Fabry Disease: Molecular Diagnosis of Hemizygotes and Heterozygotes

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Abstract
Fabry disease, an X-linked inborn error of glycosphingolipid catabolism, results from the deficient activity of the lysosomal hydrolase, a-galactosidase A. Previously, the diagnosis of affected hemizygous males and heterozygous females was based on clinical findings and the levels of a-galactosidase A activity in easily obtained sources such as plasma and isolated lymphocytes or granulocytes. Since the gene encoding a-galactosidase A undergoes random X-inactivation, the expressed level of enzymatic activity in females heterozygous for the disease gene may vary significantly, thereby making accurate carrier detection difficult. The recent cloning and characterization of the full-length cDNA encoding human a-galactosidase A now permits the accurate diagnosis of affected hemizygotes and heterozygous females. In families with gene rearrangements or an altered restriction endonuclease cleavage site, precise diagnosis can be accomplished by Southern hybridization analysis using the a-galactosidase A cDNA as probe. In families with normal restriction patterns, two restriction fragment length polymorphisms have been identified in and adjacent to the agalactosidase A gene which also allow precise hemizygote and heterozygote diagnosis. In addition, the recent identification of polymorphic, random DNA sequences (DXS17 and DXS87) located near the a-galactosidase A locus permits molecular diagnosis in informative families. Further evaluation of DXS17, DXS87 and other closely linked random DNA probes is required in order to determine their informativeness, proximity to the a-galactosidase A locus and, hence, accuracy for molecular diagnosis.

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