Wednesday, June 21, 2017

Pub MD: Erythropoietic Protoporphyria, Autosomal Recessive

Erythropoietic Protoporphyria, Autosomal Recessive.

Authors

Balwani M1Bloomer J2Desnick R1; Porphyrias Consortium of the NIH-Sponsored Rare Diseases Clinical Research Network.

Source

GeneReviews®[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2012 Sep 27 [updated 2014 Oct 16].

Excerpt

CLINICAL CHARACTERISTICS:

Erythropoietic protoporphyria (EPP) is characterized by cutaneous photosensitivity (usually beginning in infancy or childhood) that results in tingling, burning, pain, and itching within minutes of sun/light exposure and may be accompanied by swelling and redness. Blistering lesions are uncommon. Symptoms (which may seem out of proportion to the visible skin lesions) may persist for hours or days after the initial phototoxic reaction. Photosensitivity usually remains for life. Multiple episodes of acute photosensitivity may lead to chronic changes of sun-exposed skin (lichenification, leathery pseudovesicles, grooving around the lips) and loss of lunulae of the nails. Approximately 20%-30% of individuals with EPP have some degree of liver dysfunction, which is typically mild with slight elevations of the liver enzymes. Up to 5% may develop more advanced liver disease which may be accompanied by motor neuropathy similar to that seen in the acute porphyrias. Except for the small minority with advanced liver disease, life expectancy is not reduced.

DIAGNOSIS/TESTING:

Detection of markedly increased free erythrocyte protoporphyrin is the most sensitive and specific biochemical diagnostic test for EPP. Identification of biallelic pathogenic variants in FECH, encoding ferrochelatase, confirms the diagnosis.

MANAGEMENT:

Treatment of manifestations: There is no FDA-approved treatment for this disease or specific treatment for the acute photosensitivity. The pain is not responsive to narcotic analgesics. The only effective current treatment is prevention of the painful attacks by avoidance of sun/light (including the long-wave ultraviolet light sunlight that passes through window glass) through use of protective clothing (e.g., long sleeves, gloves, wide-brimmed hats, protective tinted glass for cars and windows). Although topical sunscreens are typically not useful, some tanning products containing creams which cause increased pigmentation may be helpful. Oral Lumitene™ (β-carotene) may improve tolerance to sunlight by causing mild skin discoloration due to carotenemia. Severe liver complications are difficult to treat: cholestyramine and other porphyrin absorbents (to interrupt the enterohepatic circulation of protoporphyrin and promote its fecal excretion) and plasmapheresis and intravenous hemin are sometimes beneficial. Liver transplantation may be required. Prevention of secondary complications: Vitamin D supplementation to prevent vitamin D insufficiency due to sun avoidance. Surveillance: Monitoring of: hepatic function every 6-12 months and hepatic imaging if cholelithiasis is suspected; erythrocyte protoporphyrin levels (free and zinc-chelated), hematologic indices, and iron profile annually; vitamin D 25-OH levels. Agents/circumstances to avoid: Sunlight and UV light; for those with hepatic dysfunction, drugs that may induce cholestasis (e.g., estrogens); for those with cholestatic liver failure, use of protective filters for artificial lights in the operating room to avoid phototoxic damage. Evaluation of relatives at risk: If both FECH pathogenic variants have been identified in an affected family member, at-risk relatives can be tested as newborns or infants so that those with biallelic pathogenic variants can benefit from early intervention (sun protection) and future monitoring for signs of liver dysfunction. Therapies under investigation: Clinical trials for afamelanotide, an α-melanocyte stimulating hormone analog that increases melanin production (and thus skin pigmentation) have recently been completed.

GENETIC COUNSELING:

EPP is inherited in an autosomal recessive manner. In about 96% of cases an affected individual inherits a loss-of-function FECH allele from one parent and a low-expression FECH allele from the other parent. In about 4% of cases, an affected individual has two loss-of-function FECH alleles. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) and individuals who inherit two low-expression alleles are asymptomatic. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.
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