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.