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Fabry Disease.

Authors

Mehta A1, Hughes DA2.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2002 Aug 5 [updated 2017 Jan 5].

Author information

1
Director, Lysosomal Storage Disorders Unit, Consultant Haematologist, Royal Free Hospital, University College London School of Medicine, London, United Kingdom
2
Senior Lecturer Haematology, Lysosomal Storage Disorders Unit, Department of Haematology, Royal Free Hospital, University College London, London, United Kingdom

Excerpt

CLINICAL CHARACTERISTICS:

Fabry disease results from deficient activity of the enzyme alpha-galactosidase A (α-Gal A) and progressive lysosomal deposition of globotriaosylceramide (GL-3) in cells throughout the body. The classic form, occurring in males with less than 1% α-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, they may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. In contrast, males with greater than 1% α-Gal A activity may have: (1) a cardiac variant phenotype that usually presents in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy and arrhythmia, and proteinuria, but without ESRD; or (2) a renal variant phenotype, associated with ESRD but without the skin lesions or pain; or (3) cerebrovascular disease presenting as stroke or transient ischemic attack.

DIAGNOSIS/TESTING:

Identification of deficient α-Gal A enzyme activity in plasma, isolated leukocytes, and/or cultured cells is the most efficient and reliable method of diagnosing Fabry disease in males. Identification of a hemizygous GLA pathogenic variant by molecular genetic testing confirms the diagnosis in a male proband. Identification of a heterozygous GLA pathogenic variant by molecular genetic testing confirms the diagnosis in a heterozygous female.

MANAGEMENT:

Treatment of manifestations: Diphenylhydantoin, carbamazepine, or gabapentin to reduce pain (acroparesthesia); ACE inhibitors or angiotensin receptor blockers to reduce proteinuria; chronic hemodialysis and/or renal transplantation for ESRD. Prevention of primary complications: The role of enzyme replacement therapy (ERT) in the long-term prophylaxis of renal, cardiac, and CNS manifestations is unproven; however, experts recommend that ERT be initiated as early as possible in all males with Fabry disease (including children and those with ESRD undergoing dialysis and renal transplantation) and in females with significant disease because all are at high risk for cardiac, cerebrovascular, and renal complications. Prevention of secondary complications: Prophylaxis for renovascular disease, ischemic heart disease, and cerebrovascular disease as for the general population. Surveillance: Annual or more frequent assessment of renal function; annual cardiology and audiology evaluations; biennial brain MRI/MRA. Agents/circumstances to avoid: Smoking. Evaluation of relatives at risk: Early identification of affected relatives by molecular genetic testing if the pathogenic variant in the family is known in order to initiate ERT as early as possible in affected individuals.

GENETIC COUNSELING:

Fabry disease is inherited in an X-linked manner. In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). If only one male in a family is affected, his mother is likely heterozygous; rarely, a single affected male in a family may have a de novo pathogenic variant. A heterozygous female has a 50% chance of transmitting the GLA pathogenic variant in each pregnancy. An affected male transmits his pathogenic variant to all of his daughters. Heterozygote (carrier) testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in a family is known.

Copyright © 1993-2017, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

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