[Inheritance in erythropoietic protoporphyria].

[erythropoietic protoporphyria]

Erythropoietic protoporphyria (EPP ) is an inherited disorder of heme biosynthesis that results from an accumulation of protoporphyrin IX in erythroid cells , plasma , skin and liver . EPP leads to acute photosensitivity and , in about 2 % of patients , liver disease . EPP is a complex syndrome in which two genes are independently involved : FECH and ALAS 2 . More than 96 % of unrelated EPP patients have ferrochelatase (FECH ) deficiency (MIM 177000 ). Four percent of them present with autosomal recessive inheritance with two mutated FECH alleles . In dominant cases (95 %) the inheritance of a common hypomorphic IVS 3 -48 C FECH allele trans to a deleterious FECH mutation reduces FECH activity below a critical threshold . The frequency of the IVS 3 -48 C allele differs widely from the Japanese (45 %), to Black West Africans (<1 %) populations . These differences in the frequency of this single common SNP account for the prevalence of overt EPP in different countries and for the absence of EPP in Black Africans . The phylogenic origin of the IVS 3 -48 C haplotypes strongly suggests that the IVS 3 -48 C allele arose from a single recent mutational event that occurred 60 Kyears ago . Acquired somatic mutation of FECH secondary to myeloid disease may also exceptionally cause EPP (<1 %). Finally , about 4 % of unrelated EPP patients have X-linked dominant protoporphyria (XLDPP ) (MIM 300752 ) caused by gain-of-function mutations in the ALAS 2 gene leading to an increased erythroid heme biosynthesis and subsequently an accumulation of protoporphyrin without any FECH deficiency .