Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later-onset GLA mutation c.936+919G>A (IVS4+919G>A).
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.
Hwu
Wuh-Liang
WL
Department of Pediatrics, National Taiwan University Hospital and National Taiwan University School of Medicine, Taipei, Taiwan, Republic of China.
Chien
Yin-Hsiu
YH
Lee
Ni-Chung
NC
Chiang
Shu-Chuan
SC
Dobrovolny
Robert
R
Huang
Ai-Chu
AC
Yeh
Hui-Ying
HY
Chao
May-Chin
MC
Lin
Shio-Jean
SJ
Kitagawa
Teruo
T
Desnick
Robert J
RJ
Hsu
Li-Wen
LW
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*
D000519:alpha-Galactosidase