Acute intermittent porphyria

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Acute intermittent porphyria
Other namesSwedish porphyria, pyrroloporphyria, intermittent acute porphyria
Porphobilinogen.png
Porphobilinogen
Specialty Medical genetics

Acute intermittent porphyria (AIP) is a rare metabolic disorder affecting the production of heme resulting from a deficiency of the enzyme porphobilinogen deaminase. It is the most common of the acute porphyrias. [1] [2] [3]

Contents

Signs and symptoms

The clinical presentation of AIP is highly variable and non-specific. The patients are typically asymptomatic, with most gene carriers having no family history because the condition had remained latent for several generations. The syndrome marked by acute attacks affects only 10% of gene carriers. [4] The mean age at diagnosis is 33 years old. [5] Like other porphyrias, AIP is more likely to present in women. [6] A distinguishing feature of AIP that separates it from other porphyrias is the absence of photosensitive cutaneous symptoms that occur in addition to acute attacks. [7]

Acute attacks

AIP is one of the four porphyrias that presents as an acute attack. 90% of affected individuals never experience an acute attack and are asymptomatic, while an estimated 5% of affected individuals experience repeat attacks. [8] Attacks are most common in young adult women and are rare before puberty or after menopause. [9] Severe acute attacks may require hospitalization. Patients usually experience symptoms in attacks that last from several hours to a few days. Between attacks, patients are asymptomatic.[ citation needed ]

The most frequent presenting symptoms are abdominal pain and tachycardia. [10] The abdominal pain is typically severe, colicky, poorly localized, and often associated with pain in back and legs. [10] [11] Patients may also present with vomiting and constipation, but diarrhea is unusual. [11] The onset of back and leg pain is characterized by severe pain and stiffness in back and thighs followed by loss of tendon reflexes and paralysis. [12] Psychiatric symptoms are present, such as paranoid schizophrenia-like features but rarely psychosis and hallucinations. [4] The acute attacks classically present with dark-red photosensitive urine (often called port-wine urine), but this is a nonspecific symptom. [13] Physical examination often shows no abnormalities. [14]

Hyponatremia is the most common electrolyte abnormality during acute attacks, occurring in 40% of patients and presenting as SIADH. [15] Hypomagnesemia is also common. There are no pathognomonic signs or symptoms.[ citation needed ]

The most common identified triggers for acute attacks are medications, weight loss diets, and surgery. [16] Many medications have been associated with AIP including antibiotics, hormonal contraceptives, seizure medications, anesthetics, and HIV treatment drugs. [17]

Cause

Porphyrias are caused by mutations in genes that encode enzymes in heme synthesis. In normal physiology, heme synthesis begins in the mitochondrion, proceeds into the cytoplasm, and finishes back in the mitochondrion. Heme is produced in all cells, but 80% of all heme is produced in erythropoietic cells in bone marrow and 15% in parenchymal cells in the liver, where turnover of hemoproteins is high. In AIP, over 100 mutations have been identified on the long arm of chromosome 11 at the HMBS gene, which codes for the cytoplasmic enzyme porphobilinogen deaminase. [18] This deficiency prevents heme synthesis, which can not be completed and the metabolite porphobilinogen accumulates in the cytoplasm. [19]

AIP is an autosomal dominant porphyria resulting in about 50% normal activity of the affected enzyme. [20] The penetrance of AIP is incomplete with only 10% of gene carriers experiencing acute attacks suggesting role for other modifying genes or environment. [21] [22] [23]

The exact mechanism of acute attacks is not clear. The most favored hypothesis is that porpholobilinogen buildup causes a toxic effects on neurons. The autonomic and peripheral nervous system are more vulnerable than the central nervous system because they are not protected by the blood-brain barrier. [24] This explains findings such as abdominal pain and tachycardia. Some individuals may be more likely to develop paresis based on increased susceptibility of neurons to toxins. [25]

Genetics

Inheritance

AIP has an autosomal dominant pattern of inheritance. [26] The dominance pattern is a result of partial deficiencies from the heme biosynthesis enzymes, hydroxymethylbilane synthase  (HMBS;  EC  2.5.1.61). [27] Due to the rarity of this disease it is difficult to estimate the prevalence of AIP and the inclusion criteria differs widely among studies causing varying statistics. AIP has a low penetrance when considering the general population, but within families the penetrance increases. [28] This is indicative of another interaction affecting the inheritance pattern. It is speculated that this pattern is due to AIP propensity caused by the inheritance of an additional gene mutation, HMBS, in addition to other genetic and environmental influences. There have been 421 HMBS mutations that have been linked to AIP. This suggests that AIP inheritance instead follows an oligogenic or polygenic inheritance pattern. Research shows that HMBS mutations are estimated to occur in approximately 1 in 1700 caucasians (there is not enough data in other populations) while AIP symptoms are shown to be present in approximately 1 in 200,000 caucasians. It can be inferred that the penetrance of AIP is approximately 1% of the HMBS heterozygous community, concluding that there are other factors needed to induce AIP symptoms.[ citation needed ]

Variants of AIP

There have been more than 400 mutations in the heme biosynthesis identified to cause AIP. In the erythroid variant, mutations in the exon 1 sequence of the housekeeping gene, splicing of exon 1, and splicing of exon 3 causes an alternative form of AIP wherein there is decreased activity of the liver enzyme but erythroid cells have regular activity. HMBS has two isoforms, housekeeping and erythroid. Additionally, there is also the non-erythroid variant of AIP in which there are mutations in exons 3-15 and there is decreased activity in both isozymes. Most individuals with AIP have mutations in exons 3–15. Loss of function mutations of HMBS cause decreased activity of the enzymes normally present.[ citation needed ]

Diagnosis

The initial diagnosis of acute porphyria is confirmed by urinalysis, including the common method, the Watson-Schwartz test. Elevated urine porphobilinogen confirms diagnosis of AIP, hereditary coproporphyria (HCP), or variegate porphyria (VP). A positive test should be indicated with an increase of five times normal, not just a slight increase which can occur with dehydration. To distinguish between AIP from HCP and VP, fecal porphyrin levels are normal in AIP but elevated in HCP and VP.[ citation needed ]

Rapid, accurate diagnosis is important. Delays in diagnosis may result in permanent neurological damage or death.[ citation needed ]

Diagnosis with Genetic Testing

With advancement and increased accessibility to genetic testing and follow up counseling, the morbidity of AIP has decreased because of early diagnosis. The combination of targeted mutation analysis and biochemical activity tracking have provided positive results for identifying the risk of AIP development. Mutation analysis has a 95% sensitivity and a 100% specificity for confirmation of pathogenicity of a mutation. Genetic testing can detect AIP in patients with symptoms that would have otherwise gone undiagnosed or misdiagnosed. The biochemical analysis route of detection is slightly less accurate compared to genetic testing, which has 84% sensitivity and 71% specificity, but is still chosen over other alternatives and can provide some of the predictive information that genetic testing does. Patients diagnosed with genetic testing at the asymptomatic stage were less likely to develop symptoms throughout their life. Additionally, individuals who were diagnosed at the symptomatic stage encountered more mild attacks after diagnosis, although they still had symptoms. Genetic testing availability has decreased the rate of patients seeking treatment by medical staff, as patients experiencing less severe symptoms instead opt to self treat at home.[ citation needed ]

Treatment

If drugs have caused the attack, discontinuing the offending substances is essential. A high-carbohydrate (10% glucose) infusion is recommended, which may aid in recovery.[ citation needed ]

Hemin(Hematin) Hemin.svg
Hemin(Hematin)

Hematin and heme arginate is the treatment of choice during an acute attack. Heme is not a curative treatment, but can shorten attacks and reduce the intensity of an attack. Side-effects are rare but can be serious.[ citation needed ] Pain is extremely severe and almost always requires the use of opiates to reduce it to tolerable levels. Pain should be treated as early as medically possible due to its severity.

Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot water baths or showers may lessen nausea temporarily, but can present a risk of burns or falls. [29]

Seizures often accompany this disease. Most seizure medications exacerbate this condition due to their induction of cytochrome P450. Treatment can be problematic: Barbiturates and primidone must be avoided as they commonly precipitate symptoms. [30] Some benzodiazepines are safe, and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regimen for seizure control.[ citation needed ]

Society

One of the many hypothesized diagnoses of the artist Vincent van Gogh is that he and his siblings, in particular his brother Theo, had AIP and syphilis. [31] Another theorized case was King George III of the United Kingdom [32] who even had a medallion struck to commemorate his "curing". His descendant Prince William of Gloucester was reliably diagnosed with variegate porphyria in 1968. [33] It is probable that the philosopher Jean-Jacques Rousseau had porphyria. [34] [35] [36] [37] It has even been suggested that Vlad III, Prince of Wallachia, more commonly known by his surname Dracula, had porphyria.

Related Research Articles

<span class="mw-page-title-main">Porphyria</span> Group of inherited metabolic disorders

Porphyria is a group of disorders in which substances called porphyrins build up in the body, adversely affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are rapid in onset and short in duration. Symptoms of an attack include abdominal pain, chest pain, vomiting, confusion, constipation, fever, high blood pressure, and high heart rate. The attacks usually last for days to weeks. Complications may include paralysis, low blood sodium levels, and seizures. Attacks may be triggered by alcohol, smoking, hormonal changes, fasting, stress, or certain medications. If the skin is affected, blisters or itching may occur with sunlight exposure.

<span class="mw-page-title-main">Heme</span> Chemical coordination complex of an iron ion chelated to a porphyrin

Heme, or haem, is a ring-shaped iron-containing molecular component of hemoglobin, which is necessary to bind oxygen in the bloodstream. It is composed of four pyrrole rings with 2 vinyl and 2 propionic acid side chains. Heme is biosynthesized in both the bone marrow and the liver.

<span class="mw-page-title-main">Familial Mediterranean fever</span> Medical condition

Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781–amino acid protein called pyrin. While all ethnic groups are susceptible to FMF, it usually occurs in people of Mediterranean origin—including Sephardic Jews, Mizrahi Jews, Ashkenazi Jews, Assyrians, Armenians, Azerbaijanis, Druze, Levantines, Kurds, Greeks, Turks and Italians.

<span class="mw-page-title-main">Hereditary coproporphyria</span> Medical condition

Hereditary coproporphyria (HCP) is a disorder of heme biosynthesis, classified as an acute hepatic porphyria. HCP is caused by a deficiency of the enzyme coproporphyrinogen oxidase, coded for by the CPOX gene, and is inherited in an autosomal dominant fashion, although homozygous individuals have been identified. Unlike acute intermittent porphyria, individuals with HCP can present with cutaneous findings similar to those found in porphyria cutanea tarda in addition to the acute attacks of abdominal pain, vomiting and neurological dysfunction characteristic of acute porphyrias. Like other porphyrias, attacks of HCP can be induced by certain drugs, environmental stressors or diet changes. Biochemical and molecular testing can be used to narrow down the diagnosis of a porphyria and identify the specific genetic defect. Overall, porphyrias are rare diseases. The combined incidence for all forms of the disease has been estimated at 1:20,000. The exact incidence of HCP is difficult to determine, due to its reduced penetrance.

<span class="mw-page-title-main">Variegate porphyria</span> Medical condition

Variegate porphyria, also known by several other names, is an autosomal dominant porphyria that can have acute symptoms along with symptoms that affect the skin. The disorder results from low levels of the enzyme responsible for the seventh step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

<span class="mw-page-title-main">Porphyria cutanea tarda</span> Medical condition

Porphyria cutanea tarda is the most common subtype of porphyria. The disease is named because it is a porphyria that often presents with skin manifestations later in life. The disorder results from low levels of the enzyme responsible for the fifth step in heme production. Heme is a vital molecule for all of the body's organs. It is a component of hemoglobin, the molecule that carries oxygen in the blood.

<span class="mw-page-title-main">Erythropoietic protoporphyria</span> Medical condition

Erythropoietic protoporphyria is a form of porphyria, which varies in severity and can be very painful. It arises from a deficiency in the enzyme ferrochelatase, leading to abnormally high levels of protoporphyrin in the red blood cells (erythrocytes), plasma, skin, and liver. The severity varies significantly from individual to individual.

<span class="mw-page-title-main">Gunther disease</span> Medical condition

Gunther disease is a congenital form of erythropoietic porphyria. The word porphyria originated from the Greek word porphura. Porphura actually means "purple pigment", which, in suggestion, the color that the body fluid changes when a person has Gunther's disease. It is a rare, autosomal recessive metabolic disorder affecting heme, caused by deficiency of the enzyme uroporphyrinogen cosynthetase. It is extremely rare, with a prevalence estimated at 1 in 1,000,000 or less. There have been times that prior to birth of a fetus, Gunther's disease has been shown to lead to anemia. In milder cases patients have not presented any symptoms until they have reached adulthood. In Gunther's disease, porphyrins are accumulated in the teeth and bones and an increased amount are seen in the plasma, bone marrow, feces, red blood cells, and urine.

<span class="mw-page-title-main">Protoporphyrinogen oxidase</span>

Protoporphyrinogen oxidase or protox is an enzyme that in humans is encoded by the PPOX gene.

<span class="mw-page-title-main">Uroporphyrinogen III decarboxylase</span> Mammalian protein found in Homo sapiens

Uroporphyrinogen III decarboxylase is an enzyme that in humans is encoded by the UROD gene.

<span class="mw-page-title-main">GATA1</span> Protein-coding gene in humans

GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.

<span class="mw-page-title-main">Porphobilinogen deaminase</span>

Porphobilinogen deaminase (hydroxymethylbilane synthase, or uroporphyrinogen I synthase) is an enzyme (EC 2.5.1.61) that in humans is encoded by the HMBS gene. Porphobilinogen deaminase is involved in the third step of the heme biosynthetic pathway. It catalyzes the head to tail condensation of four porphobilinogen molecules into the linear hydroxymethylbilane while releasing four ammonia molecules:

<span class="mw-page-title-main">Coproporphyrinogen III oxidase</span> Mammalian protein found in Homo sapiens

Coproporphyrinogen-III oxidase, mitochondrial is an enzyme that in humans is encoded by the CPOX gene. A genetic defect in the enzyme results in a reduced production of heme in animals. The medical condition associated with this enzyme defect is called hereditary coproporphyria.

<span class="mw-page-title-main">Ferrochelatase</span>

Protoporphyrin ferrochelatase (EC 4.98.1.1, formerly EC 4.99.1.1, or ferrochelatase; systematic name protoheme ferro-lyase (protoporphyrin-forming)) is an enzyme encoded by the FECH gene in humans. Ferrochelatase catalyses the eighth and terminal step in the biosynthesis of heme, converting protoporphyrin IX into heme B. It catalyses the reaction:

Erythropoietic porphyria is a type of porphyria associated with erythropoietic cells. In erythropoietic porphyrias, the enzyme deficiency occurs in the red blood cells.

<span class="mw-page-title-main">Delta-aminolevulinic acid dehydratase</span> Protein-coding gene in the species Homo sapiens

Aminolevulinic acid dehydratase (porphobilinogen synthase, or ALA dehydratase, or aminolevulinate dehydratase) is an enzyme (EC 4.2.1.24) that in humans is encoded by the ALAD gene. Porphobilinogen synthase (or ALA dehydratase, or aminolevulinate dehydratase) synthesizes porphobilinogen through the asymmetric condensation of two molecules of aminolevulinic acid. All natural tetrapyrroles, including hemes, chlorophylls and vitamin B12, share porphobilinogen as a common precursor. Porphobilinogen synthase is the prototype morpheein.

<span class="mw-page-title-main">ALAS2</span> Protein-coding gene in humans

Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein that in humans is encoded by the ALAS2 gene. ALAS2 is an aminolevulinic acid synthase.

<span class="mw-page-title-main">Cryopyrin-associated periodic syndrome</span> Medical condition

Cryopyrin-associated periodic syndrome (CAPS) is a group of rare, heterogeneous autoinflammatory disease characterized by interleukin 1β-mediated systemic inflammation and clinical symptoms involving skin, joints, central nervous system, and eyes. It encompasses a spectrum of three clinically overlapping autoinflammatory syndromes including familial cold autoinflammatory syndrome, the Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease that were originally thought to be distinct entities, but in fact share a single genetic mutation and pathogenic pathway, and keratoendotheliitis fugax hereditaria in which the autoinflammatory symptoms affect only the anterior segment of the eye.

<span class="mw-page-title-main">Aminolevulinic acid dehydratase deficiency porphyria</span> Medical condition

Aminolevulinic acid dehydratase deficiency porphyria is an extremely rare autosomal recessive metabolic disorder that results from inappropriately low levels of the enzyme delta-aminolevulinic acid dehydratase (ALAD), which is required for normal heme synthesis. This deficiency results in the accumulation of a toxic metabolic precursor in the heme synthesis pathway called aminolevulinic acid (ALA). Lead poisoning can also disrupt ALAD and result in elevated ALA causing the same symptoms. Heme is a component of hemoglobin which carries oxygen in red blood cells.

<span class="mw-page-title-main">Harderoporphyria</span> Medical condition

Harderoporphyria is a rare disorder of heme biosynthesis, inherited in an autosomal recessive manner caused by specific mutations in the CPOX gene. Mutations in CPOX usually cause hereditary coproporphyria, an acute hepatic porphyria, however the K404E mutation in a homozygous or compound heterozygous state with a null allele cause the more severe harderoporphyria. Harderoporphyria is the first known metabolic disorder where the disease phenotype depended on the type and location of the mutations in a gene associated with multiple disorders.

References

  1. ↑ Whatley SD, Roberts AG, Llewellyn DH, Bennett CP, Garrett C, Elder GH (September 2000). "Non-erythroid form of acute intermittent porphyria caused by promoter and frameshift mutations distant from the coding sequence of exon 1 of the HMBS gene". Human Genetics. 107 (3): 243–8. doi:10.1007/s004390000356. PMID   11071386. S2CID   40036227.
  2. ↑ Solis C, Martinez-Bermejo A, Naidich TP, Kaufmann WE, Astrin KH, Bishop DF, Desnick RJ (November 2004). "Acute intermittent porphyria: studies of the severe homozygous dominant disease provides insights into the neurologic attacks in acute porphyrias". Archives of Neurology. 61 (11): 1764–70. doi: 10.1001/archneur.61.11.1764 . PMID   15534187.
  3. ↑ Diseases of Tetrapyrrole Metabolism - Refsum Disease and the Hepatic Porphyrias at eMedicine
  4. 1 2 Narang, Neatu; Banerjee, A; Kotwal, J; Kaur, Jasmeet; Sharma, YV; Sharma, CS (April 2003). "Psychiatric Manifestations in three cases of Acute Intermittent Porphyria". Medical Journal, Armed Forces India. 59 (2): 171–173. doi:10.1016/S0377-1237(03)80075-8. ISSN   0377-1237. PMC   4923792 . PMID   27407502.
  5. ↑ Elder, George; Harper, Pauline; Badminton, Michael; Sandberg, Sverre; Deybach, Jean-Charles (September 2013). "The incidence of inherited porphyrias in Europe". Journal of Inherited Metabolic Disease. 36 (5): 849–857. doi:10.1007/s10545-012-9544-4. ISSN   1573-2665. PMID   23114748. S2CID   20442163.
  6. ↑ Puy, Hervé; Gouya, Laurent; Deybach, Jean-Charles (2010-03-13). "Porphyrias". Lancet. 375 (9718): 924–937. doi:10.1016/S0140-6736(09)61925-5. ISSN   1474-547X. PMID   20226990. S2CID   208791867.
  7. ↑ Stein, Penelope; Badminton, Mike; Barth, Julian; Rees, David; Stewart, M. Felicity; British and Irish Porphyria Network (May 2013). "Best practice guidelines on clinical management of acute attacks of porphyria and their complications". Annals of Clinical Biochemistry. 50 (Pt 3): 217–223. doi: 10.1177/0004563212474555 . ISSN   1758-1001. PMID   23605132.
  8. ↑ Elder, George; Harper, Pauline; Badminton, Michael; Sandberg, Sverre; Deybach, Jean-Charles (2012-11-01). "The incidence of inherited porphyrias in Europe". Journal of Inherited Metabolic Disease. 36 (5): 849–857. doi:10.1007/s10545-012-9544-4. ISSN   0141-8955. PMID   23114748. S2CID   20442163.
  9. ↑ Besur, Siddesh; Hou, Wehong; Schmeltzer, Paul; Bonkovsky, Herbert L. (2014-11-03). "Clinically important features of porphyrin and heme metabolism and the porphyrias". Metabolites. 4 (4): 977–1006. doi: 10.3390/metabo4040977 . ISSN   2218-1989. PMC   4279155 . PMID   25372274.
  10. 1 2 Besur, Siddesh; Schmeltzer, Paul; Bonkovsky, Herbert L. (September 2015). "Acute Porphyrias". The Journal of Emergency Medicine. 49 (3): 305–312. doi:10.1016/j.jemermed.2015.04.034. ISSN   0736-4679. PMID   26159905.
  11. 1 2 Kauppinen, Raili (15–21 Jan 2005). "Porphyrias". Lancet. 365 (9455): 241–252. doi:10.1016/s0140-6736(05)70154-9. ISSN   1474-547X. PMID   15652607.
  12. ↑ Pischik, E.; Kauppinen, R. (2009-02-16). "Neurological manifestations of acute intermittent porphyria". Cellular and Molecular Biology (Noisy-Le-Grand, France). 55 (1): 72–83. ISSN   1165-158X. PMID   19268005.
  13. ↑ Yuan, Tao; Li, Yu-Hui; Wang, Xi; Gong, Feng-Ying; Wu, Xue-Yan; Fu, Yong; Zhao, Wei-Gang (2015-07-20). "Acute Intermittent Porphyria: A Diagnostic Challenge for Endocrinologist". Chinese Medical Journal. 128 (14): 1980–1981. doi: 10.4103/0366-6999.160621 . ISSN   0366-6999. PMC   4717930 . PMID   26168842.
  14. ↑ Karim, Zoubida; Lyoumi, Said; Nicolas, Gael; Deybach, Jean-Charles; Gouya, Laurent; Puy, Hervé (September 2015). "Porphyrias: A 2015 update". Clinics and Research in Hepatology and Gastroenterology. 39 (4): 412–425. doi:10.1016/j.clinre.2015.05.009. ISSN   2210-7401. PMID   26142871.
  15. ↑ Karim, Zoubida; Lyoumi, Said; Nicolas, Gael; Deybach, Jean-Charles; Gouya, Laurent; Puy, Hervé (September 2015). "Porphyrias: A 2015 update". Clinics and Research in Hepatology and Gastroenterology. 39 (4): 412–425. doi:10.1016/j.clinre.2015.05.009. ISSN   2210-741X. PMID   26142871.
  16. ↑ Bonkovsky, Herbert L.; Maddukuri, Vinaya C.; Yazici, Cemal; Anderson, Karl E.; Bissell, D. Montgomery; Bloomer, Joseph R.; Phillips, John D.; Naik, Hetanshi; Peter, Inga (December 2014). "Acute porphyrias in the USA: features of 108 subjects from porphyrias consortium". The American Journal of Medicine. 127 (12): 1233–1241. doi:10.1016/j.amjmed.2014.06.036. ISSN   1555-7162. PMC   4563803 . PMID   25016127.
  17. ↑ Dhital, Rashmi; Basnet, Sijan; Poudel, Dilli Ram; Bhusal, Khema Raj (2017-06-06). "Acute intermittent porphyria: a test of clinical acumen". Journal of Community Hospital Internal Medicine Perspectives. 7 (2): 100–102. doi:10.1080/20009666.2017.1317535. ISSN   2000-9666. PMC   5473191 . PMID   28638573.
  18. ↑ Herrick, Ariane L.; McColl, Kenneth E. L. (April 2005). "Acute intermittent porphyria". Best Practice & Research. Clinical Gastroenterology. 19 (2): 235–249. doi:10.1016/j.bpg.2004.10.006. ISSN   1521-6918. PMID   15833690.
  19. ↑ Kauppinen, R.; Mustajoki, S.; Pihlaja, H.; Peltonen, L.; Mustajoki, P. (1995). "Acute intermittent porphyria in Finland: 19 mutations in the porphobilinogen deaminase gene". Human Molecular Genetics. 4 (2): 215–222. doi:10.1093/hmg/4.2.215. ISSN   0964-6906. PMID   7757070.
  20. ↑ Whatley, Sharon D.; Badminton, Michael N. (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A.; Wallace, Stephanie E. (eds.), "Acute Intermittent Porphyria", GeneReviews®, University of Washington, Seattle, PMID   20301372 , retrieved 2018-11-01
  21. ↑ Aarsand AK, Petersen PH, Sandberg S (April 2006). "Estimation and application of biological variation of urinary delta-aminolevulinic acid and porphobilinogen in healthy individuals and in patients with acute intermittent porphyria". Clinical Chemistry. 52 (4): 650–6. doi: 10.1373/clinchem.2005.060772 . PMID   16595824.
  22. ↑ Lannfelt L, Wetterberg L, Gellerfors P, Lilius L, Floderus Y, Thunell S (November 1989). "Mutations in acute intermittent porphyria detected by ELISA measurement of porphobilinogen deaminase". Journal of Clinical Chemistry and Clinical Biochemistry. 27 (11): 857–62. CiteSeerX   10.1.1.634.1622 . doi:10.1515/cclm.1989.27.11.857. PMID   2607315. S2CID   43066408.
  23. ↑ Pischik E, Kauppinen R (2015). "An update of clinical management of acute intermittent porphyria". The Application of Clinical Genetics. 8: 201–14. doi: 10.2147/TACG.S48605 . PMC   4562648 . PMID   26366103.
  24. ↑ Laiwah, A C; Goldberg, A; Moore, M R (May 1983). "Pathogenesis and treatment of acute intermittent porphyria: discussion paper". Journal of the Royal Society of Medicine. 76 (5): 386–392. doi:10.1177/014107688307600512. ISSN   0141-0768. PMC   1439174 . PMID   6864706.
  25. ↑ Chen, Brenden; Solis-Villa, Constanza; Hakenberg, Jörg; Qiao, Wanqiong; Srinivasan, Ramakrishnan R.; Yasuda, Makiko; Balwani, Manisha; Doheny, Dana; Peter, Inga (November 2016). "Acute Intermittent Porphyria: Predicted Pathogenicity of HMBS Variants Indicates Extremely Low Penetrance of the Autosomal Dominant Disease". Human Mutation. 37 (11): 1215–1222. doi:10.1002/humu.23067. ISSN   1059-7794. PMC   5063710 . PMID   27539938.
  26. ↑ Baumann, K.; Kauppinen, R. (May 2020). "Penetrance and predictive value of genetic screening in acute porphyria". Molecular Genetics and Metabolism. 130 (1): 87–99. doi:10.1016/j.ymgme.2020.02.003. hdl: 10138/327225 . PMID   32067921. S2CID   211159510.
  27. ↑ Ma, Liyan; Tian, Yu; Peng, Chenxing; Zhang, Yiran; Zhang, Songyun (November 2020). "Recent advances in the epidemiology and genetics of acute intermittent porphyria". Intractable & Rare Diseases Research. 9 (4): 196–204. doi:10.5582/irdr.2020.03082. ISSN   2186-3644. PMC   7586877 . PMID   33139978.
  28. ↑ Yasuda, Makiko; Chen, Brenden; Desnick, Robert J. (November 2019). "Recent advances on porphyria genetics: Inheritance, penetrance & molecular heterogeneity, including new modifying/causative genes". Molecular Genetics and Metabolism. 128 (3): 320–331. doi:10.1016/j.ymgme.2018.11.012. PMC   6542720 . PMID   30594473.
  29. ↑
  30. ↑ Marcucci L (2004). PathCards. Baltimore, MD: Lippincott Willians & Wilkins. pp. 105–106. ISBN   978-0-7817-4399-0.
  31. ↑ Arnold WN (1992). Vincent van Gogh : chemicals, crises, and creativity. Boston: Birkhäuser. ISBN   978-0-8176-3616-6.[ page needed ]
  32. ↑ Macalpine I, Hunter R (January 1966). "The "insanity" of King George 3d: a classic case of porphyria". British Medical Journal. 1 (5479): 65–71. doi:10.1136/bmj.1.5479.65. PMC   1843211 . PMID   5323262.
  33. ↑ Röhl JC, Warren M, Hunt D (1998). Purple secret : genes, 'madness' and the royal houses of Europe. London: Corgi Books. ISBN   978-0-552-14550-3.[ page needed ]
  34. ↑ Bartolo A (1995). "Le maschere dell'io: Rousseau e la menzogna autobiografica" [The ego masks: Rousseau and the autobiographical lie]. Schena (in Italian): 113.
  35. ↑ "Jean-Jacques Rousseau l'errante" [Jean-Jacques Rousseau the wanderer]. La Letteratura e Noi - diretto da Romano Luperini (in Italian). Archived from the original on 19 November 2015. Retrieved 18 November 2015.
  36. ↑ Mejía-Rivera O (8 June 2012). "Las enfermedades de Jean-Jacques Rousseau" [The diseases of Jean-Jacques Rousseau]. Revista Aleph (in Spanish). Retrieved 18 November 2015.
  37. ↑ Androutsos G, Geroulanos S (December 2000). "[Acute intermittent porphyria: a new hypothesis to explain Jean-Jacques Rousseau's urinary disorders]". Progres en Urologie. 10 (6): 1282–9. PMID   11217576.
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