title: Fabry disease: comparison of enzymatic, linkage, and mutation analysis for carrier detection in a family with a novel mutation (30delG).
abstract: Fabry disease (FD) is an X-linked recessive disorder caused by the deficient activity of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A). Affected males are reliably diagnosed by demonstration of deficient alpha-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 alpha-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 alpha-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.
authors.affiliation: Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ashton-Prolla
authors.forename: G A
authors.initials: GA
authors.lastname: Ashley
authors.forename: R
authors.initials: R
authors.lastname: Giugliani
authors.forename: R F
authors.initials: RF
authors.lastname: Pires
authors.forename: R J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: C M
authors.initials: CM
authors.lastname: Eng
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D000795:Fabry Disease / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening / Q000379:methods*; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008297:Male; D010375:Pedigree; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D020080:Tandem Repeat Sequences / Q000235:genetics; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D000519:alpha-Galactosidase