Autosomal erythropoietic protoporphyria (ORPHA:79278)
A rare hereditary disorder of the heme metabolic pathway characterized by accumulation of protoporphyrin in blood, erythrocytes and tissues, with photosensitive skin manifestations.
Epidemiology
Erythropoietic protoporphyria (EPP) has been reported worldwide, with prevalence ranging from 1/17,000 to 1/100,000.
Clinical description
It usually begins in early childhood, with the first exposure to the sun. EPP manifests as acute painful photosensitivity of the skin with erythema and edema, sometimes petechiae, together with stinging and burning sensations without phlyctens, after exposure to sunlight or illumination in the visible spectrum (particularly in the Soret band [400 - 410 nm]). These episodes have a variable severity depending on the exposure duration and may result in chronic permanent lesions on exposed skin. As protoporphyrin is a lipophilic molecule excreted by the liver, patients with EPP are at risk of cholelithiasis with obstruction of the bile ducts, and chronic liver disease which may progress to acute liver failure.
Etiology
In most cases, EPP is due to a partial deficiency of the last enzyme in the heme biosynthesis pathway, ferrochelatase, encoded by the FECH gene (NM_000140.3). The pattern of inheritance of EPP is autosomal dominant where clinical expression is modulated by the presence of the hypomorphic IVS3-48C FECH allele in trans. Autosomal recessive transmission of two mutated alleles of the FECH gene has also been reported.
Diagnostic methods
Diagnosis is established by increased levels of protoporphyrin in plasma and red blood cells, and detection of a plasma fluorescence peak at 635 nm. Further analysis is recommended, including a search for liver damage and measurement of ferrochelatase activity levels. Genetic analysis (mutations in the FECH gene, presence of the hypomorphic IVS3-48C FECH allele in trans) and family screening are also recommended.
Differential diagnosis
Differential diagnosis includes X-linked erythropoietic protoporphyria, phototoxic drug reactions, hydroa vacciniforme, solar urticaria, contact dermatitis, and angioedema.
Antenatal diagnosis
Antenatal diagnosis is theoretically possible, but is not offered.
Genetic counseling
The pattern of inheritance is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that there is a 50 % risk of transmitting the pathogenic variant. Autosomal recessive transmission of two mutated alleles of the FECH gene has also been reported.
Management and treatment
Treatment is based on preventive measures such as sun avoidance, protection against visible light (especially blue light) using a high UVA index sunscreen with a high critical wavelength (>370 nm), the use of protective filters on windows and the yellow filter on scialytics, short sessions of UVB TL01 before summer, reducing protoporphyrins (by reducing erythropoiesis with transfusions or by administration of cholestyramine, a bile acid chelator, or by careful phlebotomy), preventing the progression of liver damage to liver failure. Conventional analgesics and beta-carotene have limited effectiveness in EPP. Since liver disease is the major risk associated with EPP, regular monitoring of liver function is key. Sequential liver and bone marrow transplant should be considered in the treatment of severe cases presenting with liver damage.
Prognosis
EPP is a chronic disease, and its prognosis depends on the progression of liver disease. However, photosensitivity can affect patients' quality of life. The latter has been improved by the use of afamelanotide. Two molecules, dersimelagon and bitopertin, are currently under development. Patients with EPP should not be given iron supplements without expert medical advice.

                            Last update: 
                            March 2024


                            - Expert reviewer(s): 
                            Dr Neila TALBI | MetabERN*


                                * European Reference Network