Variegate Porphyria

Kirsch, Ralph E.; Meissner, Peter N.; Hift, Richard

doi:10.1055/s-2007-1007138

Cited by 71 publications

(59 citation statements)

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“…Thirteen of these 17 subjects showed biochemical evidence of VP in urine and stool porphyrin analysis whereas in another four, porphyrin excretion patterns were normal. These we class as "silent" cases (Kirsch et al, 1998). The mutation tracks with the disease, being present in all subjects who demonstrated FIGURE 3.…”

Section: Resultsmentioning

confidence: 99%

“…Many different PPO mutations have been described from around the world in the short period since the first report, indicating significant allelic heterogeneity for this disease (de Rooij et al, 1997;Deybach et al, 1996;Frank et al, 1996aFrank et al, , 1996b for review see Kirsch et al, 1998). Though the South African VP population is exceptional for the high degree of genetic homogeneity it demonstrates, our findings mandate caution in issuing a negative VP diagnosis based solely on the absence of the common R59W defect, because a minority of patients will harbour one of at least three mutations other than this.…”

Section: Discussionmentioning

confidence: 99%

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Identification and characterisation of a deletion (537delAT) in the protoporphyrinogen oxidase gene in a South African variegate porphyria family

Corrigall

Hift²,

Hancock³

et al. 1998

Hum. Mutat.

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Variegate porphyria is an autosomal dominant disorder of haem metabolism resulting from a partial decrease in protoporphyrinogen oxidase activity. Variegate porphyria is highly prevalent in South Africa, the result of a founder effect now confirmed genetically as a single point mutation (R59W) which has been described in nearly all South African variegate porphyria patients studied. Only two other mutations (H20P, R168C) have been reported in South Africa. We utilised simultaneous, single‐stranded conformational polymorphism and heteroduplex analysis, and direct sequencing to identify a further mutation; a 2 bp deletion in exon 6 which results in a premature stop codon 11 codons downstream from the mutation and is the first reported deletion in the protoporphyrinogen oxidase gene in a South African family. The familial segregation of this mutation strongly suggests that it is the disease causing mutation for variegate porphyria in this family. This further evidence for allelic heterogeneity limits the utility of tests for the R59W mutation in the diagnosis of variegate porphyria in South Africa. Hum Mutat 12:403–407, 1998. © 1998 Wiley‐Liss, Inc.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Identification and characterisation of a deletion (537delAT) in the protoporphyrinogen oxidase gene in a South African variegate porphyria family

Corrigall

Hift²,

Hancock³

et al. 1998

Hum. Mutat.

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“…The porphyrin excretion pattern in oxadiazontreated rodents, i.e. a substantial elevation of faecal porphyrins (in both rats and mice), and a moderate increase in urinary porphyrin precursors (in mice) resembles the quiescent phase of variegate porphyria, characterised by elevated stool protoporphyrin levels (Kirsch et al 1998) and a slight increase of urinary porphobilinogen and 5-aminolevulinic acid (Meissner et al 1993). Administration of phenobarbital or phenytoin to oxadiazon-treated animals increases the highly carboxylated porphyrin fraction in rat liver, which again corresponds with findings in variegate porphyria patients (Day et al 1980).…”

Section: Discussionmentioning

confidence: 99%

Effect of Tiagabine and Topiramate on Porphyrin Metabolism in an in vivo Model of Porphyria

Krijt

Krijtová

Sanitrák

2001

Pharmacology & Toxicology

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Administration of many antiepileptic drugs to patients with porphyria can precipitate an acute porphyric crisis. Information on the porphyrogenic activity of new antiepileptic drugs is still limited. In the presented study, the effects of tiagabine and topiramate on porphyrin metabolism were evaluated in an in vivo model of porphyria. Administration of the protoporphyrinogen oxidase inhibitor oxadiazon (12.5 mg/kg/day) for four days to male Wistar rats caused a partial block of porphyrin biosynthesis, thus mimicking the condition of quiescent variegate porphyria. Administration of phenobarbital (75 mg/kg/day) to oxadiazon-pretreated rats increased liver porphyrin content, liver porphobilinogen content (means 480 nmol/g, control less than 20 nmol/g) and urinary excretion of porphobilinogen (means 1000 mmol/l, control less than 20 mmol/l). Tiagabine (75 mg/kg/day) and topiramate (75 mg/kg/day) increased liver porphobilinogen content (means 33 and 53 nmol/g respectively) and urinary porphobilinogen concentration (240 and 490 mmol/l respectively). Similar results were obtained in oxadiazon-treated BALB/c mice. In untreated rats, tiagabine and topiramate caused a moderate increase of hepatic pentoxyresorufin-O-dealkylase activity (approximately 100 and 200 pmol/min./mg respectively, controls 15 pmol/min./mg). These data demonstrate that administration of tiagabine or topiramate to oxadiazontreated animals can provoke a condition resembling an acute porphyric attack and suggest that administration of these drugs to patients with suspected porphyria should be avoided. However, 5-day administration of both tiagabine and topiramate (75 mg/kg) is considerably less porphyrogenic than phenobarbital administered at the same dose.

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“…The most common of these disorders is acute intermittent porphyria (AIP) [1], with a worldwide prevalence within the range of 1 ± 10/ 100.000 [3]. Acute attacks of AIP are clinically more severe, even though they are formally indistinguishable from those of the less common conditions: variegate porphyria (VP) [15] and hereditary coproporphyria (HC) [16], and of the extremely rare homozygous ALAD-deficient porphyria (ALAD-P) [17]. Quite similar acute clinical manifestations may also be seen in lead poisoning (a condition also referred as plumboporphyria), which can be considered a classical example of an acquired disturbance of haem synthesis (Table 1) [18].…”

Section: The Acute Porphyriasmentioning

confidence: 99%

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

2009

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The porphyrias are a heterogeneous group of metabolic diseases resulting from a variable catalytic defect of one of the eight enzymes involved in the heme biosynthesis pathway; they are mostly inherited diseases, but in some circumstances the metabolic disturbance may be acquired. The specific patterns of tissue overproduction (and hence accumulation and excretion) of toxic heme precursors, associated with each enzymatic deficiency, are responsible for the characteristic biochemical and clinical features of each of these diseases. Moreover, even in the presence of a specific inherited enzymatic defect, many different environmental factors (such as drugs, calorie restriction, hormones, sunlight exposition, infections, etc.) often play a key role in triggering the clinical expression of the various forms of porphyrias. The porphyrias are often misdiagnosed diseases, due their multiform clinical manifestations, able to mimic many other more common diseases. For this reason, many different specialists, such as surgeons, psychiatrists, gastroenterologists, neurologists, emergency physicians and dermatologists may be variably involved in the diagnostic process, especially for the forms presenting with acute and life-threatening clinical features. According to the clinical features, the porphyrias can be classified into neuropsychiatric (characterized by neurovisceral crises involving autonomic and central nervous system but also the liver and the kidney with possible consequences in terms of neurological, psychic, cardiac, respiratory, liver and kidney functions), dermatological (mostly presenting with cutaneous lesions due to photosensitivity), and mixed forms. From a strictly clinical point of view, porphyrias presenting with neurovisceral attacks are also referred as acute porphyrias: they are the object of the present review. An accurate diagnosis of acute porphyria requires knowledge and the use of correct diagnostic tools, and it is mandatory to provide a more appropriate therapeutic approach and prevent the use of potentially unsafe drugs, able to severely precipitate these diseases, especially in the presence of life-threatening symptoms. To date, availability of a relatively stable haem preparation (haem arginate) has significantly improved the treatment outcome of acute porphyric attacks, so the knowledge about the diagnosis and the management of these diseases may be relevant for physicians working in internal medicine, neurology and emergency units.

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Variegate Porphyria

Cited by 71 publications

References 1 publication

Identification and characterisation of a deletion (537delAT) in the protoporphyrinogen oxidase gene in a South African variegate porphyria family

Identification and characterisation of a deletion (537delAT) in the protoporphyrinogen oxidase gene in a South African variegate porphyria family

Effect of Tiagabine and Topiramate on Porphyrin Metabolism in an in vivo Model of Porphyria

The acute porphyrias: a diagnostic and therapeutic challenge in internal and emergency medicine

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