Fabry disease: incidence of the common later-onset α-galactosidase A IVS4+919G→A mutation in Taiwanese newborns--superiority of DNA-based to enzyme-based newborn screening for common mutations.
Journal
Molecular medicine (Cambridge, Mass.)
Journal Volume
18
Pages
780-784
Date Issued
2012
Author(s)
Abstract
Fabry disease is a panethnic, X-linked, inborn error of glycosphingolipid metabolism resulting from mutations in the α-galactosidase A gene (GLA) that lead to the deficient activity of the lysosomal enzyme, α-galactosidase A (α-Gal A). Affected males with no α-Gal A activity have the early-onset classic phenotype, whereas those with residual activity present with the later-onset subtype. Recently, we reported that newborn enzyme-based screening using dried blood spots (DBS) in Taiwan revealed a high incidence of newborn males who had the GLA c.936+919G→A (IVS4+919G→A) mutation. This lesion causes cryptic splicing, markedly reducing the amount of wild-type GLA mRNA, and has been found in males with the later-onset Fabry phenotype, manifesting as cardiac, renal and/or cerebrovascular disease. To more accurately determine the incidence of the IVS4+919G→A mutation, 20,063 consecutive newborns were screened by a deoxyribonucleic acid (DNA)-based assay. Of the 10,499 males, 12 (1/875) and 24 of the 9,564 females (1/399) had the mutation. On the basis of these frequencies, the previous newborn enzyme-based DBS screening (cutoff: <30% of the normal mean) only identified 67% and 17% of mutation-positive males and females, respectively. The mean DBS α-Gal A activities in the mutation-positive males and females were 23% (1.54 U) and 55% (3.63 U) of normal mean male/female values, respectively. These studies confirm the high incidence of the IVS4+919G→A mutation in the Taiwanese population and indicate that its detectability by enzyme-based DBS screening is unreliable, especially in females. These studies emphasize the superiority of DNA-based newborn screening for common mutations, particularly for X-linked diseases.
SDGs
Other Subjects
alpha galactosidase; article; Asian; Fabry disease; female; genetic screening; genetics; human; incidence; male; mutation; newborn; newborn screening; nucleotide sequence; RNA splicing; Taiwan; alpha-Galactosidase; Asian Continental Ancestry Group; DNA Mutational Analysis; Fabry Disease; Female; Genetic Testing; Humans; Incidence; Infant, Newborn; Male; Mutation; Neonatal Screening; RNA Splicing; Taiwan; MLCS; MLOWN
Type
journal article