The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: Data from individual patients and family studies

• Type: Article in International Scientific Journal
• Date: 2015

Authors

Ferreira, S (Author) FMUP; Ortiz, A (Author) Other; Germain, DP (Author) Other; Viana Baptista, M (Author) Other; Caldeira Gomes, A (Author) Other; Camprecios, M (Author) Other; Fenollar Cortes, M (Author) Other; Gallegos Villalobos, A (Author) Other; Garcia, D (Author) Other; Antonio Garcia Robles, JA (Author) Other; Egido, J (Author) Other; Gutierrez Rivas, E (Author) Other; Antonio Herrero, JA (Author) Other; Mas, S (Author) Other; Oancea, R (Author) Other; Peres, P (Author) Other; Manuel Salazar Martin, LM (Author) Other; Solera Garcia, J (Author) Other; Alves, H (Author) Other; Garman, SC (Author) Other; João Paulo Oliveira (Author) FMUP

Journal

Title: Molecular Genetics and Metabolism

Vol. 114

Pages: 248-258

ISSN: 1096-7192

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 65 Citations

Scopus - 71 Citations

Other information

Authenticus ID: P-00A-7KT

DOI: 10.1016/j.ymgme.2014.11.004

Abstract (EN): Lysosomal cc-galactosidase A (alpha-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingo-lipidosis caused by pathogenic mutations affecting the GLA gene. The early-onset, multi-systemic FD classical phenotype is associated with absent or severe enzyme deficiency, as measured by in vitro assays, but patients with higher levels of residual alpha-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type alpha-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GM p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual alpha-Gal activity in vitro, it has been classified as a pathogenic mutation, mainly on the basis of theoretical arguments about the chemistry of the cysteine residue. However its pathogenicity has never been convincingly demonstrated by pathology criteria. We reviewed the clinical, biochemical and histopathology data obtained from 22 individuals of Portuguese and Spanish ancestry carrying the Cys118 allele, including 3 homozygous females. Cases were identified either on the differential diagnosis of possible FD manifestations and on case-finding studies (n = 11; 4 males), or on unbiased cascade screening of probands' close relatives (n = 11; 3 males). Overall, those data strongly suggest that the GLA p.(Arg118Cys) variant does not segregate with FD clinical phenotypes in a Mendelian fashion, but might be a modulator of the multifactorial risk of cerebrovascular disease. The Cys118 allelic frequency in healthy Portuguese adults (n = 696) has been estimated as 0.001, therefore not qualifying for "rare" condition.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 11