Congenital erythropoietic porphyria. A mild variant with low uroporphyrin I levels due to a missense mutation (A66V) encoding residual uroporphyrinogen III synthase activity.

BACKGROUND AND DESIGN: Congenital erythropoietic porphyria, an inborn error of heme biosynthesis, results from the deficient activity of the enzyme uroporphyrinogen III synthase. The clinical manifestations in unrelated patients with this autosomal recessive disorder are remarkedly variable, ranging from mild cutaneous involvement to severe transfusion-dependent hemolytic anemia. Biochemical and molecular studies were undertaken to investigate the nature of the unusually mild phenotype in a 15-year-old boy with only cutaneous manifestations. RESULTS: The proband's levels of total porphyrins, urinary uroporphyrin I, and erythrocyte coproporphyrin I were elevated, but not as dramatically as in other patients with this porphyria. Interestingly, the erythrocyte uroporphyrinogen III synthase activity in the proband was about 21% of the normal mean, indicating the presence of significant residual activity. In cultured lymphoblasts from the proband, his father, and mother, the enzymatic activities were 10%, 70%, and 50% of the normal mean, respectively. Molecular analyses revealed that the proband was heteroallelic for two uroporphyrinogen III synthase missense mutations: the C73R allele inherited from his mother and the A66V allele transmitted by his father. The A66V allele encoded residual enzymatic activity in vitro while the C73R allele did not. CONCLUSIONS: The A66V allele accounted for the proband's low levels of porphyrin accumulation and mild clinical manifestations. Such genotype-phenotype correlations should provide understanding of the remarkable clinical variability in other patients with this inherited porphyria.

Urinary porphyrin excretion in normal children and adults.

The relationship of random urinary porphyrin and creatinine values as functions of age and sex was examined in a normal population. Total urinary porphyrin was measured by a solvent extraction technique, while urinary creatinine was evaluated by an alkaline picrate method. Random urine specimens from 120 healthy patients (81 children and 39 adults) were evaluated. In both pediatric and adult populations, a strong correlation was found between urinary concentrations of porphyrin and creatinine (r = 0.7, P less than 0.0001). Urinary porphyrin excretion in mumol/mol creatinine (micrograms/g) was inversely related to both age (r = -0.59, P less than 0.0001) and weight (r = -0.61, P less than 0.0001) until approximately 9 years of age or 30 kg. Urinary porphyrin excretion in children 9 to 18 years of age was lower than that of younger children (P less than 0.0001) and approached adult values. Sex was not found to be a factor until 9 to 18 years of age, when females had higher urinary creatinine concentrations (P less than 0.05), but lower urinary porphyrin excretions (P less than 0.05) than similarly aged males. The converse was observed when similar values of adult women were compared with those of adult men. Men also had higher urinary porphyrin concentrations than women (P less than 0.01). Men had increased urinary creatinine concentration (P less than 0.05) and decreased porphyrin excretion ratios (P less than 0.05) when compared with males 9 to 18 years of age. Women had significantly lower urinary creatinine (P less than 0.001) and porphyrin (P less than 0.001) concentrations than females 9 to 18 years of age.(ABSTRACT TRUNCATED AT 250 WORDS)