Genetics and Inheritance of Fabry Disease

While the disease is rare (estimated prevalence of 1 in 40,000 males) Fabry disease is found among all ethnicities.1 As an X-linked disease, the genetic defect that causes Fabry disease can be transmitted by both males and females.

Fabry disease inheritance

Fabry disease is an X-linked disease; heterozygous mothers who, with each conception, have a 50% chance of passing the defective gene on to all offspring. Sons who inherit the gene will have Fabry disease. Daughters, once thought to be asymptomatic carriers, may in fact develop disease manifestations from mild to severe, because of X-inactivation.

Segregation of X-Linked Trait (Hemizygous Father)

Males with the defective gene transmit it to all of their daughters and none of their sons.

Segregation of X-Linked Trait (Heterozygous Mother)

Females with the defective gene have a 50% chance of passing it during each pregnancy.

Although a positive family history is a strong indicator for Fabry disease, de novo or spontaneous mutations have been documented.2, 3 Thus, absence of a family history does not rule out a diagnosis of Fabry disease.

The α-GAL gene

The α-galactosidase A (α-GAL) gene is localized to the long arm of the X chromosome (locus Xq22.1).1 The gene, which encodes a 429 amino acid polypeptide; including a 31 amino acid signal peptide, is 12 kilobases long and contains 7 exons.4 The defect that causes Fabry disease is heterogeneous: to date, more than 400 mutations of the α-GAL gene have been recorded in the Human Mutation Database.5 Moreover, most families have “private” mutations (found only in that family) 6, which may explain the variations in the clinical presentation of Fabry disease.

Family screening

Patients who have been diagnosed with Fabry disease should be encouraged to seek genetic counseling, as well as screening for family members who may also carry the genetic defect that causes Fabry disease.

Video clips

View clips from “Perspectives on genetic counseling and family testing in Fabry disease patient care” with Catherine Bove, RN, MEd, APNG. As past president of the International Society of Nurses in Genetics (ISONG) and with more than 30 years of experience in caring for patients with genetic disorders, Ms. Bove offers valuable insight into this important aspect of patient care.

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The importance of genetic counseling and family testing

How to construct a family pedigree

The value of a family pedigree

References:

1. Desnick RJ, YA Ioannou, CM Eng. α-galactosidase A deficiency: Fabry disease. In: The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill, 2001: 3733-3774.

2. Redonnet-Vernhet I, JK Ploos van Amstel, RP Jansen, et al. Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the α-galactosidase A gene. J Med Genet. 1996;33:682-688.

3. Hasholt L, SA Sorensen, A Wandall, EB Andersen, P Arlien-Soborg. A Fabry's disease heterozygote with a new mutation: biochemical, ultrastructural, and clinical investigations. J Med Genet. 1990;27:303-306.

4. Bishop DF, R Kornreich, RJ Desnick. Structural organization of the human α-galactosidase A gene: further evidence for the absence of a 3' untranslated region. Proc Natl Acad Sci U S A. 1988;85:3903-3907.

5. The Human Gene Mutation Database. www.hgmd.org. Accessed 4/07.

6. Ashton-Prolla P, GA Ashley, R Giugliani, et al. Fabry disease: comparison of enzymatic, linkage, and mutation analysis for carrier detection in a family with a novel mutation (30delG). Am J Med Genet. 1999;84:420-424.