Biochemical, molecular, and clinical features of patients with glutaric acidemia type 1 identified through large-scale newborn screening in Zhejiang Province, China

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.