High Incidence of Later-Onset Fabry Disease Revealed by Newborn Screening*

Abstract

The classic phenotype of Fabry disease, X-linked alpha -galactosidase A (alpha -Gal A) deficiency, has an estimated incidence of approximately 1 in 50,000 males. The recent recognition of later-onset variants suggested that this treatable lysosomal disease is more frequent. To determine the disease incidence, we undertook newborn screening by assaying the alpha-Gal A activity in blood spots from 37,104 consecutive Italian male neonates. Enzyme-deficient infants were retested, and "doubly screened-positive" infants and their relatives were diagnostically confirmed by enzyme and mutation analyses. Twelve (0.03%) neonates had deficient alpha-Gal A activities and specific mutations, including four novel missense mutations (M51I, E66G, A73V, and R118C), three missense mutations (F113L, A143T, and N215S) identified previously in later-onset patients, and one splicing defect (IVS5(+1G-->T)) reported in a patient with the classic phenotype. Molecular modeling and in vitro overexpression of the missense mutations demonstrated structures and residual activities, which were rescued/enhanced by an alpha-Gal A-specific pharmacologic chaperone, consistent with mutations that cause the later-onset phenotype. Family studies revealed undiagnosed Fabry disease in affected individuals. In this population, the incidence of alpha-Gal A deficiency was 1 in approximately 3,100, with an 11 : 1 ratio of patients with the later-onset : classic phenotypes. If only known disease-causing mutations were included, the incidence would be 1 in approximately 4,600, with a 7 : 1 ratio of patients with the later-onset : classic phenotypes. These results suggest that the later-onset phenotype of Fabry disease is underdiagnosed among males with cardiac, cerebrovascular, and/or renal disease. Recognition of these patients would permit family screening and earlier therapeutic intervention. However, the higher incidence of the later-onset phenotype in patients raises ethical issues related to when screening should be performed--in the neonatal period or at early maturity, perhaps in conjunction with screening for other treatable adult-onset disorders.

Fabry Disease: Treatment and diagnosis

“…A recent report on a screening test for newborns in Italy has found an incidence of a-Gal A deficiency of 1/3,100 newborn males (8). However, all but one of the newborns identified in this study had mutations predicting the later-onset phenotype.…”

Newborn screening for Krabbe disease in New York State: the first eight years’ experience

“…Fabry disease incidence in cases identified by NBS has also been reported to be elevated compared with diagnosis in symptomatic individuals. 34 The incidence of later-onset cases may be higher than reported, as suggested by the number of two-variant/mutation infants identified by NBS, and may be higher than reported in at least one other population. 35 After 8 years of NBS in a state with an annual birth rate of approximately 250,000 per year, an average of 44 infants per year screened positive for KD and were referred for follow-up, corresponding to 18 per 100,000 births.…”

Genetics of stroke

“…Fabry disease is an X-linked lysosomal storage disorder caused by deficiency of a-galactosidase A (GLA), which results in the storage of globotriaosylceramide (Gb3) in various organs, particularly in the myocardium, renal epithelium, skin, eye, and vasculature [16] . Fabry's disease is surprisingly common in young stroke patients [16] .…”

“…Fabry's disease is surprisingly common in young stroke patients [16] . Most patients carry missense or nonsense mutations in the coding region of GLA.…”