背景:戊二酸血症1型(GA1)是由戊二酰基辅酶A脱氢酶(GCDH)基因的双等位基因变体引起的可治疗的神经代谢紊乱。在中国,很少有描述GA1新生儿筛查(NBS)的大规模报道。我们报告国家统计局的结果,基因型,和通过NBS诊断的患者的临床特征。
方法:从2009年1月至2021年8月,通过串联质谱法筛选了4,202,587名新生儿。召回具有增加的戊二酰肉碱(C5DC)浓度的新生儿进行重复测试,如果第二次检查仍呈阳性,则进行验证性检查。使用计算程序预测新变体的致病性。
结果:总共693个C5DC浓度增加,19例患者诊断为GA1。因此,浙江省GA1的估计发病率为221,053例新生儿中的1例。所有19例患者的C5DC浓度和C5DC/辛酰基肉碱(C8)比率均显着增加;一个人的游离肉碱浓度略低。17例(17/18,94.4%)患者的GA浓度增加,高排泄表型15例,低排泄表型3例。检测到23种不同的GCDH变体,其中2是小说。通过计算程序预测新的变体具有潜在的致病性。c.1244-2A>C是最常见的变体,等位基因频率为14.7%,其次是c.914C>T(p。S305L)(8.8%)。最常见的临床症状是运动障碍,接着是癫痫发作,大头畸形,未能茁壮成长。西尔维安裂隙扩大是最常见的MRI发现。
结论:浙江省通过大规模NBS确诊了19例GA1患者,估计发病率为221,053名新生儿中的1名。GCDH突变谱是异质的,c.1244-2A>C变体是该人群中最常见的变体。应推广GA1的NBS,以实现及时诊断和治疗。
BACKGROUND: Glutaric acidemia type 1 (GA1) is a treatable neurometabolic disorder caused by biallelic variants in the glutaryl-CoA dehydrogenase (GCDH) gene. There are few large-scale reports describing newborn screening (NBS) for GA1 in
China. We report the NBS results, genotypes, and clinical features of patients diagnosed through NBS.
METHODS: From January 2009 to August 2021, 4,202,587 newborns were screened by tandem mass spectrometry. Newborns with increased glutarylcarnitine (C5DC) concentrations were recalled for repeated test, and confirmatory examinations were performed if the second test was still positive. The pathogenicity of novel variants was predicted using computational programs.
RESULTS: A total of 693 had increased C5DC concentrations, and 19 patients were diagnosed with GA1. Thus, the estimated incidence of GA1 in Zhejiang Province was 1 in 221,053 newborns. All the 19 patients had markedly increased C5DC concentrations and C5DC/octanoylcarnitine (C8) ratios; one had a slightly low free carnitine concentration. Seventeen (17/18, 94.4%) patients had increased GA concentrations, 15 were of high excretor phenotype and 3 were of low excretor phenotype. Twenty-three distinct GCDH variants were detected, of which 2were novel. Novel variants were predicted to be potentially pathogenic by computational programs. c.1244-2A > C was the most common variant, with an allelic frequency of 14.7%, followed by c.914C > T (p.S305L) (8.8%). The most common clinical symptom was movement disorder, followed by seizure, macrocephaly, and failure to thrive. Sylvian fissures widening was the most common MRI finding.
CONCLUSIONS: Nineteen GA1 patients were diagnosed through the large-scale NBS in Zhejiang Province, with an estimated incidence of 1 in 221,053 newborns. The GCDH mutational spectrum is heterogenous, with the c.1244-2A > C variant being the most frequent variant in this population. NBS for GA1 should be promoted to achieve timely diagnosis and treatment.