Variegate porphyria breakthrough.
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Diagnosis of variegate porphyria at birth by demonstration of the R59W mutation.
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Child↗
[Variegate porphyria (VP)].
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Biomarkers↗
King George III and porphyria: an elemental hypothesis and investigation.
In 1969 it was proposed that the episodic madness suffered by King George III (1738-1820) resulted from an acute hereditary porphyria, variegate porphyria, caused by deficiency of protoporphyrinogen oxidase. The diagnosis was based on the historical archive and a contentious claim that living members of the House of Hanover were affected with the condition. A re-examination of the medical evidence and the appearance of new historical material have suggested that porphyria did indeed exist in the Royal Houses of Europe. We report the analysis of hair obtained from George III. Although no genomic DNA could be obtained, metal analysis revealed high concentrations of arsenic. Since arsenic interferes with haem metabolism, it might have contributed to the King's unusually severe and prolonged bouts of illness. We have identified sources of arsenic in the context of the medication George III received from physicians.
Arsenic↗
Acute peripheral neuropathy due to hereditary coproporphyria.
A 23-year-old man with epilepsy and a past history of abdominal pain and ileus, developed hypertension and arm and bulbar weakness when valproic acid and carbamazepine were reinitiated. Electrophysiologic studies demonstrated a peripheral neuropathy with features of axonal degeneration and demyelination. Axonal degeneration was documented by sural nerve biopsy. Markedly elevated urinary delta-aminolevulinic acid and porphobilinogen indicated a diagnosis of acute porphyria. Other laboratory studies were most consistent with hereditary coproporphyria. Motor function improved considerably but incompletely over 1 year. An acute, primarily motor neuropathy can occur in several forms of porphyria, including acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria, sometimes even in the absence of concomitant gastrointestinal symptoms.
Acute Disease↗
Hematin therapy in porphyric attacks.
We report our experience with hematin in the treatment of 57 patients in porphyric attacks. The ratio of acute intermittent porphyria: variegate porphyria: hereditary coproporphyria was 43:11:3. More than 90% of the patients showed not only a decline in their porphyrin precursors, but also a favor able clinical response. Hematin was well tolerated and should be considered the treatment of choice in porphyric relapse.
Heme↗
The "glucose effect" in acute hepatic porphyrias and in experimental porphyria.
The "glucose effect" was investigated in human acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, coproporphyria and porphobilinogen synthase defect porphyria) and in avian liver cells. 8 patients (7 women) with acute abdominal-neurological porphyria syndrome and 3 patients (2 women) in the remission phase were treated with high carbohydrate intake (approximately 500 g/24 h), mainly in form of intravenous glucose infusions. The biochemical response with a decrease of metabolites of porphyrin biosynthesis was highly significant, accompanied by clinical improvement in 10 courses of 9 patients. Two patients with delayed detection of the disease under the condition of Landry paralysis died after temporary clinical improvement due to ventricular arrythmias in one case and septicemia in the other. The importance of early diagnosis and therapy, and omission of drugs and alcohol cannot be overemphasized. Complementary studies show the "glucose effect" in drug -mediated induction of porphyrin synthesis in liver cells grown in culture: delta-Aminolevulinic acid synthase and protoporphyrin synthesis are repressed.
Acute Disease↗
Molecular mechanisms of dominant expression in porphyria.
Partial deficiency of enzymes in the haem synthetic pathway gives rise to a group of seven inherited metabolic disorders, the porphyrias. Each deficiency is associated with a characteristic increase in haem precursors that correlates with the symptoms associated with individual porphyrias and allows accurate diagnosis. Two types of clinical presentation occur separately or in combination; acute life-threatening neurovisceral attacks and/or cutaneous symptoms. Five of the porphyrias are low-penetrance autosomal dominant conditions in which clinical expression results from additional factors that act by increasing demand for haem or by causing an additional decrease in enzyme activity or by a combination of these effects. These include both genetic and environmental factors. In familial porphyria cutanea tarda (PCTF), environmental factors that include alcohol, exogenous oestrogens and hepatotropic viruses result in inhibition of hepatic enzyme activity via a mechanism that involves excess iron accumulation. In erythropoietic protoporphyria (EPP), co-inheritance of a functional polymorphism in trans to a null ferrochelatase allele accounts for most clinically overt cases. In the autosomal dominant acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria), acute neurovisceral attacks occur in a minority of those who inherit one of these disorders. Although various exogenous (e.g. drugs, alcohol) and endogenous factors (e.g. hormones) have been identified as provoking acute attacks, these do not provide a full explanation for the low penetrance of these disorders. It seems probable that genetic background influences susceptibility to acute attacks, but the genes that are involved have not yet been identified.
Genes, Dominant↗
Biochemistry of porphyria.
1. The porphyrias are a group of metabolic disorders arising from defects in the haem biosynthetic pathway. Most forms are inherited as Mendelian autosomal dominants, but some types are recessive and others acquired through exposure to porphyrinogenic drugs and chemicals. There is a linked group of diseases, which are not porphyrias, but have in common alterations of haem biosynthesis. 2. The processes of haem biosynthesis are now well understood and the molecular biology of the functions and dysfunctions in the porphyrias are currently an area of intensive investigation. 3. The acute porphyrias, Acute Intermittent Porphyria, Variegate Porphyria and Hereditary Coproporphyria are of most importance since attacks of these may be life-threatening. 4. These diseases that usually present with a neurovisceral attack are characterized by excess production of the porphyrin precursors, 5-aminolaevulinate and porphobilinogen because of lowered activity of Porphobilinogen deaminase. 5. A variety of factors may precipitate these attacks including various drugs, alcohol, smoking, dieting or fasting and variations in steroid hormone levels. 6. The non-acute porphyrias are largely dermatological conditions, which present clinically as cutaneous photosensitivity. The dermatological changes are caused by the photosensitizing properties of circulating porphyrins and are accompanied by systemic effects of these porphyrins.
Acute Disease↗
Hepatic porphyrias. Current concepts.
Acute intermittent porphyria, variegate porphyria, and hereditary coproporphyria are hepatic porphyrias due to enzyme defects that are inherited as autosomal dominants. Porphyria cutanea tarda is considered an acquired disorder. Similar drugs or circumstances are precipitants of acute attacks in all three inherited hepatic porphyrias. The respective biochemical abnormalities are identifiable by simple, readily available laboratory tests. Management of patients with any of the inherited hepatic porphyrias is directed primarily toward prevention of attacks through avoidance of precipitants and through a diet high in carbohydrate. Therapy for porphyria cutanea tarda includes interdiction of alcohol use and repeated phlebotomy.
5-Aminolevulinate Synthetase↗
Alcohol and porphyrin metabolism.
Alcohol is a porphyrinogenic agent which may cause disturbances in porphyrin metabolism in healthy persons as well as biochemical and clinical manifestations of acute and chronic hepatic porphyrias. After excessive consumption of alcohol, a temporary, clinically asymptomatic secondary hepatic coproporphyrinuria is observable, which can become persistent in cases of alcohol-induced liver damage. Nowadays, the alcohol-liver-porphyrinuria syndrome is the first to be mentioned in secondary hepatic disturbances of porphyrin metabolism. Acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are considered to be molecular regulatory diseases, in contrast to non-acute, chronic hepatic porphyria, clinically appearing as porphyria cutanea tarda (PCT). Porphyrins do not accumulate in the liver in acute porphyrias, whereas in chronic hepatic porphyrias they do. Thus, chronic hepatic porphyria is a porphyrin-accumulation disease, whereas acute hepatic porphyrias are haem-pathway-dysregulation diseases, characterized in general by induction of delta-aminolevulinic acid synthase in the liver and excessive stimulation of the pathway without storage of porphyrins in the liver. The clinical expression of acute hepatic porphyrias can be triggered by alcohol, because alcohol augments the inducibility of delta-aminolevulinic acid synthase. In chronic hepatic porphyrias, however, which are already associated with liver damage, alcohol potentiates the disturbance of the decarboxylation of uro- and heptacarboxyporphyrinogen, which is followed by a hepatic accumulation of uro- and heptacarboxyporphyrin and their sometimes extreme urinary excretion. Especially in persons with a genetic deficiency of uroporphyrinogen decarboxylase, but also in patients with the so-called sporadic variety of PCT, alcohol is able to transform an asymptomatic coproporphyrinuria into PCT. Alcohol has many biochemical and clinical effects on porphyrin and haem synthesis both in humans and laboratory animals. Ethanol suppresses the activity of porphobilinogen synthase (synonym: delta-aminolevulinic acid dehydratase), uroporphyrinogen decarboxylase, coproporphyrinogen oxidase and ferrochelatase, whereas it induces the first and rate-limiting enzyme in the pathway, delta-aminolevulinic acid synthase and also porphobilinogen deaminase. Therefore, teetotalism is a therapeutically and prophylactically important measure in all types of hepatic porphyrias.
Acute Disease↗
The little imitator--porphyria: a neuropsychiatric disorder.
Three common subtypes of porphyria give rise to neuropsychiatric disorders; acute intermittent porphyria, variegate porphyria, and coproporphyria. The second two also give rise to cutaneous symptoms. Neurological or psychiatric symptoms occur in most acute attacks, and may mimic many other disorders. The diagnosis may be missed because it is not even considered or because of technical problems, such as sample collection and storage, and interpretation of results. A negative screening test does not exclude the diagnosis. Porphyria may be overrepresented in psychiatric populations, but the lack of control groups makes this uncertain. The management of patients with porphyria and psychiatric symptoms causes considerable problems. Three cases are described to illustrate some of these issues. Advances in molecular biology permit identification of patients and latent carriers in the family. Care to avoid relapses and improved treatments have reduced the mortality.
Adult↗
[Progress in dermatology: new biochemical aspects].
Recent biochemical advances have contributed to clarification of certain skin diseases and metabolic disturbances with predominantly cutaneous symptoms. This is illustrated by the various forms of porphyria. Today we differentiate four hepatic forms: acute intermittent porphyria, variegate porphyria, hereditary coproporphyria and porphyria cutanea tarda, and two erythropoietic forms: congenital erythropoietic porphyria and erythropoietic protoporphyria, all of which are due to an inborn enzymatic deficiency of the heme biosynthesis. From the different forms of ichthyosis, the X-recessive ichthyosis has an underlying enzymatic deficiency of the steroid sulfatase, which seems of significance in the disturbance of keratinization. In epidermolysis bullosa dystrophica type Hallopeau-Siemens an increased collagenase activity was detected. Inhibition of this enzyme by phenytoin results in improvement of the blistering in this genodermatosis. The etiology and pathogenesis of psoriasis are unclear despite extensive efforts. The recently detected deficiency of the arylhydrocarbon-hydroxylase and its inducibility must be confirmed, additionally its significance in the pathogenesis of this disease is yet to be evaluated.
Arylsulfatases↗
[Acute attacks of hepatic porphyria: specific treatment with heme arginate].
Severe hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are hereditary diseases. Each type of porphyria is the result of a specific decrease in the activity of one of the enzymes of heme biosynthesis. Acute attacks are very serious: the abdominal pains are severe and the neurological manifestations can lead to death or incomplete recovery with irreversible sequelae (usually paralysis). Since 1985, the prognosis of acute attacks has been greatly improved by the introduction of heme-arginate. The 69 acute attacks (30 patients, 4 men and 26 women) that we treated with heme-arginate between 1988 and 1991 are described in this report. All patients were infused with 250 mg/d of heme-arginate for 4 days: the mean duration of abdominal pain was 2.5 days (SD 0.72). For 95 p. 100 of the attacks, the total hospitalization time was 5 days or less; side effects were very minor. In every case, a favorable response was dependent upon the early initiation of heme therapy.
Acute Disease↗
Anxiety and depression in the acute porphyrias.
A previous study of self-rated psychosocial aspects in patients with acute porphyria found that depression, and particularly anxiety, is more common in porphyria patients than in the general population or general medical outpatient attenders. Nearly half of the sample (46%) reported at least some problem with anxiety and/or depression: anxiety caseness was 26% and depression caseness was 13%. This paper extends our previous observations and investigates further the associations between porphyria and anxiety, depression and general mental health in 90 patients (58 acute intermittent porphyria, 32 variegate porphyria). The findings of this study confirm that anxiety is raised in patients with acute intermittent porphyria and with variegate porphyria, in both males and females, compared to the normative population and, using a series of questionnaires exploring the physical and psychosocial features of anxiety, that this anxiety is experienced as a 'relatively stable personality trait', rather than a 'transitory emotional state' (i.e. intrinsic rather than secondary to the porphyria).
Anxiety↗
Photosensitivity in the elderly.
Photosensitivity to drugs and chemicals in the elderly is more prevalent due to more frequent use of medications. Phototoxic reactions to common, orally administered drugs such as diuretics, cardiac agents and antidiabetics may occur and the reactions may be remedied by discontinuing drug therapy. Photocontact dermatitis due to the ingredients in sunscreens or other agents, such as perfumes, may also arise. Diagnosis is often confirmed by photopatch testing and subsequent avoidance of these agents leads to gradual resolution. Idiopathic photodermatoses, such as sunlight-induced polymorphic light eruption or solar urticaria, may occur and persist from an early age and, in elderly subjects, they can cause mild to marked disability. The most disturbing disorder of this type is the severe, widespread eczematous chronic actinic dermatitis, which can be difficult to diagnose. Porphyrias, such as variegate porphyria or erythropoietic protoporphyria, may persist from an early age, whereas porphyria cutanea tarda generally begins in later life. Porphyrias all have specific clinical and biochemical features and, apart from variegate porphyria, usually respond well to treatment following diagnosis. Exposure of elderly skin to sunlight may also cause deterioration of many ordinary dermatoses, particularly seborrhoeic eczema, which generally respond to protection from UV exposure and to treatment of the underlying abnormality. Progress in identifying the underlying causes, the availability of increasingly sophisticated diagnostic techniques, and improvements in sunscreen preparations and therapeutic medications will probably significantly reduce abnormal photosensitivity in the elderly in the near future.
Adult↗
Effects of hematin in hepatic porphyria. Further studies.
The present study was carried out in five cases of hepatic porphyria, including three of acute intermittent porphyria, one of variegate porphyria, and one of porphyria cutanea tarda in clinical remission. In two cases of acute intermittent porphyria (in relapse), a marked lowering effect on serum and urine porphobilinogen and delta-aminolevulinic acic was observed, together with prompt and gratifying clinical improvement. In a third case, in chemical remission but with longstanding psychoneurosis, no significant effects were noted, nor were any observed in the case of porphyria cutanea tarda. Although clinical improvements occurred in the case of variegate porphyria, the results were inconclusive for reasons given. Hematin was generally well tolerated. Preliminary reference is made to a transitory renal injury, without sequelae, where an excess of hematin was given in relation to time. Limits of tolerance are proposed. In the light of these observations the basic mechanism of the acute attack is diccussed.
Adult↗
Variegate (mixed) porphyria in a Nigerian girl.
A fatal case of variegate (mixed) porphyria in an 11-year-old Nigerian girl is reported. She presented with severe abdominal pain, vomiting, constipation, quadriplegia and cutaneous bullous dermatosis. Remission was temporarily achieved with chlorpromazine, high carbohydrate diet and physiotherapy. She finally died of respiratory paralysis 17 months after diagnosis.
Child↗