Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a "sequencing cryptic" a-galactosidase a large deletion

TY - JOUR

T1 - Diagnostic dilemma

T2 - a young woman with Fabry disease symptoms, no family history, and a "sequencing cryptic" a-galactosidase a large deletion

AU - Feldt-Rasmussen, Ulla

AU - Dobrovolny, Robert

AU - Nazarenko, Irina

AU - Ballegaard, Martin

AU - Hasholt, Lis

AU - Rasmussen, Ase K

AU - Christensen, Erik Ilsø

AU - Sorensen, Soren S

AU - Wibrand, Flemming

AU - Desnick, Robert J

N1 - Copyright © 2011 Elsevier Inc. All rights reserved.

PY - 2011/11

Y1 - 2011/11

N2 - 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 (> 50. bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are "sequencing cryptic," resolving molecular diagnostic dilemmas.

AB - 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 (> 50. bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are "sequencing cryptic," resolving molecular diagnostic dilemmas.

KW - Adolescent

KW - Biopsy

KW - Enzyme Replacement Therapy

KW - Fabry Disease

KW - Female

KW - Gene Components

KW - Gene Dosage

KW - Heterozygote Detection

KW - Humans

KW - Kidney

KW - Polymerase Chain Reaction

KW - Sequence Analysis, DNA

KW - Sequence Deletion

KW - alpha-Galactosidase

U2 - 10.1016/j.ymgme.2011.05.008

DO - 10.1016/j.ymgme.2011.05.008

M3 - Journal article

C2 - 21641253

SN - 1096-7192

VL - 104

SP - 314

EP - 318

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

IS - 3

ER -