title: Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A).
abstract: Fabry disease (alpha-galactosidase A (alpha-Gal A, GLA) deficiency) is a panethnic inborn error of glycosphingolipid metabolism. Because optimal therapeutic outcomes depend on early intervention, a pilot program was designed to assess newborn screening for this disease in 171,977 consecutive Taiwanese newborns by measuring their dry blood spot (DBS) alpha-Gal A activities and beta-galactosidase/alpha-Gal A ratios. Of the 90,288 male screenees, 638 (0.7%) had DBS alpha-Gal A activity <30% of normal mean and/or activity ratios >10. A second DBS assay reduced these to 91 (0.1%). Of these, 11 (including twins) had <5% (Group-A), 64 had 5-30% (Group-B), and 11 had >30% (Group-C) of mean normal leukocyte alpha-Gal A activity. All 11 Group-A, 61 Group-B, and 1 Group-C males had GLA gene mutations. Surprisingly, 86% had the later-onset cryptic splice mutation c.936+919G>A (also called IVS4+919G>A). In contrast, screening 81,689 females detected two heterozygotes. The novel mutations were expressed in vitro, predicting their classical or later-onset phenotypes. Newborn screening identified a surprisingly high frequency of Taiwanese males with Fabry disease (approximately 1 in 1,250), 86% having the IVS4+919G>A mutation previously found in later-onset cardiac phenotype patients. Further studies of the IVS4 later-onset phenotype will determine its natural history and optimal timing for therapeutic intervention.
authors.affiliation: Department of Pediatrics, National Taiwan University Hospital and National Taiwan University School of Medicine, Taipei, Taiwan, Republic of China.
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.forename: Ni-Chung
authors.initials: NC
authors.lastname: Lee
authors.forename: Shu-Chuan
authors.initials: SC
authors.lastname: Chiang
authors.forename: Robert
authors.initials: R
authors.lastname: Dobrovolny
authors.forename: Ai-Chu
authors.initials: AC
authors.lastname: Huang
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Yeh
authors.forename: May-Chin
authors.initials: MC
authors.lastname: Chao
authors.forename: Shio-Jean
authors.initials: SJ
authors.lastname: Lin
authors.forename: Teruo
authors.initials: T
authors.lastname: Kitagawa
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Hsu
mesh_terms: D017668:Age of Onset; D000595:Amino Acid Sequence; D000795:Fabry Disease / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics; D005260:Female; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D015997:Neonatal Screening; D010375:Pedigree; D010641:Phenotype; D017386:Sequence Homology, Amino Acid; D013624:Taiwan / Q000453:epidemiology; D000519:alpha-Galactosidase / Q000737:chemistry / Q000235:genetics*
chemical_list: D000519:alpha-Galactosidase