Genetics and inheritance of Fabry disease

The alpha-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. ^[2] The defect that causes Fabry disease is heterogeneous - to date, over 200 mutations of the alpha-GAL gene have been recorded in the Human Mutation Database. Moreover, most families have “private” mutations (found only in that family) ^[3] that may explain variations in the clinical presentation of Fabry disease.

Fabry is an X-linked recessive disease. It is inherited through the mother who, with each conception, has a 50% chance of passing the defective gene on to all offspring. Her sons who inherit the gene will have Fabry disease. Daughters who inherit the gene will be carriers. Because of X-chromosomal inactivation, some female carriers develop symptoms of mild, moderate, or classical Fabry disease. ^[1]

Males with Fabry disease pass on the defective gene to none of their sons and all of their daughters.

Although a positive family history is a strong indicator for Fabry disease, de novo or spontaneous mutations have been documented. ^{[4, 5]} Thus, absence of a family history does not rule out a diagnosis of Fabry disease.

^References

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

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

3. Ashton-Prolla P, Ashley GA, Giugliani R, Pires RF, Desnick RJ, Eng CM. 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.

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

5. Redonnet-Vernhet I, Ploos van Amstel JK, Jansen RP, Wevers RA, Salvayre R, Levade T. Uneven X inactivation in a female monozygotic twin pair with Fabry disease and discordant expression of a novel mutation in the alpha-galactosidase A gene. J Med Genet. 1996;33:682-688.