The molecular genetics of erythropoietic protoporphyria.

[erythropoietic protoporphyria]

Erythropoietic protoporphyria (EPP ) is a syndrome in which accumulation of protoporphyrin IX in erythroid cells , plasma , skin and liver leads to acute photosensitivity and , in about 2 % of patients , liver disease . More than 95 % of unrelated patients have ferrochelatase (FECH ) deficiency (MIM 177000 ) while about 2 % have X-linked dominant protoporphyria (XLDPP ) (MIM 300752 ) caused by gain-of-function mutations in the ALAS 2 gene . Most FECH -deficient patients are compound heterozygotes for a hypomorphic allele (FECH IVS 3 -48 C ) and a deleterious FECH mutation that together lower FECH activity to around 30 % of normal . The frequency of the IVS 3 -48 C allele varies between populations , ranging from less than 1 % to 45 %. About 4 % of unrelated FECH -deficient patients are compound heterozygotes or homozygotes for rare FECH mutations and have lower enzyme activities . Acquired somatic mutation of FECH secondary to myeloid disease may rarely cause EPP . The risk of liver disease is increased in XLDPP and in FECH -deficient patients who are hetero- or homoallelic for rare FECH mutations . Inherited FECH -deficient EPP is an autosomal recessive disorder with some families showing pseudodominant inheritance ; the proportion of such families being determined by the population frequency of the IVS 3 -48 C allele .