title: Recurrence of Fabry disease as a result of paternal germline mosaicism for alpha-galactosidase a gene mutation.
abstract: We present two sisters with a severe form of Fabry disease, who both carry the same mutation in the alpha-galactosidase A (alpha-gal A) gene (Q330X). Each of the sisters developed renal failure in the third decade of life; the older sibling underwent renal transplantation at 40 years of age. The severe phenotype of the siblings correlates with results of the X-inactivation study: examination of methylation status in human androgene receptor (HUMARA) gene suggests preferential inactivation of the wild-type allele in both patients. Patients' parents had no symptoms of Fabry disease and were tested negative for the mutation Q330X in DNA isolated from peripheral leukocytes, mouth wash cells, and urinary sediment cells. Genotype analysis using DXS7424 marker showed paternal origin of the mutation. The father's sperm was then tested for presence of the mutation to examine the possibility of the germline mosaicism. Both mutant and wild-type alleles were found in DNA isolated from father's sperm. The apparent explanation of these findings is germline mosaicism due to mutation event during the embryonic development of sperm producing cells (spermatogonia). This is the first case of germline mosaicism in Fabry disease reported in the literature.
authors.affiliation: Institute of Inherited Metabolic Disorders, 1st Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Robert
authors.initials: R
authors.lastname: Dobrovolný
authors.forename: Lenka
authors.initials: L
authors.lastname: Dvoráková
authors.forename: Jana
authors.initials: J
authors.lastname: Ledvinová
authors.forename: Sudheera
authors.initials: S
authors.lastname: Magage
authors.forename: Jan
authors.initials: J
authors.lastname: Bultas
authors.forename: Jean C
authors.initials: JC
authors.lastname: Lubanda
authors.forename: Helena
authors.initials: H
authors.lastname: Poupetová
authors.forename: Milan
authors.initials: M
authors.lastname: Elleder
authors.forename: Debora
authors.initials: D
authors.lastname: Karetová
authors.forename: Martin
authors.initials: M
authors.lastname: Hrebícek
mesh_terms: D000328:Adult; D004303:Dosage Compensation, Genetic; D000795:Fabry Disease / Q000201:enzymology / Q000235:genetics*; D005192:Family Health; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D009030:Mosaicism; D010375:Pedigree; D011944:Receptors, Androgen / Q000235:genetics; D000519:alpha-Galactosidase / Q000235:genetics* / Q000378:metabolism
chemical_list: D011944:Receptors, Androgen; D000519:alpha-Galactosidase