sense because APF represents all porphyria types. However, whether by design or ignorance, it was obvious that the US’s AIP equation was skewed to genetics and gastroenterology but inadequate in blood representation. I delved into each AIP component:
1)Genetics. Mount Sinai is the preferred provider of genetic information/services for the APF and its associated Porphyrias Consortium. In 2008, when Mount Sinai’s DNA testing confirmed that my daughter had the mutant HBMS gene, like so many before me, I turned to the APF for information and support. But because her body did not generate the urinary biochemical proof during attacks, APF experts remained highly skeptical that her AIP was active. I was not. They considered her AIP latent. She and I both knew it was not latent, but active.
However, the APF has long been dead set against recognizing anyone who doesn’t produce high-level urinary biochemical “proof” (i.e. ALA and PBG) as having AIP. A recent article based on a study conceived and supervised by Dr. Desnick, director of Mount Sinai’s genetics department and member of the APF’s SAB, clearly leans in that direction. The article, Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease, states that more than “400 HMBS mutations have been reported”[xxv] yet concedes that “the prevalence of HMBS mutations in genomic/exomic databases and the actual disease penetrance are unknown.”[xxvi] To clarify, the HMBS gene (aka PBGD gene) is associated with AIP.
The article provides highlights of how the study was carried out before segueing into genetic-speak and a reference to the Human Gene Mutation Database (HGMD), then concluding that “the estimated penetrance of acute attacks was ~1% of heterozygotes (individuals) with likely-pathogenic mutations.”[xxvii] Perhaps this is why APF recently began identifying AIP as ultra-rare (in the US, an ultra-rare orphan disease is defined as a disorder that affects less than 2000 people[xxviii]). That AIP should be considered ultra-rare (or even rare) in today’s day and age is up for dispute by the expanding group of very sick individuals referenced throughout this paper. With all due deference to the Mount Sinai authors, I submit that along with AIP pathogenicity, AIP’s pathophysiology must be thoroughly investigated and documented before publicizing what appears to be incomplete information about AIP expression because as said on page 3, there is no explanation for how the AIP patient’s blood may be affected from beginning (gene) to end (urinary excretion). Yes, the heme biosynthetic pathway is well known, but the building, maintenance and possible manipulation of blood proteins/enzymes throughout those pathways as they encounter various and changeable endogenous and exogenous factors may hold the key as to why some AIP patients produce high-levels of PBG and others don’t (after all, porphobilinogen is a blood precursor). Mount Sinai’s report raised some other concerning points:
- [Regarding AIP] “most [individuals] remain asymptomatic and undiagnosed.”[xxix] For many patients, not only in the US but other countries where AIP is concerned, use of the word “asymptomatic” to describe what they endure is not only wrong, it is irresponsible;
- The referenced demographic/racial groups included 69,530 individuals comprised of Caucasian, Latino, African, South Asian and East Asian patients of which the majority was Caucasian (45,955).[xxx] Furthermore, it was noted that the “Caucasian [gene] sequences [were] European and Finnish.”[xxxi] For a study to have been conceived, supervised, carried out and promoted by a team of American genetic experts/professionals, why were no American AIP subjects included?
- HMBS is a protein coding type gene which means blood involvement (addressed in the next section), and
- “The acute hepatic…porphyrias…are among a unique group of monogenic [controlled by a single gene] disorders.”[xxxii] In the case of AIP, that would be the HMBS gene.
However, where gene expression is concerned, the last point is addressed by an August 2016 article released by St. Jude Hospital’s Department of Pharmaceutical Sciences, The Severity of Hereditary Porphyria is Modulated by the Porphyrin Exporter and Lan antigen ABGB6. [xxxiii] It is based on a study in which St. Jude researcher John Schuetz, PhD and an international collaboration of scientists set out to solve the long-standing clinical mystery of “why some porphyria patients become more ill than others, even within the same pedigree.”[xxxiv] The study was conducted at the Royal Prince Alfred Hospital in Australia and included 36 porphyria patients of European descent with pathogenic mutations of different porphyria: HMBS (AIP), CPOX (HCP), PPOX (VP) or FECH (EPP) genes.[xxxv] The group of scientists ultimately showed “that severely affected porphyria patients harbor variant alleles in the ABCB6 gene, also known as Lan.”[xxxvi] They also discovered that the variant alleles were more common in patients with severe porphyria than in those with less severe symptoms (although “severe” was not defined). The scientists discovered that, “the severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen.[xxxvii] According to the Nature Communications journal which published the information, this is the first report to link any transport proteins to porphyria. The study raised hopes among expert-confirmed and non-expert-confirmed AIP patients alike.
A 2013 Norwegian study, Conformational stability and activity analysis of two hydroxymethylbilane synthase mutants K132N and V215E, with different phenotypic association with acute intermittent porphyria provided what I’d sought for so long—explanation of the inexorable connection between all three AIP equation components. And surprise, surprise some study participants were shown to have atypical AIP biochemical findings. Like Sweden, Norway maintains a porphyria registry; study participants came from that registry. The Norwegian study’s intent was to “interpret the molecular mechanisms for dysfunction of HMBS mutants and to establish genotype-phenotype relations for AIP.”[xxxviii] The scientists studied “two uncharacterized AIP-associated mutants K132N and V215E with wt (wild-type or original state before mutation) HMBS and the previously reported AIP-associated mutants R116W, R167W and R173W”mutations.[xxxix] Apparently, the V215E mutation has a high association with AIP in Norway while the K132N mutation had not been previously reported. However, it was found in a patient [when] sequencing of the HMBS gene was performed based on the individual’s abdominal pain and indistinct porphyria-related biochemical findings. The patient was then included in the study. Following further biochemical studies, it was found that neither the index K132N patient nor…nine family members confirmed to have the Lys→Asn substitution [had] at any time presented biochemical findings consistent with a diagnosis of AIP.”[xl]
Both the St. Jude-sponsored and Norwegian articles clearly indicate that more than one gene variant can be involved in how an individual’s acute porphyria is expressed.
Another issue that has been floated among porphyrics is the possibility that a single patient could have more than one type of porphyria. For years, the APF position on that was it was not possible. More recently the answer has been something along the lines of it’s very rare to have more than one type of porphyria. I happened to speak with a genetic researcher who said that with eight genes connected to the biosynthetic pathway, more than one could be mutant. There are also articles that discuss dual porphyrias.
AIP gene therapy (in hopes of finding a cure) has been, and continues to be, actively researched in various countries including Australia, Israel, Spain and Sweden. But I have yet to find definitive demonstration that US porphyria experts are contributing to that cause.
In 2014, Dr. Desnick of Mount Sinai inexplicably “revisited” and “revised” my daughter’s DNA diagnosis. With nothing more than a letter addressed to her PCP saying that her AIP gene was now known to be a polymorphism classified as “non-disease causing” the geneticist concluded that she “is most likely not affected with AIP.” He added, “To support this diagnosis [of AIP] it would be important to obtain urinary porphobilinogen (PBG) and aminolevulinic acid (ALA) if the patient or a family member experiences symptoms of an acute porphyric attack, such as abdominal pain, peripheral neuropathy, and/or central nervous system involvement.”[xli] An APF colleague weighed in with, “Her urine ALA and PBG amounts are persistently normal, ruling out an acute attack at each of these times. If, however, you wish to pursue this, please collect a 24-hour urine for ALA and PBG….”[xlii]
Based on Dr. Desnick’s expert opinion that urinary biochemical proof was required to prove that her AIP was active, my daughter’s treating hematologist stopped all AIP treatments. After nearly six years of receiving intermittent treatment for transient AIP symptoms and acute porphyric attacks (described in Dr. Desnick’s letter as “abdominal pain, peripheral neuropathy, and/or central nervous system involvement),”[xliii] my daughter was left hanging in the wind because her body still did not generate the requisite urinary proof. As I’d suspected, over time, without heme replenishment, her physical, neurological and psychiatric health declined, leaving me unassured that US experts had a handle on the AIP turnstile.
The Norwegian study was exceedingly interesting to me because it included terms like cofactors, substrates, thermal stability and covalent binding. This is in line with epigenetics—a science that invokes personalized, precision medical treatments which I believe will ultimately prove significant in treating the individual variability of not just AIP, but all the porphyrias. That enzymes and proteins found in the blood play such important roles in AIP expression leads to the next major AIP component:
2)The Blood. I happen to parent two adopted siblings, one with type 1 diabetes, the other with other acute intermittent porphyria. Neither condition was reported on their biological parentage health histories—we were blindsided. While the diseases share commonalities (both were identified in ancient times; both were ultimately found to be genetic, metabolic disorders with life-threatening potential and both are considered complex), my son’s diabetes diagnosis was based on symptoms and clinical findings confirmed by urinalysis and blood tests. My daughter’s AIP diagnosis, first determined by DNA analysis which I’d sought due to her severe, chronic symptoms and rapidly deteriorating health condition has been met with skepticism by US experts time and again because her urinary biochemical analyses did not match DNA findings. Unlike diabetes, no blood tests were recommended to verify or refute the DNA results. However, the neurologist we’d encountered a few months before the 2008 DNA test was arranged had ordered PBGD testing. I didn’t know it then but eight years later those PBGD results would help make a life-saving difference:
My daughter’s first documented PBGD level (2008) was 6.9 (indeterminate—“normal” being 7). I asked the doctors if the 6.9 level could be considered “borderline.” The reply was a firm “No.” Just a few weeks later, her PBGD level had dropped to 5.3 (diminished). By then she was experiencing daily convulsions and severe cognitive impairment. Although I really didn’t know its significance at the time, PBGD became the first clue that it might be an indicator to measure my daughter’s AIP activity. I clung to that theory and continued researching and observing.
I located articles that said researchers had determined that three distinct subtypes of AIP could be identified by measuring erythrocyte PBGD.[xliv] Immune-modulating agents known as cross-reactive immunologic material (CRIM) were key to making that determination. Two subtypes were noted as being CRIM-negative but one, CRIM positive, particularly got my attention because it is characterized by decreased PBGD levels[xlv] which sure seemed to fit my daughter’s profile. Another article identified two CRIM-positive subtypes and noted that while the protein/enzyme is synthesized normally in these subtypes, it cannot catalyze deamination or elongate the pyrrole chain normally.[xlvi] This offered a plausible connection (to me) between my daughter’s decreased PBGD levels and increased AIP activity.
I found that APF SAB members (Dr. Desnick and Dr. Anderson) had co-authored articles about CRIM subtypes as early as 1979.[xlvii] However, I didn’t recall ever having seen anything about this or any AIP subtype in APF literature. As it turns out, before my introduction to porphyria and this organization, the practice of measuring CRIM to diagnose AIP had apparently been supplanted by DNA testing. Still, a highly respected porphyria expert, Dr. Shigeru Sassa (now deceased, formerly of Rockefeller University Hospital) had noted, “…DNA-based testing is for the diagnosis of the gene carrier status, not for the diagnosis of clinical syndrome or severity of the disease.”[xlviii]
To this day, I have not received an answer to my question, “What prompted Mount Sinai’s decision to “revisit” my daughter’s DNA results?” Given all the information I’ve uncovered and Dr. Desnick’s steadfast refusal to respond to letter, email and even an in-person opportunity, as a mother of an atypical AIP patient, it is no wonder why I continue to be skeptical of this group’s motives and diagnostic processes.
Following his reversal of her active AIP diagnosis in 2014, my daughter’s health slowly and steadily unraveled. Not surprisingly, so did her PBGD measures. By April 2016, her PBGD level had dropped to 5.8 and she was struggling with severe, persistent abdominal pains and other escalating AIP prodomes/symptoms. The APF executive director suggested that her AIP-like symptoms were likely attributed to a something “besides porphyria” and blithely offered, “After all, there are 7,000 rare diseases.” By the fall of 2016, her PBGD level had fallen to 5.4 and she was right back to 2008 pre-AIP diagnosis presentations—collapsing into frequent fainting/convulsive episodes.
Regardless of what the APF group says (or doesn’t say) about it, the bottom line is that for years, PBGD levels have played a significant role in my daughter’s AIP expression. Some time ago we were able to determine that the closer her PBGD reading gets to “normal,” her AIP symptoms reduce and the better she feels. As PBGD measurements decrease, her symptoms increase—from mild (restlessness, irritability, insomnia) to potentially life-threatening (respiratory difficulty, convulsions). As Panhematin is administered, her symptoms almost immediately start to resolve and she continues to improve. It doesn’t take a rocket scientist to see that her PBGD level serves as a barometer to heme adequacy or deficiency. Interestingly, in Japan (where AIP prevalence is 5-10 per 100,0000 inhabitants[xlix]) porphyria experts’ research “suggest[s] that the activity of PBG-D is more sensitive to the conditions prevailing during a crisis than ALA, PBG, and UP”…and conclude “that PBG-D is a good indicator to predict or detect the AIP attack before its onset.”[l] Furthermore, “The activity normalizes as the patient improves, suggesting that this enzyme is a more sensitive monitor for acute intermittent attacks than the urinary parameters currently used for diagnosis…Physicians treating porphyric patients should use monthly testing schedules to estimate the potential risk of an AIP attack and to establish opportune heme therapy.”[li] Given that this information appears to parallel my daughter’s plight for well over ten years, it sure seems to me that Japanese AIP experts deserve a place at the European/American expert/theorist discussion table, not only because of the information and experience they can provide, but to honor the memory of esteemed Dr. Shigeru Sassa (of Japanese ancestry) who did so much to further porphyria knowledge.
I finally located a hematologist who was willing to help my daughter. We presented a history of her medically documented PBGD test results, records of her corresponding clinical AIP symptoms and a number of related medical articles I’d assembled. He reviewed the information, ordered copies of her extensive pediatric hematology records, spoke with the hematologist who had treated her with glucose and/or Panhematin for the majority of those five and half years and saw what we needed him to see—as her PBGD levels decreased below the normal range, her AIP symptoms increased in severity and frequency. At age twenty, more than two years after AIP treatments had been stopped based on Dr. Desnick’s insistence that biochemical proof was required to diagnose AIP, the “new” hematologist ordered a Panhematin trial. As her body’s heme supply was replenished, once again her condition substantially improved. Proof, as if any more is needed that the blood component (PBGD) of the AIP equation needs better definition of and attention to its integrated role in AIP expression. Which brings us to the third major component:
3)The Liver. The vast majority of information about the porphyrias is focused on the liver’s heme biosynthetic pathway where about fifteen percent of the daily production of heme synthesis in developing red blood cells takes place and where heme-containing enzymes are formed. [lii] While the heme biosynthetic sequence of events has obvious significance in porphyria, much more takes place within the abdominal cavity. For example, activation of the liver’s cytochrome P450 system and its direct connection to the enzyme deficiency and AIP’s pharmacogenetic characteristic is of supreme importance. Other than saying that some intermediates undergo changes after leaving liver and bone marrow cells before being excreted,[liii]nothing explains how those “heme-containing enzymes are formed”[liv] or if any are misfolded or otherwise flawed. This clearly is an area of interest but is not presented. Neither is erythropoiesis, a process that begins when the kidneys sense that blood levels of oxygen are low (known as hypoxia) which stimulates renal production of erythropoietin, a hormone that prompts (and is required for) red blood cell production.[lv][lvi] The connection between hypoxia, kidneys, red blood cell production (which includes production of precursors, the excess of which may be secreted in soft tissues or excreted in urine), the liver and surplus excretions is an important one. However the process is virtually ignored in AIP literature.
Acute vs. Chronic Nature of AIP – In the same 1939 article in which Dr. Waldenstrom noted that a young patient’s urine or bile did not contain porphyrins, the prescient physician also re-thought the “acute” designation of the disease and said, “The name acute porphyria seems to have been pretty commonly accepted and I have, therefore, thought it better to use it even if the disease is not caused by porphyrins nor is it acute.”[lvii] Interestingly, seventy-eight years later, that seems to be coming apparent to the US experts. During a March 1, 2017 FDA meeting with APF-coordinated patients, staff and scientific advisory board members in attendance (https://www.youtube.com/watch?v=urHxVYVAals), a panel of acute porphyria patients articulated his/her suffering. Later in that meeting, APF scientific advisory board chair Dr. Anderson stated the reality of severe chronic pain some patients described and the connection that such pain is not always accompanied by high concentrations of urinary biochemical excretion had only just begun to be recognized among the expert group.[lviii]
That AIP symptoms are chronic has been acknowledged by some patients for years. During an Alnylam Pharmaceutical 2015 Roundtable Session held two years ago, Desiree Lyon Howe was credited for having mentioned that “almost 50% of the [acute porphyria] patients reported they had persistent chronic symptoms…[and] don’t go back to being totally well in between the severe attack crisis that occur.”[lix] One has to wonder why it took two years to make this information public.
Upon hearing Dr. Anderson’s comments about chronicity during that FDA meeting, I was reminded of a finding I’d made in the 2011 Textbook of Medical Biochemistry in which author Dinesh Puri, MD, PhD noted, “if the metabolic block lies early in the pathway, so that synthesis of even the first tetrapyrrole ring does not occur, the defect may present as an acute pain crisis. This is because the accumulated metabolites cause excitation of visceral pain fibres.”[lx] That a metabolic block in the biosynthetic pathway was mentioned was of particular interest. So was the description of the results of that blockage. “Acute pain crisis” eerily matches what US experts have for decades deemed “vague” neurological symptoms when referring to atypical acute porphyrics’ complaints of severe pain. It is easy to call a symptom vague without ever having experienced, measured or even witnessed it. And both information pieces point to the finding that not all expert-documented AIPorphyrics produce darkened urine during every pain-filled attack.
AIP Urine: Darkened Color – Although uroscopy was long ago replaced by chemical urinalysis, simply viewing a sick patient’s urine may still have merit as a preliminary indicator. That is because some individuals with the HMBS gene generate urine that is red-purplish in color, especially when in acute attack. As said before, such “red-urine-holes-in-the-snow “proof” is associated with Swedish Porphyria presentation. Even so, I’ve been told by several expert-diagnosed and/or confirmed AIPorphyrics that they do not produce darkened urine with every attack (even those who had been originally diagnosed based on that criteria). In fact, one intrepid acute porphyric, diagnosed long before DNA was even thought of and living in a temperate climate, shared that she had placed vials of her urine beneath an outside tree in hopes of observing color change. She checked them repeatedly. For years. None changed color. Nonetheless, she has suffered the ravages of acute porphyria for decades.
It appears that coloration, like symptom severity, varies among individuals too. My daughter has produced tea-colored, brown urine only twice during attacks—the first was just prior to the 2008 DNA testing, but none of the medical staff would entertain my concern that she might have AIP so the samples were disposed of. The next time was in 2016, when her PBGD level registered 5.4 and she’d been experiencing convulsive episodes almost daily.
AIP Urine: Biochemicals – Other than the Swedish expert saying that the Swedes are exploring the possibility that biochemicals may come in “stages” during attack, it seems no one else is even interested that. Perhaps Dr. Anderson’s comment made during the FDA/APF meeting about only recently having recognized that not all AIPorphyrics generate heightened PBG during severe chronic pain episodes is an indication that the APF group will eventually open up to the idea that not all AIPorphyrics generate heightened urinary biochemicals during acute attacks.
Once scientists discovered that porphyrins and precursors were excreted in the urine, especially during attacks and figured out which chemicals specifically identify ALAs and PBGs (because many substances can impart different colors to urine[lxi]), the practice of uroscopy was abandoned and replaced with chemical urinalysis.
As it turns out, analyzing even normal urine is called for because large amounts of PBG can actually be present even when urine is uncolored. According to the APF website, both ALA and PBG are colorless but “…when present in large amounts in a solution such as urine, PBG can spontaneously form uroporphyrin, which is reddish, and other products that are brownish.” [lxii] Author and chemistry professor Finian Leeper [Biosynthesis: Polyketides and Vitamins, 1998] provides further detail, “The porphryin precursor (PBG) is an unstable molecule and the reddish color in urine arises due to slow reaction of the PBG with oxygen in the air, so normally would only develop if the urine is left to stand for a long time (e.g. a day).” [lxiii] Several sources concurred, “Because PBG is a colorless compound, freshly excreted urine from patients with AIP appears normal in color. On exposure to light and air, two reactions are accelerated that cause PBG containing urine to darken. First, PBG is oxidized to porphobilin, a dark brown, amphorous product. Second, PBG may be non-enzymatically converted to a mixture of porphryins, especially uroproporphyrin, a reaction favored at acidic pH….”[lxiv] “Urine samples must be fresh, especially if [one is] searching for porphobilinogen, since this is converted on standing to a substance resembling porphyrins. It is important to remember…that fresh urine from porphyriuric subjects does not necessarily show any marked abnormality of color, though it will do so upon standing.” [lxv]
I wondered where and how the fluorescence characterization came in. According to Dr. Leeper, “FluoroPBG is…a modified form of the PBG molecule that has a flourine atom replacing a hydrogen atom. It does not occur naturally. The normal PBG is not fluorescent or even coulored…We synthesized FluoroPBG in our lab. As I understand it the clinical test for PBG in urine does not rely on this red colour but tests for the PBG molecule directly.” [lxvi]
Yet another source weighed in, “Theoretically, the urine “dipstick” test for urobilinogen should record porphobilinogen, too. This just doesn’t work in practice, because porphobilinogen is very unstable and there’s not enough to turn color anyway.” [lxvii] Things were beginning to make sense. Porphobilinogen’s color change involves a natural oxidation process. However, to take advantage of PBGs chemical reactivity and to avoid lengthy time needed to let urine samples “age,” chemical testing was developed to speed things up.
For decades, measurement of both urinary ALA and PBG was required to diagnose AIP. Then in 2015, a study done by an APF scientific advisory board member identified ALA as the root of AIP [pain] [lxviii] and although it is unspecific and does not distinguish AIP from other acute porphyrias, experts now contend that measuring urinary PBG is the best biochemical test to diagnose AIP. [lxix] Their position is that unless urinary PBG excretion levels during attack are greater than 5 times the normal level, the cause of the acute activity cannot be ascribed to AIP.[lxx] In fact, one source notes that “screening tests for porphobilinogen may not be positive until the concentration in urine exceeds 10 to 20 times.”[lxxi]
On the other side of the spectrum, information about PBG excretion from a study of 196 DNA-confirmed Finnish patients and their families seems to challenge that: “Because the acute increase in PBG is often modest, the medical history, signs and symptoms must be evaluated carefully during an acute attack…”[lxxii] In a population base with generations of AIPorphyrics available for clinical study, the phrase “PBG is often modest,” [lxxiii] is noteworthy and makes one wonder if “modest” PBG levels” have been documented (and accepted as such) in yet another recognized AIPorphyria population pool, why can’t the US accept similar acute porphyria expression in this country?
To add more ambiguity to the scenario, it is fairly well accepted that concentrations of ALA and PBG vary among individuals…and [that t]he variation among individuals implies a role for genetic and/or environmental modifiers, which is an area of active investigation.[lxxiv] It would be interesting to know who or which entity in the US is actively investigating these “genetic and/or environmental modifiers”[lxxv] that allegedly play a role in generating ALA and PBG concentrations so updates/results on such research can be obtained. In 2007, the Japanese weighed in, “…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.[lxxvi]
Another presentation well known among porphyria experts is that of asymptomatic high excreters or ASHE. These individuals don’t have attacks but generate frequent (sometimes ongoing) high biochemically-imbued urine and are highly coveted as clinical testing subjects. Since learning of this category―individuals who don’t have AIP symptoms yet produce high levels of biochemical “proof,” I haven’t been able to completely wrap my mind around why porphyria experts steadfastly deny the idea that the reverse presentation (AIP symptomatic, sometimes severe, with no, low or infrequent biochemical proof) occurs.
Onerous Testing – With the exception perhaps of certain high-prevalence porphyria populations such as found in Sweden (AIP), South Africa (VP), Norway and Finland (AIP), generally speaking, porphyria testing is problematic the world over. Many US patients and doctors are especially confused and frustrated by the acute porphyria testing process. In answer to a question posed during the FDA/APF meeting concerning patients who don’t have ALA and PBG diagnoses, DNA expert Dr. Desnick’s deliberate response was, “That’s the gold standard (PBG). To do a genetic diagnosis is another level.”[lxxvii] Yet APF’s web site contends that DNA testing “is the most accurate and reliable method for determining if a person has a specific porphyria and is considered the ‘gold standard’ for the diagnosis of genetic disorders.”[lxxviii] The definition of gold standard is, “the supreme example of something against which others are judged or measured.”[lxxix] How could it be that there are two gold standards for testing acute porphyria?
Achieving an acute porphyria diagnosis based on biochemical proof can be wrought with challenges―for patients, caregivers, doctors, lab technicians and pretty much anyone involved. Testing “fresh” urine excreted during acute attack is required. However, some individuals aren’t able to generate urine when having a porphyria attack. And when should the sample be collected? First void? At the “peak?” Anytime extreme pain is felt? Besides, what exactly constitutes an attack? There is no universally accepted agreement regarding exactly what an AIP attack entails: when one begins, what and when constitutes the “peak,” etc. Is random, spot collection or 24 hour collection best? Should both be done? (Remember, the APF expert told me in writing that if I wanted to pursue biochemical testing for my daughter, I should ‘collect a 24 hour urine for ALA and PBG’ and that is what the APF web site indicates should be done.[lxxx])
Shipping may involve hundreds of miles and multiple transfers. I can’t express how many times I’ve been told that a physician, after receiving negative lab results referred to the possibility of specimen “mishandling” or “bad timing” likely being the reason for the disappointing results. To add insult to injury, it is a fairly common occurrence for porphyria lab results to be lost.
Of course, ours is not a perfect world. Reality is that every individual and set of circumstances is unique and subject to a host of procedural, biological and environmental factors. Still, it is not at all unusual for individuals suffering from some pretty severe conditions to undergo the testing process many, many times. In that way, a lot of patients and/or caregivers become proficient overseers of the entire sample process which has sometimes led to dissension between untrained, uninterested or uncaring lab personnel and the patient or caregiver who is trying to make sure that all procedures are carried out in a timely, complete manner.
In mid-March 2017, I happened upon an APF Facebook discussion concerning the frustrations associated with porphyria testing. A patient expressed concern that her sample had been collected more than a week after the attack occurred and was annoyed because lab staff had no idea the sample was to be protected from light. This prompted a response from APF’s executive director who had already posted a reminder about covering samples with aluminum foil. She noted, “For acute porhy [sic] hcp and vp, pbg can be tested up to a week after the attack. For aip, pbg can be tested up to a month after the attack. Light exposure is relative but doesn’t change substantially according to porphyria labs. If it sat all day it might. Note [name of a forum participant] posted that her urine sat in a hot car uncovered for a day or two and it was still high. Research is being done on the light exposure issue.”[lxxxi]
Another participant queried, “So who came up with this rule that light ruins the sample and has to be refrigerated etc…does anyone know how that came about? Especially strange to me, that you can do a home urine by leaving it in the sun and it turning dark has some validity to porphyria. That has always been a contradiction to me…does anyone know the answer to that. Is it because the porphyrins in the light change to dark red color?”[lxxxii]
No one responded to her queries. The concept of PBG/oxidation was not mentioned. And no one took the opportunity to pursue and/or expand on comments made by Drs. Desnick and Anderson during the FDA/APF patient meeting only two weeks prior. At that time. a meeting attendee brought up the “controversy” of some patients having had their acute porphyria diagnoses “taken away” when participating in research projects. The attendee asked Dr. Desnick to address this, which he did by saying, “There are patients that don’t have ALA and PBG diagnoses…if you are symptomatic and if you’re having problems and your doctor thinks you have it, ALA and PBG in the urine is simple, it’s not an expensive test and it’s not influenced by a lot…a lot of people are thinking that well, light influences it, how long it sits and so forth. If you have a high level, you have a high level and you’re not going to change that very much” [lxxxiii] Dr. Anderson added, “There are a lot of people who are misdiagnosed as having porphyria. And so I guess those people might have their diagnosis taken away.”[lxxxiv] He continued, “If someone is having an acute attack, the ALA and PBG will be high” and went on to discuss the scientific group’s “recent” finding concerning so many patients having chronic pain not necessarily associated with high ALA and PBG levels. [lxxxv] The APF executive director then interjected, “These are people whose ALA and PBG are no high during attack. These people complaining of their diagnosis being taken away. What happened was they volunteered for research then they had to get a real diagnosis and don’t understand why you can’t take my diagnosis because [in] a research project, you have to have a real diagnosis and they found out that they do not have it…”[lxxxvi]
I can state with certainty that the reversal of my daughter’s diagnosis in the summer of 2014 had absolutely nothing to do with any APF-sponsored research project. But I was gratified to hear that others—enough to cause a controversy—had expressed similar concerns. The issue of Swedish Porphyria presentation patients’ chronic pain without generating high ALA and PBG levels is just a step in getting to the bottom line of a very concerning three-pronged matter: 1) why not all acute porphyria patients produce high levels of PBG with every attack; 2) why atypical acute porphyria patients produce no or low levels of PBG during attack and 3) why ASHE don’t have symptoms but produce high PBG levels. It seems that the answers lie in what happens between start (gene) and end (excretion of urine) of blood components during the pathophysiological path of acute porphyria.
Childhood AIP – I decided to write Purple Canary largely because the overwhelming prevailing sentiment at the time was that children didn’t “get” AIP. That was wrong then and still is. AIP is an inherited disorder. Children don’t “get” it; if they’ve inherited the gene, they have it. It may go through alternate periods (even long-term) of activity and latency during their lifetime (the reason why Dr. Waldenstrom also noted the non-acute, e.g. chronic, nature of AIP). During a January 2009 medical appointment with an APF expert who met with my then 12-year-old daughter and me, I asked if it was possible that AIP children don’t generate biochemical evidence. I didn’t get a response. After that appointment, I located a 2003 Swedish article about that very subject (mentioned on page 2 of this paper). The article described a study of 61 Swedish DNA AIP-verified children
Another source noted, “prepubertal children usually do not have increased urinary porphyrin metabolites and enzyme analysis in liver or red cell lysates and genetic analysis provide the only means of diagnosis.”[lxxxvii] And another, “[s]ymptoms of porphyria may occur in heterozygotes during childhood…even when urinary porphyria precursors are not elevated.”[lxxxviii]
Porphyria specialists in India reported in 1967 having seen a prepubertal girl with AIP and noted, “More elaborate descriptions of the disease in childhood continue to appear from time to time…It is important to know that acute intermittent porphyria may even occur in children.”[lxxxix] That was fifty years ago and still the concept that children can present with acute porphyria is not widely accepted. I felt validated when I read these articles, but since I couldn’t get a doctor or the experts to even read, never mind corroborate or refute them, we continued to stay stuck.
About a year before my book’s publication, I was contacted by an Australian mother regarding a post I’d made on GlobalGenes.com about my daughter’s lack of urinary proof required to definitively diagnose AIP. This mother shared that two of her three children had been diagnosed with an acute porphyria via DNA testing. The eldest (a girl, same age as my daughter) had recurrent, debilitating symptoms yet had not produced the “requisite” urinary proof. However, her younger brother had produced the favored urinary biochemical profile since the age of seven. So, he was (and still is) provided treatment. His sister was (and still is) not. Flashback to Dr. Waldenstrom’s 1939 case. Similar story. One family, three siblings, same parentage. Different urinary presentations (2 “typical,” 1 “atypical.”) The Australian family also contains 3 siblings. 1 “normal;” 1 “typical” a.p.; 1 “atypical” a.p. Hmmm. The treatment injustice weighs heavy on my mind and heart.
An APF SAB member co-authored an article that was released a few months after Purple Canary’s publication. Interestingly, this article, Acute Intermittent Porphyria in children: A case report and review of the literature made five specific points about the study:
- “Acute Intermittent Porphyria (AIP) rarely presents in childhood.
- First report of a biochemically and genetically confirmed pediatric patient with AIP.
- Seizures may precede the diagnosis in pediatric patients.
- Clinical presentation may include neuropathy, hypertension, and behavioral changes.
- Long term natural history studies are needed in mutation confirmed pediatric patients.”[xc] The same article featured the case of a nine-year old male pediatric patient who “presented with acute abdominal pain, vomiting and constipation followed by hyponatremia, seizures, weakness and neuropathy [and] after a diagnostic odyssey his urine PBG was found to be elevated; genetic testing showed…[HMBS] mutation…confirming the diagnosis of AIP.”[xcii] I located a 2008 India-released article [https://www.tropicalgastro.com/articles/36/4/acute-intermittent.html] that parallels the case of a 9 year old boy. The case of a 10 year old girl was also referenced. Additionally, a symptom roster included in that article noted, “…urine discoloration (pink) [25%].”[xciii] But whether the PBG level was elevated and if the second child’s urine manifested with any coloration was not disclosed. In stark contrast to the 2003 study conducted on DNA-confirmed children studied by Swedish scientists, it appears none of the individuals’ cases mentioned in this article were examined first-hand by US experts.Based on what I’ve seen and what concerned parents who’ve contacted me have shared, the number of US children who present with acute porphyria symptoms appears to be rising—or perhaps it is just that their symptoms are not being dismissed by parents who know better. Yet rather than address the issue head on, APF and its SAB have continued to throw down rumble strips and roadblocks, routinely saying (as they do with adults who don’t fit their acute porphyria “mold”) that the bizarre constellation of physical, neurological and psychiatric symptoms could be due to any number of reasons. That is certainly understood. But the incidence of children born of “questionable, latent or asymptomatic” AIP parentage who exhibit similar symptoms continues. These children’s presentations often mimic those of their parent(s), who themselves contend with unrecognized acute intermittent or other type of acute porphyria. When a child demonstrates symptoms matching parental (or other biological relative’s) known AIP symptomology, it is not only irresponsible to not put AIP on the differential diagnosis list, it is negligent. While the “acute porphyria” in Smeed’s report is not specifically identified as AIP, the story sure matched reports of so many with “questionable” US acute porphyria diagnoses. The case report was itself interesting but Dr. Smeed’s opening statement begs the question, “How many cases of acute porphyria (including AIP) actually are in the US?” One would think that with the limited number of AIP cases touted, it shouldn’t be too difficult to come up with hard numbers to support better responses than, “prevalence of the acute porphyrias has been estimated in several European countries and in the US to be about 2 to 5 symptomatic patients per 100,000 population.”[xcix] Or, “AIP…has a prevalence of about 5 per 100,000 which includes cases that are not manifest or latent;”[c] Or, “approximately 5,000 patients in the US and Europe suffer acute porphyria attacks annually, and approximately 500 patients are afflicted with recurrent debilitating attacks.”[ci] Or, the total number of acute hepatic porphyrias patients is around 37,000 of which about 12,500 patients are symptomatic acute intermittent porphyria patients [including] both the recurrent attack patients as well as the acute attack patients.”[cii]A final point that adds to skepticism about APF statistics involves the acute porphyria known as ALAD (aka ADP). APF states that ALAD is a severe disorder with less than 10 cases identified to date.[cv] Further doubt stems from the fact that ALAD does not appear in the diagnosis and treatment chart found on APF’s website nor is there an option to select ALAD (or ADP) on Mount Sinai’s DNA testing order form. If this is happening worldwide, is it any wonder why the number of ALAD cases hasn’t changed?Conclusion – Andrei Lenkov said, “To not have your suffering recognized is an almost unbearable form of violence.”[cvi]Author Philip Reilly noted that a physician’s main goal is to relieve suffering.[cvii] To get to the truth of what may amount to hundreds of people’s suffering, a convergence of these ideas is imperative. Reilly’s outstanding book also describes how it can take a world’s village of heroic brain (and will-) power, focus, determination, time and financial support to figure out a rare disorder’s pathophysiology before treatment can be considered. Instead, time and attention was afforded to pharmaceutical companies interested in developing therapies to aid the expert-confirmed Swedish porphyria presentation population. Never mind if the biochemical phenomenon happened but one time, the individual is designated as having achieved manifest AIP and is ok’d for treatment. For so many others, getting to that point (if they get to that point) can take years (sometimes decades) of suffering with AIP prodomes, symptoms, attacks and chronic, neurological pain. In our world of quick fixes, doctor after doctor routinely prescribes pharmaceuticals for the litany of symptoms that plague as-yet undiagnosed (or “misdiagnosed) AIPorphyrics. The Chinese proverb, “It is easy to get a thousand prescriptions but hard to get one single remedy” speaks directly to these circumstances. The pharmacogenetic aspect of AIP lends itself to routine, go-to medications possibly inciting acute attacks from which, as the Swedes say, “unfortunate outcomes” may result. In other words: death, paralysis and/or a vegetative state. I can’t imagine even one doctor, patient or caregiver being comfortable with that.
- A long-standing member of APF SAB recently conceded, “So I think that we don’t fully understand the scope of the disease (AIP).”[cviii] From where I and so many others sit, that is a sad reality. Following are thoughts from anonymous patients:
- Unrecognized (or ignored), AIP is potentially life threatening. When my daughter first began presenting with bizarre symptoms that I ultimately found were associated with AIP, that statement punched me in the mom-gut. Having known relatives who’ve lived with different potentially life-threatening illnesses, I assumed that her not producing the “expected” urinary profile was just a glitch in the AIP “spectrum.” But when I heard similar stories from individuals around the world, I knew it wasn’t just a US problem, and that she was not alone. Over the years, the fears of patients who exhibit acute porphyria symptoms but don’t produce urinary biochemical proof and their doctors’ inklings that they were/are possibly dealing with porphyria should have been enough for researchers to commit to sorting out the “questionable/latent/ asymptomatic” mess that has fallen under the AIP umbrella. But it has not been.
- Most sources here and abroad report that the majority of people who inherit a mutated AIP gene don’t ever become symptomatic. In fact, the APF SAB chairman said, “the percent of patients who remain asymptomatic most of their lives [is] greater than 80%.”[ciii] Making such statements is problematic because: 1) the numbers are not verified by independent audit; 2) the fact that great attempts are made to route “AIP diagnostics” through APF and its bevy of medical experts contributes to skepticism, 3) the issue that permeates this paper—denial that individuals who suffer measurable, documented symptoms yet have urinary biochemical output inconsistent with the experts’ immutable diagnosis criterion actually suffer from AIP and, finally, 4) the discrepancy between experts (never having seen never mind examined the persons when in attack) who insist such symptoms are “vague”[civ] and the patients who endure the symptoms/attacks along with the doctors who are at a loss on how to help them.
- US Statistics/AIP Rarity – “It is becoming increasingly clear that the disease [porphyria] is not as rare in this country as has been thought, even in patients with no Scandinavian ancestry.”[xcv] I.M.P. Smeed, former house physician at North Middlesex Hospital in London made this statement—in 1956. The observation preceded a case report of a young woman who’d had, “several epileptiform fits without the development of manifestation in the nervous system.”[xcvi] Prior to that, the twenty-three year old patient had suffered abdominal pain for three months. Nothing abnormal had been noticed “about her urine before, during or after these attacks.”[xcvii] The pain had accelerated so phenobarbitone had been administered intermittently during the four days prior to admission. The patient then suffered a “major epileptiform attack (without incontinence)” which prompted the hospital visit. Once there, more phenobarbitone was administered. She suffered more “fits.” Her urine, left to stand, turned port-wine colored and gave a “[strong] positive reaction to Ehrlich’s aldehyde reagent.”[xcviii] Again, should this patient’s condition have been considered latent prior to the administration of unsafe phenobarbital which created the “necessary” reaction to Ehrlich’s aldehyde? And should phenobarbital be used in an attempt to generate port-wine colored urine? Once again my response is, “Of course not.”
- Sadly, in spite of its proudly touted protect the future program, it appears US experts don’t intend to fully address 1) the occurrence of AIP presentation in children or 2) getting to the root of this typical versus atypical acute porphyria presentation any time soon. Until that happens, protecting the future is simply a marketing phrase without follow-up.
- Finally, the Mount Sinai article noted, “Long term natural history studies are needed in mutation confirmed pediatric patients.” I submit that epidemiological studies are also needed. The article closed with, “Thus, AIP should be considered in the differential diagnosis of children presenting with unexplained abdominal pain, seizures, weakness and neuropathy.”[xciv] Indeed. Just as it should have been when my eleven year old daughter began exhibiting the same symptoms.
- The article states that the authors reviewed “15 reported pediatric cases since the last review 30 years ago” as well as childhood-onset cases reported in an (undated) Porphyrias Consortium-coordinated Longitudinal Study. It also reported that 11 of the 204 genetically and biochemically confirmed (adult) patients in that longitudinal story reported onset of attacks in childhood. [xci] However, nothing was said about any of these adults having produced (and recorded) biochemical confirmation at any time in childhood.
- “It really is not a matter of diagnosis, but preventing attacks. Acute porphyria is a dangerous disease that can’t be monitored. If we could monitor ALA or any relevant enzyme, then at least we would know when a measure was approaching a dangerous level.”
- “My physician is hesitant about APF SAB experts diagnosing off lab reports. I need a statement on the propriety of that.”
- “Most doctors do not comprehend the full-body involvement of acute porphyric activity.”
- “Doctors follow what the experts say and withhold treatment if high levels are not met.” [This causes an untold number of patients to “beat themselves up” because their bodies do not produce what the experts require.]
- “I personally believe that the acute porphyrias are vastly under-diagnosed—everywhere.”
- “[Someone] needs to get to the root of this ‘almost’ AIP thing. I hurt. I suffer. I have a lot pain—a lot of the time. My doctor tells me it should only be intermittent pain but it seems like my attacks go on for weeks.”
- Every doctor takes an oath to do no harm. How is it that these very same doctors can see a patient with all the porphyria symptoms who doesn’t produce the required testing levels and yet refuse to treat the symptoms? How can this not be a violation of this oath?
A life-threatening porphyria medical health crisis has been ignored for too long. Intentionally or not, an acute porphyria hierarchy was established decades ago and has become entrenched. Purple Canary has hit nerves and made waves. That is good. The book has been well received by the most important of audiences—acute porphyrics. That is also good because patients are experts when it comes to living with the disorder. But it is not enough. Atypical AIP adults and child patients continue to be victimized by a medical community led by deniers of their condition and suffering. There is much work to do. First and foremost, the number of AIPorphyrics with Swedish Porphyria presentation and atypical presentation must be determined. Individuals struggling with atypical acute porphyria presentation in particular need the intervention of any and all medical/science organizations with responsibility for overseeing human health issues. Clear delineation (made by unbiased physicians, scientists and other researchers) of the different subsets of each acute porphyria must be established. Only then can the way be cleared for beneficial changes to be made for all those stuck in the porphyria quagmire. The time to start was decades ago.
On behalf of my daughter, the Australian mother’s daughter; the Arizona mother’s son and daughter; the California mother’s daughter; the mother in England and her daughter; the Indiana mother who is caregiver for a very sick atypical acute porphyric man and her daughter; the Nebraska mother’s son; the Oregon mother’s daughter; the Pennsylvania mom and her toddler and the as yet untold number of atypical acute porphyria patients out there I say “Enough is enough. How dare experts continue to minimize the suffering of atypical patients and marginalize their humanity! Pushing them to severely destructive health conditions, financial ruin and/or suicidal ideation, attempt or success is the gut-roiling antithesis of what medical expertise stands for. All purple canaries (porphyrics) deserve to have their porphyria type (typical and/or atypical, symptomatic or asymptomatic) realistically and objectively fully identified, acknowledged and treated as necessary.”
“I will respect the hard-won, scientific gains of those physicians in whose steps I walk, and will gladly share such knowledge as is mine with those who are to follow. I will not be ashamed to say “I know not” nor will I fail to call in my colleagues when the skills of another are needed for a patient’s recovery. I will remember that I do not treat a fever chart, a cancerous growth, but a sick human being, whose illness may affect the person’s family and economic stability. I will prevent disease whenever I can, for prevention is preferable to care. Above all, I must not play God.”[cix]
As a caregiver having become familiar with all that acute porphyria brings, I am continually humbled by all that porphyrics endure. Besides the wretched, debilitating physical, neurological and psychiatric pain, the financial burden and societal strain that comes with having porphyria of any type can be overwhelming. And for those who become parents of children with symptoms that mimic parental or other relatives’ symptomology, the burden is even heavier.
I was blessed to have found closed Facebook communities filled with atypical porphyria presenters when I did. For I have learned much from so many intelligent, compassionate, generous porphyrics and caregivers. I offer special thanks to A. Ballan; S. Gwinn.; A. Lankeuau; L. Meyer.; K. Pelton; W. Petit.; L. Riddle and B.Wilcox. The burning desire of each of these exceptional women to effect change in the lives of porphyrics in the midst of their own very challenging lives is truly remarkable.
[i] Waldenstrom, Jan; Neurological Symptoms Caused by Socalled Acute Porphyria; pub. in Acta Psychiatrica Scandinavica; Wiley Online Library; June 1939; https://onlinelibrary.wiley.com/doi/10.111/j.1600-0447.1939.tb06652.x/abstract
[ii] Anonymous; patient guaranteed privacy.
[iii] Besur, Hou, Smeltzer, Bonkovsky; Clinically Important Features of Porphyrins and Heme Metabolism and the Porphyrias; www.mdpi.com/2218-1989/4/4/977/htm; published online by Metabolites; Nov 2014.
[iv] Lyon, Desiree; APF Facebook post; Sept 16, 2016 (10:02 PM).
[v] Reilly, Philip R.; Orphan, The Quest to Save Children with Rare Genetic Disorders; Cold Spring Habor,NY, Cold Spring Harbor Laboratories Press; 2015; xvii.
[viii] Genetics Home Reference; Founder effect definition; http://ghr.nlm.nih.gov/glossary=foundereffect
[ix] http://focus-migration. hwwi.de/Sweden.6254.0.html.?&L=1
[xiii] Lithner, et al of Swedish Information Centre for Rare Diseases; English version; 3/23/2015; http://www.socialstyrelsen.se/rarediseases/acuteintermittentporphyria.
[xiv] Ibid. 5.
[xvi] Waldenstrom, Jan; Neurological Symptoms Caused by Socalled Acute Porphyria; pub. in Acta Psychiatrica Scandinavica; Wiley Online Library; June 1939; https://onlinelibrary.wiley.com/doi/10.111/j.1600-0447.1939.tb06652.x/abstract
[xvii] Email response from expert @ Karolinska Institute, Stockholm. June 19, 2015.
[xix] Desnick, R.J.; Alnylam Pharmaceuticals’ RNAi Roundtable Session transcript; Sep 24, 2015
[xxi] Howe, Desiree Lyon; Porphyria, A Lyon’s Share of Trouble; Howewrite, Inc.; 2004; 22.
[xxii] Howe, Desiree Lyon; Porphyria, The Movie; youtube presentation; https://www.youtube.com/watch?Tpuhm2ljzo8; @25:33
[xxiv] Porphobilinogen, Reference range; http://emedicine.medscape.com/article/2088383-overview
[xxv] Chen…Desnick et al; Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease; pub in Human Mutation, Vol 37, Issue 11; November 2016; https://onlinelibrary.wiley.com/doi/10.1002/humu.23067/
[xxviii] Beck, Michael; Rare and Ultra Rare Diseases?; Journal of Developing Drugs; February 10, 2012; 2. http://www.omicsgroup.org/journals/rare-and-ultra-rare-diseases-2329-6631.1000e107.ph….
[xxix] Chen…Desnick et al; Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease; pub in Human Mutation, Vol 37, Issue 11; November 2016; 4; http://onlinelibrary.wiley.com/doi/10,1002/humu.23067/full
[xxxiii] Fukuda, et al; The severity of hereditary porphyria is modulated by the porphyrin exporter and Lan antigen ABCB6; August 2016; https:www.ncbi.nlm.nih.gov/pmc/articles/PMC4987512
[xxxviii] Bustad, et al University of Bergen and Norwegian Porphyria Center; Conformational stability and activity analysis of two hydroxymethylbilane synthase mutants K132N and V215E, with different phenotypic association with acute intermittent porphyria; pub. Bioscience Reports, Jul 02, 2013.
[xli] Desnick, Robert; PhD, MD, director, Porphyria DNA Laboratory, Mount Sinai Genetic Testing Laboratory; letter to my daughter’s primary care physician; Jun 12, 2014.
[xlii] Tishler Peter, MD; Channing Division of Network Medicine, Brigham and Women’s Hospital/Harvard Medical School, letter addressed to Dr. Joyce Gould; Jun 4, 2015
[xliii] Desnick, Robert; PhD, MD, director, Porphyria DNA Laboratory, Mount Sinai Genetic Testing Laboratory; letter to my daughter’s primary care physician; Jun 12, 2014.
[xlvi] Mustajoki, Sami; Molecular Genetics of Acute Intermittent Porphyria in Finland; ethethis.helsinki.fi/julkaisut/laa/klinn/vk/mustajoki/review.html; University of Helsinky; 1999.
[xlix] Tanaka, et al; Long-term Follow-up of Erythrocyte Porphobilinogen Deaminase Activity in a Patient With Acute Intermittent Porphyria: The Relationship between the Enzyme Activity and Abdominal Pain Attacks; pub. in Bulletin of the Osaka Medical College; June 18, 2007.
[lii] Ajoika, Phillips, Kushner; Biosynthesis of heme in mammals; porphyria:pdf-doi:10.1016/j.bbamcr.2006.05.005
[liii] >Testing and treatment>Testing for porphyria> Porphryins and porphyria diagnosis; www.porphyriafoundation.com
[lv] Oglivie, et al; Erthyropoietin stimulates proliferation and interferes with differentiation of myoblasts;//www/ncbi.nlm.nih.gov/pubmed/10995753
[lvi] https://en.wikipedia.org/wiki/Erthropoiesis and www.interactive-biology.com/3969.erythropoiesis-formation-of-red-blood-cells by Paul S.
[lviii] Patient Focused Drug Development (PFDD) meeting for the Acute Porphyrias, Wednesday March 1,2017; Meeting sponsored and managed by the American Porphyria Foundation; https://www.youtube.com/watch?v=urHxVYVAals
[lx] Puri, Dinesh; Textbook of Medical Biology; Elsevier; 2011; 340.
[lxiii] Leeper, F; Email to author; Aug 22, 2016
[lxiv] Kauppinin, von und zu Fraunberg; Molecular and Biochemical Studies of Acute Intermittent Porphyria in 196 Patients and Their Families; November 2002; 2; http://clinchem.aaccjnls.org/content/48/11/1891.full?related-urls=yes148/11/1891.
[lxv] Lynch, MD, Matthew; Medical Laboratory Technology and Clinical Pathology, 1969; pub. W.B. Saunders Company; 410.
[lxvi] Leeper, Finian Dr.; email response to the author; Aug 22, 2016.
[lxvii] Friedlander, Dr.; The Pathology Guy, Kansas City MO; www.pathguy.com
[lxix] Kauppinin, von und zu Fraunberg; Molecular and Biochemical Studies of Acute Intermittent Porphyria in 196 Patients and Their Families; Nov 2002; 2; http://clinchem.aaccjnls.org/content/48/11/1891.full?related-urls=yes148/11/1891.
[lxxi] Bick, Roger; Hematology Clinical & Laboratory Practice, Volume 1; Mosby; 1993; 588.
[lxxii] Kauppinin, von und zu Fraunberg; Molecular and Biochemical Studies of Acute Intermittent Porphyria in 196 Patients and Their Families; Nov 2002; 2; http://clinchem.aaccjnls.org/content/48/11/1891.full?related-urls=yes148/11/1891.
[lxxiv] Bissell, D.M.; Role of delta-Aminolevulinic Acid in the Symptoms of Acute Porphyria; Nov 2014; https://www.ncbi.nlm.nih
[lxxvi] Tanaka, et al; Long-term Follow-up of Erythrocyte Porphobilinogen Deaminase Activity in a Patient With Acute Intermittent Porphyria: The Relationship between the Enzyme Activity and Abdominal Pain Attacks; pub. in Bulletin of the Osaka Medical College; June 18, 2007.
[lxxvii] Patient Focused Drug Development (PFDD) meeting for the Acute Porphyrias, Wednesday March 1,2017; Meeting sponsored and managed by the American Porphyria Foundation; (~3:13:53 on video).
[lxxviii] www.porphyriafoundation.com; >Testing for Porphyrias>DNA Testing for Porphyria
[lxxix] http://www.the freedictionary.com/gold-standard;
[lxxx] www.porphyriafoundation.com; >Testing for Porphyria>Directions for Collecting a 24-hour Urine Sample
[lxxxi] Lyon, D.; APF Facebook page, March 18, 2017 9:36 pm
[lxxxii] Name withheld for privacy, APF Facebook open forum, March 19, 2017.
[lxxxiii] Patient Focused Drug Development (PFDD) meeting for the Acute Porphyrias, Wednesday March 1,2017; Meeting sponsored and managed by the American Porphyria Foundation; (~3:14:23 on video).
[lxxxiv] Ibid. (3:13:53)
[lxxxv] Ibid. (3:14:43)
[lxxxvi] Ibid. (3:16:52)
[lxxxvii] Suchy, Soko, Balistreri; Liver Diseases in Children; pub Lippincott Williams & Wilkins; 2001. 655
[lxxxviii] Kliegman, et al; Nelson Textbook of Pediatrics, Elsevier; 2016. 762
[lxxxix] Singh, Chugh; More on porpyrias; http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)71079-5/fulltext; 2005.
[xc] Balwani, Desnick et al; Intermittent Porphyria in children: A case report and review of the literature; pub. Molecular Genetics and Metabolism, Elsevier; Dec 2016; http://sciencedirect.com/science/article//pii/S1096719216301706; Acute.
[xciii] Shrivastava; Acute intermittent porphyria: a missed diagnosis in pre-puteral children with abdominal pain; http://www.tropicalgastro.com/articles/36/4/acute-intermittent-html.
[xciv] Balwani, Desnick et al; Acute Intermittent Porphyria in children: A case report and review of the literature; pub. Molecular Genetics and Metabolism, Elsevier; Dec 2016; http://sciencedirect.com/science/article//pii/S1096719216301706;.
[xcv] Smeed, I.M.P.; Acute Porphyria With Epileptiform Convulsions; https://www.ncbi.nlm.nih.gov/pubmed/13388999 ; 1956.
[c] Anderson, K.A.; Alnylam Pharmaceuticals RNAi Roundtable; August 21, 2014.
[cii] Anderson, K; Alnylam Pharmaceuticals RNAI Roundtable, Aug 21, 2014
[cvi] Lenkov, Andre; www.goodreads.com/6507239-to-not-have-your-suffering….
[cvii] Reilly, Philip; Orphan: The Quest to Save Children with Rare Genetic Disorders; pub. Cold Spring Harbor Laboratory Press; 2015; ix.
[cviii] Desick, R.J.; Alnylam Pharmaceuticals RNA1 Roundtable Session; September 24, 2015
[cix] From Hippocratic Oath; http://www.medicinenet.com/script/main/art.asp?articlekey=20909