Fabry disease: Comparison of enzymatic, linkage, and mutation analysis for carrier detection in a family with a novel mutation (30delG)

Fabry disease (FD) is an X-linked recessive disorder caused by the deficient activity of the lysosomal enzyme α-galactosidase A (α-Gal A). Affected males are reliably diagnosed by demonstration of deficient α-Gal A activity in plasma or leukocytes. However, identification of female carriers is problematic due to Lyonization, requiring mutation identification and/or linkage studies for accurate carrier detection. Here, we describe a large Brazilian kindred with Fabry disease that permitted comparison of biochemical and molecular diagnostic techniques. Initially, the plasma α-Gal A activities were determined in at-risk affected males and potential female carriers; affected males were readily diagnosed, while the females had variable results. To detect carrier females, haplotype analysis using 10 polymorphic markers adjacent to the gene was performed. Subsequently, solid- phase direct sequencing of the α-Gal A gene demonstrated a novel single base deletion in exon 1 (30delG). Discrepancies were observed between the enzymatic and molecular diagnoses in two at-risk females. These findings emphasize the need for precise heterozygote diagnosis by mutation and/or haplotype analyses in all families with Fabry disease.