Autosomal recessive erythropoietic protoporphyria in the United Kingdom: prevalence and relationship to liver disease

Erythropoietic protoporphyria (EPP; MIM 177000) is an inherited disorder of haem biosynthesis characterised by the onset in early childhood of lifelong acute photosensitivity of sun-exposed skin.1 It results from partial deficiency of ferrochelatase (FECH; E.C. 4.99.1.1.), which leads to accumulation of protoporphyrin IX in erythrocytes, plasma, skin, and liver. Up to 35% of patients have mildly abnormal biochemical tests of liver function, while liver failure caused by the hepatotoxic action of protoporphyrin complicates about 2% of cases.2–5 Over 70 mutations in the FECH gene have been identified in EPP families (Human Gene Mutation Database: http://www.hgmd.org/).6–10 Most individuals who are heterozygous for these mutations are asymptomatic, despite having half-normal FECH activities.11 For protoporphyrin to accumulate sufficiently to cause photosensitivity, reduction of FECH activity to below a critical threshold of about 35% of normal is required.11–14 In most patients, this additional reduction results from inheritance of a low expression FECH allele trans to a severe mutation.10,15–18 The low expression allele is the C variant of a single nucleotide polymorphism (SNP; IVS3-48C/T) in intron 3 of the FECH gene.18 Because the IVS3-48C allele is common in the general population, being present in about 11% of the white inhabitants of France,18 inheritance trans to a severe FECH mutation occurs within EPP families at a frequency that is high enough to produce a pattern of inheritance of overt EPP resembling an autosomal dominant disease with incomplete penetrance. Although co-inheritance of an IVS3-48C allele appears to explain the occurrence of photosensitivity in most EPP families,8,10,17,18 alternative mechanisms may reduce FECH activity to below threshold activity in some patients. These include autosomal recessive inheritance with an FECH mutation on both alleles,15,19–23 deletion of an FECH gene …