Ferrochelatase (FECH) Gene, Full Gene Analysis
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
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 8 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 / Porphyrins Evaluation, 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.
Confirmation of a diagnosis of erythropoietic protoporphyria (EPP) following positive biochemical genetic test results obtained through PEE / Porphyrins Evaluation, Blood
Carrier testing for individuals with a family history of EPP in the absence of known mutations in the family
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A small percentage of individuals who are carriers or have a diagnosis of erythropoietic protoporphyria (EPP) disease may have mutations that are not identified by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation(s), therefore, does not eliminate the possibility of positive carrier status or the diagnosis of EPP disease. For carrier testing, it is important to first document the presence of a ferrochelatase (FECH) gene mutation in an affected family member.
This test does not exclude the presence of mutations within other genes, such as ALAS2 (aminolevulinate, delta-, synthase 2), that are associated with EPP, X-linked or otherwise.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
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.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Lecha M, Puy H, Deybach JC: Erythropoietic protoporphyria. Orphanet J Rare Dis 2009;4:19
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