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PubMed2004

A systematic study of the clinical and biochemical expression of variegate porphyria in a large South African family.

BACKGROUND: Variegate porphyria (VP) is an autosomal dominant disorder associated with deficient haem synthesis. Recent reports indicate that the clinical penetrance of VP may have been overestimated in studies which predated the availability of DNA-based testing for VP. OBJECTIVES: To undertake a study specifically designed to assess the clinical and biochemical penetrance of VP in a kindred characterized by gene status. METHODS: We studied a large family carrying the South African founder mutation which is known to result in almost complete haplodeficiency. All informative members were tested for the R59W mutation. Biochemical evidence of porphyria was sought by porphyrin analysis and by plasma fluorescence scanning. The presence of clinically expressed porphyria was assessed using a structured questionnaire and telephone or personal interview. RESULTS: Of 62 informative subjects, 33 had inherited the mutation. Of 28 adults, one subject had experienced a single acute attack. She and a further 10 subjects had experienced photosensitivity. The frequency of acute attacks in this family is therefore 4% (95% confidence interval, CI 1-18%), and of photosensitivity is 39.3% (95% CI 24-58%). The sensitivity and specificity of porphyrin analysis in this family were 0.46 (95% CI 0.30-0.64) and 1.00 (95% CI 0.85-1.00), respectively, and for plasma scanning the values were 0.85 (95% CI 0.58-0.96) and 1.00 (95% CI 0.72-1.00), respectively. CONCLUSIONS: The clinical penetrance of VP in our family is approximately 40%. Many more subjects with VP are diagnosed in an asymptomatic phase than previously, and the acute attack is now an uncommon manifestation of VP. Plasma scanning is more sensitive than faecal porphyrin analysis, but neither is sufficiently sensitive for the detection of carrier status.

Acute Disease↗
PubMed1978

Variegate porphyria.

In temperate and cold climates the most usual presenting symptom of variegate porphyria is an acute porphyric attack, indistinguishable from that seen in acute intermittent porphyria. Increased fragility of the skin in sun-exposed areas occurs in only half of such patients, and even then is usually mild and easily overlooked. The diagnosis depends on fecal excretion of porphyrins, which is greatly increased in variegate porphyria and consists predominantly of protoporphyrin. Urinary excretion of porphobilinogen and delta-aminolevulinic acid increases only during acute attacks. There are reasons for thinking that variegate porphyria is commoner than hitherto supposed. During an acute attack a patient without skin symptoms may well be misdiagnosed as having acute intermittent porphyria, because of identical symptoms and excretion of porphobilinogen in the urine. Thus, for a correct diagnosis, every patient presenting with symptoms of acute porphyria requires a fecal analysis.

Acute Disease↗
PubMed1986

Protoporphyrinogen oxidase and porphobilinogen deaminase in variegate porphyria.

Two enzymes of the haem biosynthetic pathway were investigated in patients with variegate porphyria. Protoporphyrinogen oxidase in cultures of Epstein-Barr virus transformed lymphoblasts from twenty-seven patients showed a mean maximal velocity (Vmax) of 0.39 +/- 0.08+ nmol of protoporphyrin mg protein-1 h-1, a 52% reduction (P less than 0.001) from a non-porphyric control group (0.82 +/- 0.10). Km values (1.00 +/- 0.27 microM) did not differ significantly (P greater than 0.05) from control values in any of the patients. The mean Vmax of porphobilinogen deaminase in the cultures was 1.50 +/- 0.18 nmol of uroporphyrin mg protein-1 min-1, a 24% reduction (P less than 0.001) from controls (1.94 +/- 0.14). Mean porphobilinogen deaminase activity in the erythrocytes of twenty-one patients with variegate porphyria was 8.37 +/- 1.99 nmol of uroporphyrin 1 erythrocytes-1 s-1, a 28% reduction (P less than 0.001) from normal (11.98 +/- 2.11). The reduced activities of these two enzymes comply with the expression of variegate porphyria during its quiescent and acute phases.

Ammonia-Lyases↗
PubMed1990

Homozygous variegate porphyria: a case report.

Homozygous variegate porphyria is described in a 14-year-old girl with a unique clinical presentation of photosensitivity from the second year of life, mental retardation, clinodactyly, and normal growth rate. The erythrocyte protoporphyrin concentration was raised with the protoporphyrin being predominantly zinc-chelated, which appears to be characteristic for all homozygous hepatic porphyrias. Protoporphyrinogen oxidase activity in lymphoblasts was decreased in both patient and parents despite the latter having normal porphyrin excretion.

Adolescent↗
PubMed2002

Functional studies of mutations in the human protoporphyrinogen oxidase gene in variegate porphyria.

The autosomal dominant disorder, variegate porphyria (VP), results from mutations in the protoporphyrinogen oxidase (PPOX) gene. We have investigated the effects of 22 disease-associated missense mutations in this gene on enzyme activity. Mutants were generated in the expression plasmid pHPPOX by site-directed mutagenesis. They were screened for PPOX activity by complementation of the Escherischia coli strain SAS38X which lacks PPOX activity. Ten mutants (G40E, L85P, G232R, de1281H, V282D, L295P, V335G, S350P, L444P, G453V) had no detectable PPOX activity. PPOX activity of the remaining 12 mutants (L15F, R38P, L73P, V84G, D143V, R152C, L154P, V158M, R168H, A172V, V290L, G453R) ranged from less than 1% to 9.2% of wild-type activity. Our findings show that all 22 mutations substantially impair or abolish PPOX activity in a prokaryotic expression system and add to the evidence that they cause VP.

Escherichia coli↗
PubMed1980

Variegate porphyria. Clinical and laboratory features.

Variegate porphyria (VP) is a rare disease infrequently diagnosed in the United States. The typical cutaneous signs of VP, including fragility, bullae, scarring, hypertrichosis, and photosensitivity, are indistinguishable from those of porphyria cutanea tarda (PCT). Inadequate laboratory evaluation of porphyrins present in, or improper interpretation of porphyrin test results from, biologic specimens from patients with VP may lead to inappropriate diagnosis and treatment. Clinical and laboratory data for three such cases of VP are presented. A plasma porphyrin fluorescence criterion which appears specific for patients with VP was observed in all three cases.

Adult↗
PubMed1998

Homozygous variegate porphyria: identification of mutations on both alleles of the protoporphyrinogen oxidase gene in a severely affected proband.

Homozygous variegate porphyria is a severe skin and neurologic disease manifesting in early infancy, and characterized by markedly reduced levels of the penultimate enzyme in the heme biosynthetic pathway, protoporphyrinogen oxidase. We investigated the molecular basis of variegate porphyria, usually an autosomal dominantly inherited trait, in a severely affected female proband and her parents. The mutation detection strategy included heteroduplex analysis, automated sequencing, and allele specific oligonucleotide hybridization. We identified two underlying missense mutations in the protoporphyrinogen oxidase gene, consisting of a G-to-A transition in exon 6 (G169E), and a G-to-A transition in exon 10 (G358R). Our study establishes the molecular basis of "homozygous" variegate porphyria for the first time, in demonstrating that this patient is a compound heterozygote for two different missense mutations in the protoporphyrinogen oxidase gene.

Adult↗
PubMed1995

[A case report of variegate porphyria].

We reported a 30-year-old woman with variegate porphyria. Family history disclosed that her mother had the same skin lesions as the present case. She has had repeated vesicles and brownish pigmentation on her upper extremities since eighteen years of age. Recently she was suffering from common cold, and was treated with drugs. One week later, she started to develop weakness and dysesthesia in all limbs, hallucination, and urinary disturbance. Three weeks later, she was admitted to our hospital because she could not stand any more. On general examination, she had brownish pigmentations and crusts in hands and forearms. Neurologically she had moderate weakness, dysesthesia and hyperreflexia in all limbs. Urine was dark-red. Head and cervical MRI was normal. Nerve conduction studies and somatosensory evoked potentials were within normal limits. Excretion of porphyrins, especially protoporphyrin and X-porphyrin in the feces were markedly increased, and the diagnosis of variegate porphyria was made. Intravenous administration of glucose was effective and her symptoms began to improve in two weeks after her admission. However, recovery of weakness took two months and dysesthesia did not disappear in three months. We considered that her clinical manifestations were caused by involvement of the central and peripheral nervous systems.

Adult↗
PubMed1997

Characteristics of human protoporphyrinogen oxidase in controls and variegate porphyrias.

Protoporphyrinogen oxidase (E.C.1.3.3.4) (PPO) catalyzes the penultimate step in the heme biosynthetic pathway. Deficiency in activity of this enzyme results in the human genetic disease variegate porphyria. Herein we detail the cloning, expression, purification and characterization of the normal and variegate porphyria forms of human PPO. The cDNA sequence for human ppo is approximately 1.8 kb in length and codes for a protein of 477 amino acids. This protein, which does not contain a typical cleavable mitochondrial targeting sequence, is approximately 51 kDa and contains a putative dinucleotide binding motif near the amino terminus. The active enzyme is a homodimer and contains an FAD. Attachment of a six his amino terminal tag allows for the rapid and efficient purification of approximately 10 mg of enzyme from one liter of E. coli culture. Three variegate porphyria mutant PPO enzymes were expressed and characterized. These mutations, R59W, R168C and A433P, result in decreased enzyme activity by causing a decrease in kcat without a significant change in Km for the substrate protoporphyrinogen IX. Purified R59W lacks the FAD cofactor which may be explained by the fact that this mutation resides within the dinucleotide binding motif of PPO.

Amino Acid Sequence↗
PubMed1990

An unusual case of variegate porphyria with possible homozygous inheritance.

We report an unusual case of variegate porphyria in a young girl with epilepsy, mental retardation and premature adrenarche. Symptoms of porphyria commenced about the age of 12 years and death occurred about 18 months later. The patient had very low protoporphyrinogen oxidase activity in her cultured fibroblasts. Both parents had half the normal activity of this enzyme in lymphocytes and are heterozygous for the abnormal gene for variegate porphyria. Therefore, it is possible that the patient was a homozygous variant. Anticonvulsant therapy and low hepatic 5 alpha reductase activity were probably other contributing factors to the severity of the condition in this patient.

Animals↗
PubMed1997

Variegate porphyria in South Africa, 1688-1996--new developments in an old disease.

Variegate porphyria, an autosomal dominant inherited trait resulting in decreased activity of protoporphyrinogen oxidase, the penultimate haem biosynthetic enzyme, is characterised clinically by photosensitive skin disease and a propensity to acute neurovisceral crises. The disease has an exceptionally high frequency in South Africa, owing to a founder effect. The specific mutation in the protoporphyrinogen oxidase gene sequence which represents this founder gene has been identified. Genetic diagnosis is therefore now possible in families in whom the gene defect is known. However, the exact nature and degree of activity of the porphyria can only be determined by detailed quantitative biochemical analysis of excreted porphyrins. The relative contributions of the acute attack and the skin disease to the total disease burden of patients with variegate porphyria is not static, and in South Africa there have been significant changes over the past 25 years, with fewer patients presenting with acute attacks, leaving a greater proportion to present with skin disease or to remain asymptomatic with the diagnosis being made in the laboratory. The most common precipitating cause of the acute attack of VP is administration of porphyrinogenic drugs. Specific suppression of haem synthesis with intravenous haem arginate is the most useful treatment of a moderate or severe acute attack. Although cutaneous lesions are limited to the sun-exposed areas, management of the skin disease of VP remains inadequate.

Animals↗
PubMed1998

Variegate porphyria: identification of a nonsense mutation in the protoporphyrinogen oxidase gene.

The porphyrias are disorders of porphyrin metabolism that result from inherited or acquired aberrations in the control of the heme biosynthetic pathway. Variegate porphyria is characterized by a partial reduction in the activity of protoporphyrinogen oxidase. In this study, we identified the first nonsense mutation in a family with variegate porphyria. The mutation consisted of a previously unreported G-to-T transversion in exon 5 of the protoporphyrinogen oxidase gene, resulting in the substitution of glutamic acid by a nonsense codon, designated E133X. Our investigation establishes that a nonsense mutation in the protoporphyrinogen oxidase gene is the underlying mutation in this family with variegate porphyria.

Adult↗
PubMed2004

Recovery from a variegate porphyria by a liver transplantation.

The porphyrias are a group of inherited or acquired enzymatic defects of heme biosynthesis. Each type of porphyria has a characteristic pattern of overproduction and accumulation of heme precursors based on the location of dysfunctional enzyme in the heme synthetic pathway. Variegate porphyria, one of the acute hepatic porphyrias, is characterized by a partial reduction in protoporphyrinogen oxidase, the seventh enzyme of the heme biosynthetic pathway. A case of liver transplantation is described with a recovery from a variegate porphyria. Acute porphyria is commonly worsened by a wide variety of medications. We describe a step-by-step perioperative management protocol.

Humans↗
PubMed2006

Genetic studies in variegate porphyria in Spain. Identification of gene mutations and family study for carrier detection.

BACKGROUND: First, to establish the mutations of the protoporphyrinogen-oxidase (PPOX) gene in four Spanish patients with variegate porphyria (VP). Second, study of carrier status detection in the families, including a four-generation Balearic family. Third, evaluation of the results of carrier detection screening methods. DESIGN: Blood samples of four patients and of 139 members belonging to four families, including four generations of a Balearic family were processed for mutation analysis of the 13 exons of PPOX gene. Biochemical studies were performed together (blood and faecal porphyrin analysis) and plasma fluorescence scanning for 626 nm peak emission detection. A questionnaire regarding clinical manifestations was submitted to all family members studied. RESULTS: Single strand conformational analysis (SSCP) of DNA allowed the detection of the following mutations: W224R, 746delT: exon 7, 1077-1082insC: exon 10, and IVS6+2T-->A. Mutation was present in 19 of the 139 members of the families studied. Clinical manifestations or biochemical alterations were checked in the carriers detected and found as not relevant or not present. Only 11 members of the 19 mutation-bearing individuals showed plasma fluorescence PV peak positivity. CONCLUSION: Demonstration of gene mutation is the most reliable means of detecting carriers in studies of variegate porphyria families. DNA analysis is the most sensitive carrier detection method and also allows transmission behaviour of the genetic defect to be established in successive generations of the affected families.

Adult↗
PubMed1992

Rapid normalization of antipyrine oxidation by heme in variegate porphyria.

Effects of heme on hepatic xenobiotic drug metabolism were investigated in eight subjects with variegate porphyria. A single infusion of heme arginate (3 mg/kg heme) reversed rapidly the prolonged mean elimination half-life of antipyrine from 27.2 to 12.7 hours (p less than 0.001) and increased total clearance from 0.23 to 0.44 ml/min/kg (p less than 0.001). Excretion of 6 beta-hydroxycortisol and D-glucaric acid increased significantly during heme infusion. Excretion of urinary porphyrin precursors increased during the antipyrine test but was normalized by heme. It is concluded that in variegate porphyria a partial block in heme biosynthesis results in subnormal capacity of P450-associated monooxygenases, but this is easily normalized by exogenous heme.

Adult↗