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

Ulla Feldt-Rasmussen; Robert Dobrovolny; Irina Nazarenko; Martin Ballegaard; Lis Hasholt; Ase K Rasmussen; Erik Ilsø Christensen; Soren S Sorensen; Flemming Wibrand; Robert J Desnick

doi:10.1016/j.ymgme.2011.05.008

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

Ulla Feldt-Rasmussen, Robert Dobrovolny, Irina Nazarenko, Martin Ballegaard, Lis Hasholt, Ase K Rasmussen, Erik Ilsø Christensen, Soren S Sorensen, Flemming Wibrand, Robert J Desnick

8 Citationer (Scopus)

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

Originalsprog	Engelsk
Tidsskrift	Molecular Genetics and Metabolism
Vol/bind	104
Udgave nummer	3
Sider (fra-til)	314-8
Antal sider	5
ISSN	1096-7192
DOI	https://doi.org/10.1016/j.ymgme.2011.05.008
Status	Udgivet - nov. 2011

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10.1016/j.ymgme.2011.05.008

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Feldt-Rasmussen, U., Dobrovolny, R., Nazarenko, I., Ballegaard, M., Hasholt, L., Rasmussen, A. K., Christensen, E. I., Sorensen, S. S., Wibrand, F., & Desnick, R. J. (2011). Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a "sequencing cryptic" a-galactosidase a large deletion. Molecular Genetics and Metabolism, 104(3), 314-8. https://doi.org/10.1016/j.ymgme.2011.05.008

Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a "sequencing cryptic" a-galactosidase a large deletion. / Feldt-Rasmussen, Ulla; Dobrovolny, Robert; Nazarenko, Irina et al.
I: Molecular Genetics and Metabolism, Bind 104, Nr. 3, 11.2011, s. 314-8.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Feldt-Rasmussen, U, Dobrovolny, R, Nazarenko, I, Ballegaard, M , Hasholt, L, Rasmussen, AK, Christensen, EI, Sorensen, SS, Wibrand, F & Desnick, RJ 2011, 'Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a "sequencing cryptic" a-galactosidase a large deletion', Molecular Genetics and Metabolism, bind 104, nr. 3, s. 314-8. https://doi.org/10.1016/j.ymgme.2011.05.008

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title = "Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a {"}sequencing cryptic{"} a-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 (> 50. bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are {"}sequencing cryptic,{"} resolving molecular diagnostic dilemmas.",

keywords = "Adolescent, Biopsy, Enzyme Replacement Therapy, Fabry Disease, Female, Gene Components, Gene Dosage, Heterozygote Detection, Humans, Kidney, Polymerase Chain Reaction, Sequence Analysis, DNA, Sequence Deletion, alpha-Galactosidase",

author = "Ulla Feldt-Rasmussen and Robert Dobrovolny and Irina Nazarenko and Martin Ballegaard and Lis Hasholt and Rasmussen, {Ase K} and Christensen, {Erik Ils{\o}} and Sorensen, {Soren S} and Flemming Wibrand and Desnick, {Robert J}",

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doi = "10.1016/j.ymgme.2011.05.008",

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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

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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.

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KW - Heterozygote Detection

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KW - Kidney

KW - Polymerase Chain Reaction

KW - Sequence Analysis, DNA

KW - Sequence Deletion

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ER -

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

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