Novel ACAD8 variants identified in Isobutyryl-CoA dehydrogenase deficiency: challenges in phenotypic variability and management

Isobutyryl-CoA dehydrogenase deficiency (IBDD) is a rare autosomal recessive disorder caused by biallelic variants in the <i>ACAD8</i> gene, which disrupts valine metabolism. In this study, we report seven individuals identified through newborn screening (NBS) with elevated C4-acylcarnitine levels, including five confirmed patients and two heterozygous carriers. Genetic analysis identified 12 distinct <i>ACAD8</i> variants, seven of which were novel (c.221C>T, c.518T>C, c.727A>G, c.868G>A, c.947A>T, c.966G>A, c.1058T>C). According to ACMG classification criteria, c.221C>T was classified as likely pathogenic, while the remaining variants were categorized as variants of uncertain significance (VUS). During a mean follow-up of 4.81 years, all patients maintained normal growth patterns but two patients developed neurological symptoms that included recurrent febrile seizures and sensory integration dysfunction. These findings expand the <i>ACAD8</i> variant spectrum, highlight the phenotypic variability of IBDD, and underscore the importance of long-term follow-up and individualized management strategies.