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.

Figures

Figure 1

Scheme used to identify and confirm α-Gal A deficiency in newborns. Note cut-offs for male (M) and female (F) newborns differ. The number and percentage of newborns detected under each category are indicated.

Figure 2

Distribution of α-Gal A activity in 606 normal newborns. The X- and Y-axes indicate the percent (%) of normal mean and the percent (%) of the distribution for each activity percentage, respectively.

Figure 3

Phylogenetic conservation of wild-type human α-Gal A amino acid residues, highlighting the amino acids substituted in mutant enzymes p.C12_L14del, p.H46P, p.L120V, p.I219T, p.R356Q, and p.G360C due to the novel missense mutations identified in the newborns.

Figure 4

Pedigrees of two Fabry families detected by newborn screening: a) Proband 1, affected males and obligate female heterozygotes are indicated, and b) Proband 11, note that the maternal grandmother had end stage renal disease (ESRD).