通过在中国浙江省的大规模新生儿筛查鉴定出的 1 型戊二酸血症患者的生化、分子和临床特征。
Biochemical, molecular, and clinical features of patients with glutaric acidemia type 1 identified through large-scale newborn screening in Zhejiang Province, China.
机构信息
Department of Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China; Center of Neonatal Disease Screening, Quanzhou Maternity and Children's Hospital, Quanzhou, China.
Department of Genetics and Metabolism, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China; Department of Pediatrics, Yiwu Maternity and Children's Hospital, Yiwu Branch of Children's Hospital Zhejiang University School of Medicine, Yiwu, China.
出版信息
Clin Chim Acta. 2022 May 1;530:113-118. doi: 10.1016/j.cca.2022.03.026. Epub 2022 Apr 1.
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.
背景
1 型戊二酸血症（GA1）是一种可治疗的神经代谢疾病，由谷氨酸酰辅酶 A 脱氢酶（GCDH）基因的双等位基因突变引起。中国鲜有大规模报道描述 GA1 的新生儿筛查（NBS）。我们报告了通过 NBS 诊断的患者的 NBS 结果、基因型和临床特征。
方法
从 2009 年 1 月至 2021 年 8 月，对 4202587 名新生儿进行串联质谱法筛查。对谷氨酸酰肉碱（C5DC）浓度升高的新生儿进行召回进行重复检测，如果第二次检测仍为阳性，则进行确认检查。使用计算程序预测新变异的致病性。
结果
共有 693 例 C5DC 浓度升高，19 例患儿被诊断为 GA1。因此，浙江省 GA1 的估计发病率为每 221053 名新生儿中有 1 例。所有 19 例患儿的 C5DC 浓度和 C5DC/辛酰肉碱（C8）比值均明显升高；1 例患儿游离肉碱浓度略低。17 例（17/18，94.4%）患儿 GA 浓度升高，15 例为高排泄表型，3 例为低排泄表型。共检测到 23 种不同的 GCDH 变异，其中 2 种为新变异。计算程序预测新变异可能具有致病性。c.1244-2A>G 是最常见的变异，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，其次是癫痫、大头畸形和生长不良。大脑外侧裂增宽是最常见的 MRI 发现。
结论
在浙江省进行的大规模 NBS 诊断出 19 例 GA1 患儿，估计发病率为每 221053 名新生儿中有 1 例。GCDH 突变谱具有异质性，c.1244-2A>G 变异是该人群中最常见的变异。应推广 GA1 的 NBS，以实现及时诊断和治疗。
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