Interpretive Handbook

Erythropoietic protoporphyria (EPP) is an inherited disorder of porphyrin metabolism whose clinical manifestations include painful photodermatosis without blisters and liver disease. The disorder results from decreased activity of the enzyme ferrochelatase (FECH). FECH is the last of eight enzymes acting sequentially in the heme biosynthetic pathway and is encoded by the FECH gene located on chromosome 18.

The skin symptoms in EPP include immediate painful photosensitivity, usually beginning in early infancy upon sun exposure. Repeated photosensitivity episodes result in skin thickening and areas of hyperkeratosis. This is typically noted on areas where sun exposure is most common, such as the dorsa of the hands and on the face. A small number of patients with EPP develop liver complications. Hepatic disease in EPP may include cholelithiasis and chronic liver disease progressing to rapid acute liver failure.

Biochemically, EPP is characterized by elevated protoporphyrin levels in red blood cells, which fluorescence under Wood’s light due to the accumulation of free protoporphyrin IX. Protoporphyrin elevations may also be found in plasma and stool, but not in all patients. Urine protoporphyrin levels are usually normal unless there is liver involvement. Studies have also suggested that a reduction in activity of ferrochelatase to <50% of normal levels can induce clinical manifestations. The gold standard test for the diagnosis of EPP is biochemical analysis (PEE/88886 Porphyrins Evaluation, Whole Blood), interpreted in the context of clinical features.

In most patients with EPP, a pathogenic FECH mutation that reduces enzyme activity by 50% can be identified on only 1 allele. Clinical expression of EPP typically requires a hypomorphic (low expression) FECH allele (IVS3-48T->C) in trans (on a different chromosome) with the mutation. IVS3-48T->C is a variant of the FECH gene associated with reduced gene expression. This variant is found in approximately 10% of the general Caucasian population. Autosomal recessive inheritance (2 pathogenic mutations in trans) is infrequent, accounting for <4% of EPP cases. In contrast to patients with 1 pathogenic mutation and the low-expression allele, missense mutations are far more common than null mutations.

It is uncertain whether protoporphyric liver failure is more common among individuals with a single null (splicing defect, nonsense, or frameshift) mutation than those with 2 pathogenic mutations as some literature has suggested. In any case, it is certain that all EPP patients should be monitored for hepatic disease and actively manage their photosensitivity.

Diagnostic confirmation of ferrochelatase (FECH) deficiency when familial mutations have been previously identified

Carrier screening of at-risk individuals when a mutation in the FECH gene has been identified in an affected family member

An interpretive report will be provided.

The identification of a disease-causing mutation in an affected family member is necessary before predictive testing for other family members can be offered. If a familial mutation has not been previously identified, order FECHS/60371 Ferrochelatase (FECH) Gene, Full Gene Analysis.

Analysis is performed for the familial mutation(s) provided only. This assay does not rule out the presence of other mutations within this gene or within other genes that may be associated with erythropoietic protoporphyria (EPP) disease.

We strongly recommend that patients undergoing predictive testing receive genetic counseling both prior to testing and after results are available.

Predictive testing of an asymptomatic child is not recommended.

Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Any error in the diagnosis or in the pedigree provided to us, including false-paternity, could lead to erroneous interpretation of results.

A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.

An interpretive report will be provided.

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2. Schneider-Yin X, Gouya L, Meier-Weinand A, et al: New insights into the pathogenesis of erythropoietic protoporphyria and their impact on patient care. Eur J Pediatr 2000;159:719-725

3. Rufenacht UB, Gouya L, Schneider-Yin X, et al: Systematic analysis of molecular defects in the ferrochelatase gene from patients with erythropoietic protoporphyria. Am J Hum Genet 1998;62:1341-1352

4. Whatley SD, Mason NG, Holme SA, et al: Molecular epidemiology of erythropoietic protoporphyria in the U.K. Br J Dermatol 2010;162:642-646