Abstract
Isobutyryl-CoA dehydrogenase deficiency (IBDHD, MIM: #611283) is a rare autosomal recessive hereditary disease, which is caused by genetic mutations of acyl-CoA dehydrogenase (ACAD) 8 and associated with valine catabolism. Here, tandem mass spectrometry (MS/MS) was applied to screen 302,993 neonates for inherited metabolic diseases (IMD) in Ningbo of China from 2017 to 2020. The results suggest that 198 newborns (0.7‰) were initially screened positive for IBDHD with C4-Carnitine, and 27 cases (0.1‰) were re-screened positive. Genetic diagnosis was performed on 21 of the 27 cases. Seven compound heterozygous variations, three biallelic variations, and one heterozygous variation of ACAD8 were found with a pathogenicity rate of 33.3% (7/21). In addition, seven biallelic variations, one heterozygous variation of acyl-CoA dehydrogenase short chain (ACADS), and one biallelic variation of acyl-CoA dehydrogenase short/branched chain (ACADSB) was detected. Further research showed that ACAD8 mutations of 11 IBDHD cases distributed in six different exons with total 14 mutation sites. Five of which were known suspected pathogenic sites (c.286G > A, c.553C > T, c.1000C > T, c.409G > A, c.500del) and six were novel mutation sites: c.911A > T, c.904C > T, c.826G > A, c.995T > C, c.1166G > A, c.1165C > T. This finding enriched the mutation spectrum of ACAD8 in IBDHD.
Highlights
IBD is a mitochondrial enzyme that catalyzes the conversion from isobutyryl-CoA to methacryloyl-CoA in valine catabolism (Roe et al, 1998a; Battaile et al, 2004; Lin et al, 2018)
Through NBS program and DNA analysis, we demonstrated the pathogenicity of ACAD8 gene mutations and identified seven novel possible pathogenic sites
Ten cases of biallelic variations and one case of single heterozygous mutation were detected of ACAD8 gene encoding IBD, and seven cases of biallelic variations and one heterozygous mutation of acyl-CoA dehydrogenase short chain (ACADS) encoding short-chain acyl-CoA dehydrogenase, one case of biallelic variations of acyl-CoA dehydrogenase short/branched chain (ACADSB) gene encoding 2-methylbutyryl-CoA dehydrogenase were detected
Summary
IBD (isobutyryl-CoA dehydrogenase) is a mitochondrial enzyme that catalyzes the conversion from isobutyryl-CoA to methacryloyl-CoA in valine catabolism (Roe et al, 1998a; Battaile et al, 2004; Lin et al, 2018). The ACAD8 gene is composed of 11 exons, encoding 415 amino acids, consisting of the NH2 terminal a-helix domain, the inner b-chain domain and the C-terminal a-helix domain Most of the published ACAD8 gene variants occur in exons 4 and 9 (Lin et al, 2018). Homozygous or compound heterozygous mutations in the ACAD8 gene often cause IBDD, which is a rare autosomal recessive genetic metabolic disease. Since it was first reported in 1998 (Roe et al, 1998b), the prevalence and clinical significance of the disease have remained unclear, and the natural course of the disease is still unclear, and most patients are asymptomatic
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