Spada Marco, Pagliardini Severo, Yasuda Makiko, Tukel Turgut, Thiagarajan Geetha, Sakuraba Hitoshi, Ponzone Alberto, Desnick Robert J
Department of Pediatrics, University of Torino, Italy.
Am J Hum Genet. 2006 Jul;79(1):31-40. doi: 10.1086/504601. Epub 2006 Apr 28.
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.
法布里病的经典表型为X连锁α-半乳糖苷酶A（α-Gal A）缺乏症，据估计在男性中的发病率约为五万分之一。近期对迟发型变异型的认识表明，这种可治疗的溶酶体疾病更为常见。为确定该病的发病率，我们对37104名连续的意大利男婴血斑中的α-Gal A活性进行检测，从而开展新生儿筛查。对酶缺乏的婴儿进行了复测，并通过酶和突变分析对“双重筛查呈阳性”的婴儿及其亲属进行了诊断确认。12名（0.03%）新生儿α-Gal A活性缺乏且存在特定突变，包括4种新的错义突变（M51I、E66G、A73V和R118C）、3种先前在迟发型患者中发现的错义突变（F113L、A143T和N215S），以及1种在一名具有经典表型的患者中报道的剪接缺陷（IVS5(+1G→T)）。错义突变的分子建模和体外过表达显示了其结构和残余活性，这些可被一种α-Gal A特异性药理伴侣挽救/增强，这与导致迟发型表型的突变一致。家族研究揭示了受影响个体中未被诊断出的法布里病。在该人群中，α-Gal A缺乏症的发病率约为三千一百分之一，迟发型与经典表型患者的比例为11:1。如果仅纳入已知的致病突变，发病率约为四千六百分之一，迟发型与经典表型患者的比例为7:1。这些结果表明，法布里病的迟发型表型在患有心脏、脑血管和/或肾脏疾病的男性中未得到充分诊断。识别这些患者将有助于进行家族筛查和更早的治疗干预。然而，患者中迟发型表型的较高发病率引发了与何时进行筛查相关的伦理问题——是在新生儿期还是在成年早期，或许与其他可治疗的成人发病疾病筛查同时进行。
