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Porphyria

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This article is about the medical condition. For other uses, see Porphyry (disambiguation).
Not to be confused with Porphyra.

Porphyria
SpecialtyEndocrinology Edit this on Wikidata

The porphyrias( poor-FEAR-e-uh) are a group of rare diseases in which chemical substances called porphyrins accumulate with high metabolism. The body requires porphyrins to produce heme, which carries oxygen in the blood. But in the porphyrias, there is a deficiency (inherited or acquired) of the enzymes that transform the various porphyrins into others, leading to abnormally high levels of one or more of these substances. This manifests with neurological symptoms or skin problems, or occasionally both.

Porphyrias are classified in two ways, by symptoms and by pathophysiology. Symptomatically, acute porphyrias primarily cause brain and nerve involvement, often with severe abdominal pain, vomiting, neuropathy, and mental disturbances. Cutaneous porphyrias cause skin problems, often after exposure to sunlight, because porphyrins react with light.[1] Physiologically, porphyrias are classified as hepatic or erythropoietic based on the sites of accumulation of heme precursors, either in the liver or in the bone marrow and red blood cells.[1]

The term porphyria is derived from the Greek πορφύρα, porphyra, meaning "purple pigment," a reference to the color of the porphyrins. Although original descriptions are attributed to Hippocrates, the disease was first explained biochemically by Felix Hoppe-Seyler in 1871,[2] and acute porphyrias were described by the Dutch physician Barend Stokvis in 1889.[3][4]

Signs and symptoms

Acute porphyrias

The acute porphyrias are acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP), and ALA dehydratase (also known as porphobilinogen synthase) porphyria. These diseases primarily affect the nervous system, resulting in episodic crises known as acute attacks. The major symptom of an acute attack is abdominal pain, often accompanied by vomiting, hypertension (elevated blood pressure), and tachycardia (an abnormally rapid heart rate). The most severe episodes may involve neurological complications: typically motor neuropathy (severe dysfunction of the peripheral nerves that innervate muscle), which leads to muscle weakness and potentially to quadriplegia (paralysis of all four limbs) and central nervous system symptoms such as seizures and coma. Occasionally, there may be short-lived psychiatric symptoms such as anxiety, confusion, hallucinations, and, very rarely, overt psychosis. All these symptoms resolve once the acute attack passes. Porphyria is not a cause of chronic psychiatric illness, though an association with anxiety and depression has been suggested.[citation needed]

Given the many presentations and the relatively low occurrence of porphyria, patients may initially be suspected to have other, unrelated conditions. For instance, the polyneuropathy of acute porphyria may be mistaken for Guillain-Barré syndrome, and porphyria testing is commonly recommended in those situations.[5]

Non-acute porphyrias

The non-acute porphyrias are X-linked dominant protoporphyria (XLDPP), congenital erythropoietic porphyria (CEP), porphyria cutanea tarda (PCT), and erythropoietic protoporphyria (EPP). None of these are associated with acute attacks; their primary manifestation is with skin disease. For this reason, these four porphyrias — along with two acute porphyrias, VP and HCP, that may also involve skin manifestations — are sometimes called cutaneous porphyrias.

Skin disease is encountered where excess porphyrins accumulate in the skin. Porphyrins are photoactive molecules, and exposure to light results in promotion of electrons to higher energy levels. When these return to the resting energy level or ground state, energy is released. This accounts for the property of fluorescence typical of the porphyrins. This causes local skin damage.

Two distinct patterns of skin disease are seen in porphyria:

  • Immediate photosensitivity. This is typical of XLDPP and EPP. Following a variable period of sun exposure — typically about 30 minutes — patients complain of severe pain, burning and discomfort in exposed areas. Typically, the effects are not visible, though occasionally there may be some redness and swelling of the skin.
  • Vesiculo-erosive skin disease. This — a reference to the characteristic blistering (vesicles) and open sores (erosions) noted in patients — is the pattern seen in CEP, PCT, VP, and HCP. The changes are noted only in sun-exposed areas such as the face and back of the hands. Milder skin disease, such as that seen in VP and HCP, consists of increased skin fragility in exposed areas with a tendency to form blisters and erosions, particularly after minor knocks or scrapes. These heal slowly, often leaving small scars that may be lighter or darker than normal skin. More severe skin disease is sometimes seen in PCT, with prominent lessons, darkening of exposed skin such as the face, and hypertrichosis: abnormal hair growth on the face, particularly the cheeks. The most severe disease is seen in CEP and a rare variant of PCT known as hepatoerythropoietic porphyria (HEP); symptoms include severe shortening of digits, loss of skin appendages such as hair and nails, and severe scarring of the skin with progressive disappearance of ears, lips, and nose. Patients may also show deformed, discolored teeth or gum and eye abnormalities.

Diagnosis

Porphyrin studies

Porphyria is diagnosed through biochemical analysis of blood, urine, and stool.[6][7] In general, urine estimation of porphobilinogen (PBG) is the first step if acute porphyria is suspected. As a result of feedback, the decreased production of heme leads to increased production of precursors, PBG being one of the first substances in the porphyrin synthesis pathway.[8] In nearly all cases of acute porphyria syndromes, urinary PBG is markedly elevated except for the very rare ALA dehydratase deficiency or in patients with symptoms due to hereditary tyrosinemia type I.[9] In cases of mercury- or arsenic poisoning-induced porphyria, other changes in porphyrin profiles appear, most notably elevations of uroporphyrins I & III, coproporphyrins I & III and pre-coproporphyrin.[10]

Repeat testing during an attack and subsequent attacks may be necessary in order to detect a porphyria, as levels may be normal or near-normal between attacks. The urine screening test has been known to fail in the initial stages of a severe, life-threatening attack of acute intermittent porphyria.[citation needed]

Up to 90% of the genetic carriers of the more common, dominantly inherited acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been noted in DNA tests to be latent for classic symptoms and may require DNA or enzyme testing. The exception to this may be latent post-puberty genetic carriers of hereditary coproporphyria.[citation needed]

As most porphyrias are rare conditions, general hospital labs typically do not have the expertise, technology or staff time to perform porphyria testing. In general, testing involves sending samples of blood, stool and urine to a reference laboratory.[6] All samples to detect porphyrins must be handled properly. Samples should be taken during an acute attack, otherwise a false negative result may occur. Samples must be protected from light and either refrigerated or preserved.[6]

If all the porphyrin studies are negative, one must consider pseudoporphyria. A careful medication review often will find the cause of pseudoporphyria.

Additional tests

Further diagnostic tests of affected organs may be required, such as nerve conduction studies for neuropathy or an ultrasound of the liver. Basic biochemical tests may assist in identifying liver disease, hepatocellular carcinoma, and other organ problems.

Cause

The porphyrias are generally considered genetic in nature.

Triggers

Acute porphyria can be triggered by a number of drugs, most of which are believed to trigger it by interacting with enzymes in the liver which are made with heme. Such drugs include:[11][12][13]

Pathogenesis

In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, catalase, peroxidase, respiratory and P450 liver cytochromes.

Heme synthesis—note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)

Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. Heme function plays a central role in cellular metabolism. This is not the main problem in the porphyrias; most heme synthesis enzymes—even dysfunctional enzymes—have enough residual activity to assist in heme biosynthesis. The principal problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine the location of accumulation, whether they induce photosensitivity, and whether the intermediate is excreted (in the urine or feces).

There are eight enzymes in the heme biosynthetic pathway, four of which—the first one and the last three—are in the mitochondria, while the other four are in the cytosol. Defects in any of these can lead to some form of porphyria.

The hepatic porphyrias are characterized by acute neurological attacks (seizures, psychosis, extreme back and abdominal pain and an acute polyneuropathy), while the erythropoietic forms present with skin problems, usually a light-sensitive blistering rash and increased hair growth.

Variegate porphyria (also porphyria variegata or mixed porphyria), which results from a partial deficiency in PROTO oxidase, manifests itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. All other porphyrias are either skin- or nerve-predominant.

Subtypes

Subtypes of porphyrias depend on which enzyme is deficient.

Porphyria type Deficient enzyme Type of porphyria Inheritance Symptoms Prevalence
X-linked dominant protoporphyria (XLDPP) 5-aminolevulinate (ALA) synthase (ALAS) Erythropoietic X-linked dominant Photosensitivity, cirrhosis[14] Rare; about 50 cases reported [15]
Aminolevulinate dehydratase deficiency porphyria (ALADP) 5-aminolevulinate dehydratase (ALAD) Hepatic Autosomal recessive [16] Abdominal pain, neuropathy[16] Extremely rare; fewer than 10 cases ever reported.[17]
Acute intermittent porphyria (AIP) Hydroxymethylbilane synthase (HMBS) formerly porphobilinogen deaminase (PBGD) Hepatic Autosomal dominant [16] Periodic abdominal pain, peripheral neuropathy, psychiatric disorders, tachycardia[16] 1 in 10,000[18]–20,000[18]
Congenital erythropoietic porphyria (CEP) uroporphyrinogen synthase (UROS) Erythropoietic Autosomal recessive [16] Severe photosensitivity with erythema, swelling and blistering. Hemolytic anemia, splenomegaly[16] 1 in 1,000,000 or less.[6]
Porphyria cutanea tarda (PCT) uroporphyrinogen decarboxylase (UROD) Hepatic Autosomal dominant [16] Photosensitivity with vesicles and bullae[16] 1 in 10,000[19]
Hereditary coproporphyria (HCP) coproporphyrinogen oxidase (CPOX) Hepatic Autosomal dominant [16] Photosensitivity, neurologic symptoms, colic[16] 1 in 500,000[19]
Harderoporphyria coproporphyrinogen oxidase (CPOX) Erythropoietic Autosomal recessive [16] Jaundice, anemia, enlarged liver and spleen, often neonatal. Photosensitivity later. Extremely rare; fewer than 10 cases ever reported.
Variegate porphyria (VP) protoporphyrinogen oxidase (PPOX) Hepatic Autosomal dominant[20] Photosensitivity, neurologic symptoms, developmental delay 1 in 300 in South Africa[19]
1 in 75,000 in Finland[21]
Erythropoietic protoporphyria (EPP) Ferrochelatase (FECH) Erythropoietic Autosomal dominant [16] Photosensitivity with skin lesions. Gallstones, mild liver dysfunction[16] 1 in 75,000[19]–200,000[19]

Management

Acute porphyria

Carbohydrates and heme

Often, empirical treatment is required if the diagnostic suspicion of a porphyria is high since acute attacks can be fatal. A high-carbohydrate diet is typically recommended; in severe attacks, a dextrose 10% infusion is commenced, which may aid in recovery.

Hematin (trade name Panhematin) and heme arginate (trade name NormoSang) are the drugs of choice in acute porphyria, in the United States and the United Kingdom, respectively. These drugs need to be given very early in an attack to be effective; effectiveness varies amongst individuals. They are not curative drugs but can shorten attacks and reduce the intensity of an attack. Side effects are rare but can be serious. These heme-like substances theoretically inhibit ALA synthase and hence the accumulation of toxic precursors. In the United Kingdom, supplies of NormoSang are kept at two national centers; emergency supply is available from St Thomas' Hospital, London.[22] In the United States, Lundbeck manufactures and supplies Panhematin for infusion.[23]

Heme Arginate (NormoSang) is used during crises but also in preventive treatment to avoid crises, one treatment every 10 days.[citation needed]

Any sign of low blood sodium (hyponatremia) or weakness should be treated with the addition of hematin, heme arginate, or even tin mesoporphyrin, as these are signs of impending syndrome of inappropriate antidiuretic hormone (SIADH) or peripheral nervous system involvement that may be localized or severe, progressing to bulbar paresis and respiratory paralysis.[citation needed]

Cimetidine has also been reported to be effective for acute porphyric crisis and possibly effective for long-term prophylaxis.[24]

Symptom control

Pain is severe, frequently out of proportion to physical signs, and often requires the use of opiates to reduce it to tolerable levels. Pain should be treated as early as medically possible. Nausea can be severe; it may respond to phenothiazine drugs but is sometimes intractable. Hot baths and showers may lessen nausea temporarily, though caution should be used to avoid burns or falls.

Early identification

It is recommended that patients with a history of acute porphyria, and even genetic carriers, wear an alert bracelet or other identification at all times. This is in case they develop severe symptoms, or in case of accidents where there is a potential for drug exposure, and as a result they are unable to explain their condition to healthcare professionals. Some drugs are absolutely contraindicated for patients with any form of porphyria.[citation needed]

Neurologic and psychiatric problems

Patients who experience frequent attacks can develop chronic neuropathic pain in extremities as well as chronic pain in the abdomen.[25] Intestinal pseudo-obstruction, ileus, intussusception, hypoganglionosis, encopresis in children and have been associated with porphyrias. This is thought to be due to axonal nerve deterioration in affected areas of the nervous system and vagal nerve dysfunction.

Pain treatment with long-acting opioids, such as morphine, is often indicated, and, in cases where seizure or neuropathy is present, Gabapentin is known to improve outcome.[26]

Depression often accompanies the disease and is best dealt with by treating the offending symptoms and if needed the judicious use of anti-depressants. Some psychotropic drugs are porphyrinogenic, limiting the therapeutic scope. Other psychiatric symptoms such as anxiety, restlessness, insomnia, depression, mania, hallucinations, delusions, confusion, catatonia, and psychosis may occur.[27]

Seizures

Seizures often accompany this disease. Most seizure medications exacerbate this condition. Treatment can be problematic: barbiturates especially must be avoided. Some benzodiazepines are safe and, when used in conjunction with newer anti-seizure medications such as gabapentin, offer a possible regime for seizure control. Gabapentin has the additional feature of aiding in the treatment of some kinds of neuropathic pain.[26]

Magnesium sulfate and bromides have also been used in porphyria seizures, however, development of status epilepticus in porphyria may not respond to magnesium alone. The addition of hematin or heme arginate has been used during status epilepticus.[citation needed]

Underlying liver disease

Some liver diseases may cause porphyria even in the absence of genetic predisposition. These include hemochromatosis and hepatitis C. Treatment of iron overload may be required.[citation needed]

Patients with the acute porphyrias (AIP, HCP, VP) are at increased risk over their life for hepatocellular carcinoma (primary liver cancer) and may require monitoring. Other typical risk factors for liver cancer need not be present.[citation needed]

Hormone treatment

Hormonal fluctuations that contribute to cyclical attacks in women have been treated with oral contraceptives and luteinizing hormones to shut down menstrual cycles. However, oral contraceptives have also triggered photosensitivity and withdrawal of oral contraceptives has triggered attacks. Androgens and fertility hormones have also triggered attacks.[citation needed]

Erythropoietic porphyria

These are associated with accumulation of porphyrins in erythrocytes and are rare.

The pain, burning, swelling, and itching that occur in erythropoietic porphyrias generally require avoidance of bright sunlight. Most kinds of sunscreen are not effective, but SPF-rated long-sleeve shirts, hats, bandanas, and gloves can help. Chloroquine may be used to increase porphyrin secretion in some EPs.[6] Blood transfusion is occasionally used to suppress innate heme production.

The rarest is congenital erythropoietic porphyria (C.E.P) otherwise known as Gunther's disease. The signs may present from birth and include severe photosensitivity, brown teeth that fluoresce in ultraviolet light due to deposition of Type 1 porphyrins, and later hypertrichosis. Hemolytic anemia usually develops. Pharmaceutical-grade beta carotene may be used in its treatment.[28] A bone marrow transplant has also been successful in curing CEP in a few cases, although long-term results are not yet available.[29]

In December 2014, afamelanotide received authorization from the European Commission as a treatment for the prevention of phototoxicity in adult patients with EPP.[30]

Epidemiology

The prevalence of all types of porphyria taken together has been estimated to be approximately one in 25,000 in the United States.[31] The worldwide prevalence has been estimated to be between one in 500 and one in 50,000 people.[32]

Culture and history

Porphyrias have been detected in all races and in multiple ethnic groups on every continent, including Africans, Asians, Aboriginal Australians, Caucasians, Peruvians, Mexicans, Native Americans, and Sami. There are high incidence reports of AIP in areas of India and Scandinavia. More than 200 genetic variants of A IP are known, some of which are specific to families, although some strains have proven to be repeated mutations.

The links between porphyrias and mental illness have been noted for decades. In the early 1950s, patients with porphyrias (occasionally referred to as "porphyric hemophilia"[33]) and severe symptoms of depression or catatonia were treated with electroshock therapy.

Vampires and werewolves

Porphyria has been suggested as an explanation for the origin of vampire and werewolf legends, based upon certain perceived similarities between the condition and the folklore.

In January 1964, L. Illis' 1963 paper, "On Porphyria and the Aetiology of Werwolves," was published in Proceedings of the Royal Society of Medicine. Later, Nancy Garden argued for a connection between porphyria and the vampire belief in her 1973 book, Vampires. In 1985, biochemist David Dolphin's paper for the American Association for the Advancement of Science, "Porphyria, Vampires, and Werewolves: The Aetiology of European Metamorphosis Legends," gained widespread media coverage, popularizing the idea.

The theory has been rejected by a few folklorists and researchers as not accurately describing the characteristics of the original werewolf and vampire legends or the disease, and as potentially stigmatizing sufferers of porphyria.[34][35]

A 1995 article from the Postgraduate Medical Journal (via NIH) explains:

As it was believed that the folkloric vampire could move about freely in daylight hours, as opposed to the 20th century variant, congenital erythropoietic porphyria cannot readily explain the folkloric vampire but may be an explanation of the vampire as we know it in the 20th century. In addition, the folkloric vampire, when unearthed, was always described as looking quite healthy (″as they were in life″), while due to disfiguring aspects of the disease, sufferers would not have passed the exhumation test. Individuals with congenital erythropoietic porphyria do not crave blood. The enzyme (hematin) necessary to alleviate symptoms is not absorbed intact on oral ingestion, and drinking blood would have no beneficial effect on the sufferer. Finally, and most important, the fact that vampire reports were literally rampant in the 18th century, and that congenital erythropoietic porphyria is an extremely rare manifestation of a rare disease, makes it an unlikely explanation of the folkloric vampire.[36]

Notable cases

George III in his coronation robes

The mental illness exhibited by King George III in the regency crisis of 1788 has inspired several attempts at retrospective diagnosis. The first, written in 1855, thirty-five years after his death, concluded that he suffered from acute mania. M. Guttmacher, in 1941, suggested manic-depressive psychosis as a more likely diagnosis. The first suggestion that a physical illness was the cause of King George's mental derangement came in 1966, in a paper called "The Insanity of King George III: A Classic Case of Porphyria,"[37] with a follow-up in 1968, "Porphyria in the Royal Houses of Stuart, Hanover and Prussia."[38] The papers, by a mother/son psychiatrist team, were written as though the case for porphyria had been proven, but the response demonstrated that many experts, including those more intimately familiar with the manifestations of porphyria, were unconvinced. Many psychiatrists disagreed with the diagnosis, suggesting bipolar disorder as far more probable. The theory is treated in Purple Secret,[39] which documents the ultimately unsuccessful search for genetic evidence of porphyria in the remains of royals suspected to have suffered from it.[40] In 2005, it was suggested that arsenic (which is known to be porphyrogenic) given to George III with antimony may have caused his porphyria.[41] Despite the lack of direct evidence, the notion that George III (and other members of the royal family) suffered from porphyria has achieved such popularity that many forget that it is merely a hypothesis. In 2010, an exhaustive analysis of historical records concluded that the porphyria claim was based on spurious and selective interpretation of contemporary medical and historical sources.[42]

Mary Stuart c.1578.

The mental illness of George III is the basis of the plot in The Madness of King George, a 1994 British film based upon the 1991 Alan Bennett play The Madness of George III. The closing credits of the film include the comment that the illness suffered by King George has been attributed to porphyria and that it is hereditary. Among other descendants of George III theorized by the authors of Purple Secret to have suffered from porphyria (based on analysis of their extensive and detailed medical correspondence) were his great-great-granddaughter Princess Charlotte of Prussia (Emperor William II's eldest sister) and her daughter Princess Feodora of Saxe-Meiningen. They uncovered better evidence that George III's great-great-great-grandson Prince William of Gloucester was reliably diagnosed with variegate porphyria.[43]

It is believed that Mary, Queen of Scots — King George III's great-great-great-great-great-grandmother — also suffered from acute intermittent porphyria,[44] although this is subject to much debate. It is assumed she inherited the disorder, if indeed she had it, from her father, James V of Scotland; both father and daughter endured well-documented attacks that could fall within the constellation of symptoms of porphyria.

Maria I of Portugal in a c. 1790s portrait attributed to Giuseppe Troni or Thomas Hickey.

Maria I of Portugal — known as "Maria the Pious" or "Maria the Mad" because of both her religious fervor and her acute mental illness, which made her incapable of handling state affairs after 1792 — is also thought to have suffered from porphyria. Francis Willis, the same physician who treated George III, was even summoned by the Portuguese court, but returned to England after the court limited the treatments he could oversee. Contemporary sources, such as Secretary of State for Foreign Affairs Luís Pinto, noted that the queen suffered from ever-worsening stomach pains and abdominal spasms: hallmarks of porphyria.[45]

Vlad III was also said to have suffered from acute porphyria, which may have started the notion that vampires were allergic to sunlight.[46]

Other commentators have suggested that Vincent van Gogh may have suffered from acute intermittent porphyria.[47] It has also been speculated that King Nebuchadnezzar of Babylon suffered from some form of porphyria (cf. Daniel 4).[48] However, the symptoms of the various porphyrias are so extensive that a wide constellation of symptoms can be attributed to one or more of them.[citation needed]

Physician Archie Cochrane was born with porphyria, which caused health problems throughout his life.[49]

Paula Frías Allende, the daughter of the Chilean novelist Isabel Allende, fell into a porphyria-induced coma in 1991,[50] which inspired Isabel to write the memoir Paula, dedicated to her.

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  34. ^ American Vampires: Fans, Victims, Practitioners, Norine Dresser, W. W. Norton & Company, 1989.
  35. ^ "Did vampires suffer from the disease porphyria — or not?" The Straight Dope, May 7, 1999.
  36. ^ Cox, Ann M. (1995). "Porphyria and vampirism: another myth in the making". Postgraduate Medical Journal. 71 (841): 643–644. doi:10.1136/pgmj.71.841.643-a. PMC 2398345. PMID 7494765.
  37. ^ Macalpine I, Hunter R (January 1966). "The "insanity" of King George 3d: a classic case of porphyria". Br Med J. 1 (5479): 65–71. doi:10.1136/bmj.1.5479.65. PMC 1843211. PMID 5323262.
  38. ^ Macalpine I, Hunter R, Rimington C (January 1968). "Porphyria in the royal houses of Stuart, Hanover, and Prussia. A follow-up study of George 3d's illness". Br Med J. 1 (5583): 7–18. doi:10.1136/bmj.1.5583.7. PMC 1984936. PMID 4866084.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  39. ^ Warren, Martin; Rh̲l, John C. G.; Hunt, David C. (1998). Purple secret: genes, "madness" and the Royal houses of Europe. London: Bantam Books. ISBN 0-593-04148-8.{{cite book}}: CS1 maint: multiple names: authors list (link)
  40. ^ The authors demonstrated a single point mutation in the PPOX gene, but not one that has been associated with disease.
  41. ^ Cox TM, Jack N, Lofthouse S, Watling J, Haines J, Warren MJ (2005). "King George III and porphyria: an elemental hypothesis and investigation". The Lancet. 366 (9482): 332–335. doi:10.1016/S0140-6736(05)66991-7. PMID 16039338.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  42. ^ Peters TJ, Wilkinson D (2010). "King George III and porphyria: a clinical re-examination of the historical evidence". History of Psychiatry. 21 (81 Pt 1): 3–19. doi:10.1177/0957154X09102616. PMID 21877427.
  43. ^ Smith, Martin; Smith, Alison (21 December 2009). "Tetrapyrroles: Birth, Life and Death". ISBN 9780387785189. Retrieved 9 April 2014. {{cite journal}}: Cite journal requires |journal= (help); Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  44. ^ "bulletin: The University of Sussex NewsletterThe Royal Family's Toxic Time-Bomb Friday 25th June 1999".
  45. ^ Roberts, Jenifer (2009). The Madness of Queen Maria [The Remarkable Life of Maria I of Portugal]. Templeton Press. ISBN 978-0954558918.
  46. ^ "BBC News - UK - Charles visits 'relative' Dracula's home".
  47. ^ Loftus LS, Arnold WN (1991). "Vincent van Gogh's illness: acute intermittent porphyria?". BMJ. 303 (6817): 1589–1591. doi:10.1136/bmj.303.6817.1589. PMC 1676250. PMID 1773180.
  48. ^ Beveridge A (2003). "The madness of politics". J R Soc Med. 96 (12): 602–604. doi:10.1258/jrsm.96.12.602. PMC 539664. PMID 14645615.
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  50. ^ Allende, Isabel (1995). Paula. New York, NY: HarperCollins. ISBN 0-06-017253-3.
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