Clinical, biochemical and genetic analysis of Chinese patients with isobutyryl-CoA dehydrogenase deficiency

Isobutyryl-CoA dehydrogenase deficiency (IBDHD) is a rare autosomal recessive metabolic disorder related to valine catabolism and results from variants in ACAD8. Here, we present the clinical, biochemical, and genotypes of seven patients with IBDHD in China for the first time. Five patients remained asymptomatic during follow-up, whereas one juvenile had speech delay and one newborn exhibited clinical symptoms. All patients showed remarkably increased concentrations of C4-aclycarnitine with elevated C4/C2 and C4/C3 ratios. In urine organic acid tests, only one patient presented with an increased concentration of isobutyrylglycine excretion. Genetic testing was performed to detect the causative variants. Five previously unreported variants, c.235C > G, c.286G > A, c.444G > T c.1092 + 1G > A, and c.1176G > T, and one known variant, c.1000C > T, in ACAD8 were identified. These previously unreported variants in ACAD8 were predicted to be disease-causing and the c.1092 + 1G > A variant was confirmed to cause skipping of exon 9 by reverse transcription PCR. The most common variant was c.286G > A, which showed an allelic frequency of 50% (7/14), and thus may be a prevalent variant among Chinese patients. Our results broaden the mutational spectrum of ACAD8 and improve the understanding of the clinical phenotype of IBDHD.