title: Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a "sequencing cryptic" α-galactosidase a large deletion.
abstract: Fabry disease, an X-linked lysosomal storage disorder, results from the deficient activity of α-galactosidase A (α-Gal A). In affected males, the clinical diagnosis is confirmed by the markedly decreased α-Gal A activity. However, in female heterozygotes, the α-Gal A activity can range from low to normal due to random X-chromosomal inactivation, and diagnostic confirmation requires identification of the family's α-Gal A gene mutation. In a young female who had occasional acroparesthesias, corneal opacities, and 15 to 50% of the lower limit of normal leukocyte α-Gal A activity, α-Gal A sequencing in two expert laboratories did not identify a confirmatory mutation, presenting a diagnostic dilemma. A renal biopsy proved diagnostic and renewed efforts to detect an α-Gal A mutation. Subsequent gene dosage analyses identified a large α-Gal A deletion confirming her heterozygosity, and she was started on enzyme replacement therapy. Thus, gene dosage analyses can detect large deletions (>50bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are "sequencing cryptic," resolving molecular diagnostic dilemmas.
authors.affiliation: Department of Medical Endocrinology, National University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. ufeldt@rh.dk
authors.forename: Ulla
authors.initials: U
authors.lastname: Feldt-Rasmussen
authors.forename: Robert
authors.initials: R
authors.lastname: Dobrovolny
authors.forename: Irina
authors.initials: I
authors.lastname: Nazarenko
authors.forename: Martin
authors.initials: M
authors.lastname: Ballegaard
authors.forename: Lis
authors.initials: L
authors.lastname: Hasholt
authors.forename: Ase K
authors.initials: AK
authors.lastname: Rasmussen
authors.forename: Erik I
authors.initials: EI
authors.lastname: Christensen
authors.forename: Soren S
authors.initials: SS
authors.lastname: Sorensen
authors.forename: Flemming
authors.initials: F
authors.lastname: Wibrand
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000293:Adolescent; D001706:Biopsy; D056947:Enzyme Replacement Therapy; D000795:Fabry Disease / Q000175:diagnosis* / Q000188:drug therapy / Q000473:pathology; D005260:Female; D040461:Gene Components; D018628:Gene Dosage / Q000235:genetics*; D006580:Genetic Carrier Screening / Q000379:methods*; D006801:Humans; D007668:Kidney / Q000473:pathology; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion / Q000235:genetics*; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D000519:alpha-Galactosidase