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 …