TY - JOUR
T1 - The alpha-galactosidase A p.Arg118Cys variant does not cause a Fabry disease phenotype: Data from individual patients and family studies
AU - Baptista, Miguel José de Carvalho Viana
N1 - PMID: 25468652
WOS:000348973100313
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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. (C) 2014 Elsevier Inc. All rights reserved.}
AB - 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. (C) 2014 Elsevier Inc. All rights reserved.}
KW - GLA gene
KW - 5' UNTRANSLATED REGION
KW - IDENTIFICATION
KW - A GENE
KW - Fabry disease
KW - R118C
KW - CLASSICAL PHENOTYPE
KW - alpha-Galactosidase A
KW - GLA GENE
KW - HYPERTROPHIC CARDIOMYOPATHY
KW - YOUNG-PATIENTS
KW - Variant p.(Arg118Cys)
KW - MUTATIONS
KW - CEREBROVASCULAR-DISEASE
KW - PREVALENCEInformaçoes sobre autores
KW - Endocrinology & Metabolism
KW - Genetics & Heredity
KW - Medicine, Research & Experimental
U2 - 10.1016/j.ymgme.2014.11.004
DO - 10.1016/j.ymgme.2014.11.004
M3 - Article
C2 - 25468652
VL - 114
SP - 248
EP - 258
JO - Molecular Genetics And Metabolism
JF - Molecular Genetics And Metabolism
SN - 1096-7192
IS - 2
ER -