Erythropoietic protoporphyria (EPP) is an inherited disorder, which results in raised levels of a phototoxic molecule, protoporphyrin IX (PPIX), in the bone marrow, skin and liver.
Most patients with EPP inherit two genetic mutations, one from each parent.
In the most common form of inheritance a patient inherits a genetic mutation from one parent which causes markedly decreased or abolished ferrochelatase activity (0 to less than 10% of normal activity). In most cases the patient inherits what is known as a “low expression” FECH gene, which results in less than 30% of the normal activity, from the other parent. This is known as the “pseudodominant” inheritance pattern. The combination of the two mutations means that an EPP patient has less than 25% of normal ferrochelatase activity.
Individuals with a single mutation resulting in no activity will have 50% of normal activity (the 50% activity is derived from the normal gene from the other parent) and this is sufficient to prevent protoporphyrin levels from increasing. Individuals with the low expression gene in combination with a normal gene will have about 70 – 80% of normal activity, and no complaints.
In rarer instances a child may inherit markedly decreased or abolished activity FECH mutations from both parents, resulting in EPP (known as the “autosomal recessive” form).
The combination of a severe mutation and the low expression mutation accounts for approximately 90% of EPP cases in Europe. The low expression ferrochelatase gene varies between different populations and is common in Europe and some parts of Asia, but rare in Africa.
Ferrochelatase (FECH) is the specific deficient enzyme in erythropoietic protoporphyria. Consequently there is a reduced capacity to bind iron with protoporphyrin IX to form haem. PPIX accumulates mainly in red blood cells, and slowly passes from the cells into plasma and into blood vessel linings. Light waves, penetrating through the skin, are absorbed by the protoporphyrin, activating it to cause phototoxic reactions.
The gene for the ferrochelatase enzyme, is located on chromosome 18q21.3. Molecular studies on the gene in families throughout the world show that more than 160 different mutations exist.
X-linked dominant EPP
In a small number of patients EPP is not caused by ferrochelatase mutations, but by a mutation in the first enzyme of porphyrin and haem production in red blood cells – called aminolevulinic acid synthase-2 – and is referred to as X-linked dominant EPP. This mutation results in an increase in the production of porphyrins including protoporphyrin IX, overwhelming the capacity of the red cell to import iron to make haem, and resulting in high levels of both free protoporphyrin IX and zinc protoporphyrin. The ALAS-2 gene is located on the X-chromosome, which means that all males inheriting the mutation will have EPP. Females can also develop symptoms. The effects of the high levels of protoporphyrin IX (derived from red cells) on the skin are identical to those seen with ferrochelatase deficiency, with phototoxicity the main symptom.