High incidence of later-onset Fabry disease revealed by newborn screening
High incidence of later-onset Fabry disease revealed by newborn screening
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DOI：
10.1086/504601
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发表时间：
2006-07-01
影响因子：
9.8
通讯作者：
Desnick, Robert J.
中科院分区：
文献类型：
--
作者：
Spada, Marco;Pagliardini, Severo;Desnick, Robert J.
法布里病的典型表型是x连锁α -半乳糖苷酶A （α -gal A）缺乏症，估计发病率约为5万分之一。最近对晚发性变异的认识表明，这种可治疗的溶酶体疾病更为常见。为了确定疾病的发病率，我们对37104名连续出生的意大利男性新生儿进行了新生儿筛查，检测血液中α - gal A的活性。对酶缺乏的婴儿进行重新检测，并通过酶和突变分析对“双重筛查阳性”婴儿及其亲属进行诊断确认。12例（0.03%）新生儿存在α - gal A活性缺陷和特异性突变，包括4个新的错义突变（M51I、E66G、A73V和R118C）， 3个错义突变（F113L、A143T和N215S），以及1例经典表型患者报告的剪接缺陷（IVS5(+1G -> T)）。分子模型和体外过表达的错义突变显示了结构和残留活性，这些结构和残留活性由α - gal a特异性药理学伴侣拯救/增强，与导致晚发表型的突变一致。家庭研究显示，受影响个体中存在未确诊的法布里病。在这一人群中，α -半乳糖A缺乏症的发生率为1 / 3100，其中发病晚的典型表型患者的比例为11.1。如果只包括已知的致病突变，发病率将是1 / 4600，发病较晚的典型表型患者的比例为7:1。这些结果表明，在患有心、脑血管和/或肾脏疾病的男性中，法布里病的晚发表型未被充分诊断。识别这些患者将允许家庭筛查和早期治疗干预。然而，患者中晚发表型的较高发生率引发了与何时进行筛查相关的伦理问题-在新生儿期或早期成熟，可能与筛查其他可治疗的成人发病疾病相结合。
The classic phenotype of Fabry disease, X-linked alpha-galactosidase A ( alpha-Gal A) deficiency, has an estimated incidence of similar to 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 similar to 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 similar to 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.