TY - JOUR
T1 - High incidence of later-onset Fabry disease revealed by newborn screening
AU - Spada, Marco
AU - Pagliardini, Severo
AU - Yasuda, Makiko
AU - Tukel, Turgut
AU - Thiagarajan, Geetha
AU - Sakuraba, Hitoshi
AU - Ponzone, Alberto
AU - Desnick, Robert J.
PY - 2006/7
Y1 - 2006/7
N2 - The classic phenotype of Fabry disease, X-linked α-galactosidase A (α-Gal A) deficiency, has an estimated incidence of ∼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 α-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 α-Gal A activities and specific mutations, including four novel missense mutations (M511, E66G, A73V, and R118C), three missense mutations (F113L, A143T, and N215S) identified previously in later-onset patients, and one splicing defect (1VS5+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 α-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 α-Gal A deficiency was 1 in ∼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 ∼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.
AB - The classic phenotype of Fabry disease, X-linked α-galactosidase A (α-Gal A) deficiency, has an estimated incidence of ∼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 α-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 α-Gal A activities and specific mutations, including four novel missense mutations (M511, E66G, A73V, and R118C), three missense mutations (F113L, A143T, and N215S) identified previously in later-onset patients, and one splicing defect (1VS5+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 α-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 α-Gal A deficiency was 1 in ∼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 ∼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.
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U2 - 10.1086/504601
DO - 10.1086/504601
M3 - Article
C2 - 16773563
AN - SCOPUS:33745280137
VL - 79
SP - 31
EP - 40
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -