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

Ulla Feldt-Rasmussen; Robert Dobrovolny; Irina Nazarenko; Martin Ballegaard; Lis Frydenreich Hasholt; Ase K Rasmussen; Erik I 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" α-galactosidase a large deletion

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

8 Citations (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.

Original language	English
Journal	Molecular Genetics and Metabolism
Volume	104
Issue number	3
Pages (from-to)	314-8
Number of pages	5
ISSN	1096-7192
DOIs	https://doi.org/10.1016/j.ymgme.2011.05.008
Publication status	Published - Nov 2011

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Feldt-Rasmussen, U., Dobrovolny, R., Nazarenko, I., Ballegaard, M., Hasholt, L. F., 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" α-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" α-galactosidase a large deletion. / Feldt-Rasmussen, Ulla; Dobrovolny, Robert; Nazarenko, Irina et al.

In: Molecular Genetics and Metabolism, Vol. 104, No. 3, 11.2011, p. 314-8.

Research output: Contribution to journal › Journal article › Research › peer-review

Feldt-Rasmussen, U, Dobrovolny, R, Nazarenko, I, Ballegaard, M, Hasholt, LF, 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" α-galactosidase a large deletion', Molecular Genetics and Metabolism, vol. 104, no. 3, pp. 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{"} 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 (> 50. bp) in suspect heterozygotes for X-linked and autosomal dominant diseases that are {"}sequencing cryptic,{"} resolving molecular diagnostic dilemmas.",

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

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T1 - Diagnostic dilemma: a young woman with Fabry disease symptoms, no family history, and a "sequencing cryptic" α-galactosidase a large deletion

AU - Feldt-Rasmussen, Ulla

AU - Dobrovolny, Robert

AU - Nazarenko, Irina

AU - Ballegaard, Martin

AU - Hasholt, Lis Frydenreich

AU - Rasmussen, Ase K

AU - Christensen, Erik I

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.

U2 - 10.1016/j.ymgme.2011.05.008

DO - 10.1016/j.ymgme.2011.05.008

M3 - Journal article

SN - 1096-7192

VL - 104

SP - 314

EP - 318

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

IS - 3

ER -

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

Abstract

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