TY - JOUR
T1 - The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype
T2 - Data from individual patients and family studies
AU - Ferreira, Susana
AU - Ortiz, Alberto
AU - Germain, Dominique P.
AU - Viana-Baptista, Miguel
AU - Caldeira-Gomes, António
AU - Camprecios, Marta
AU - Fenollar-Cortés, Maria
AU - Gallegos-Villalobos, Ángel
AU - Garcia, Diego
AU - García-Robles, José Antonio
AU - Egido, Jesús
AU - Gutiérrez-Rivas, Eduardo
AU - Herrero, José Antonio
AU - Mas, Sebastián
AU - Oancea, Raluca
AU - Péres, Paloma
AU - Salazar-Martín, Luis Manuel
AU - Solera-Garcia, Jesús
AU - Alves, Helena
AU - Garman, Scott C.
AU - Oliveira, João Paulo
N1 - Funding Information:
J. P. Oliveira is a member of the European Advisory Board of the Fabry Registry, a global observational registry of patients with Fabry disease sponsored by Genzyme Corporation. He has received unrestricted research grants and funding for research projects from Genzyme Corporation; consulting honoraria and speaker's fees from Genzyme Corporation; conference registration fees and travel grants from Genzyme Corporation, Shire Human Genetic Therapies and Amicus Therapeutics.
Funding Information:
S. Ferreira has received unrestricted research grants and funding for research projects from Genzyme Corporation; conference registration fees and travel grants from Genzyme Corporation and Shire Human Genetic Therapies.
Funding Information:
M. Viana-Baptista is member of the Global Neurological Fabry Board supported by Genzyme Corporation. He has received consultant honoraria and speaking fees from Genzyme Corporation and Genzyme Portugal. He has received unrestricted research grants and funding for research projects from Genzyme Portugal.
Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2015/2/1
Y1 - 2015/2/1
N2 - Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis 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 α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-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.
AB - Lysosomal α-galactosidase A (α-Gal) is the enzyme deficient in Fabry disease (FD), an X-linked glycosphingolipidosis 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 α-Gal activity may have later-onset, more organ-restricted clinical presentations. A change in the codon 118 of the wild-type α-Gal sequence, replacing basic arginine by a potentially sulfhydryl-binding cysteine residue - GLA p.(Arg118Cys) -, has been recurrently described in large FD screening studies of high-risk patients. Although the Cys118 allele is associated with high residual α-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.
KW - Fabry disease
KW - GLA gene
KW - R118C
KW - Variant p.(Arg118Cys)
KW - α-Galactosidase A
UR - http://www.scopus.com/inward/record.url?scp=84921670805&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2014.11.004
DO - 10.1016/j.ymgme.2014.11.004
M3 - Article
C2 - 25468652
AN - SCOPUS:84921670805
SN - 1096-7192
VL - 114
SP - 248
EP - 258
JO - Molecular Genetics And Metabolism
JF - Molecular Genetics And Metabolism
IS - 2
ER -