Isobutyryl-coenzyme a dehydrogenase deficiency: disease, or non-disease?

Isobutyryl-coenzyme A dehydrogenase deficiency (IBDD) is a rare inborn error of valine metabolism caused by variants in the ACAD8 gene. Since its initial description in 1998, a wide range of clinical features has been reported, but the disease status and clinical significance of IBDD remain under debate. We systematically studied all published cases of IBDD to provide an overview of the reported phenotype and molecular spectrum.

A comprehensive literature review identified 172 individuals with IBDD reported up to December 2024. Seven children were diagnosed following selective screening due to family history or clinical suspicion, while 165 were identified through expanded newborn screening programs. Elevated blood or plasma C4-acylcarnitine was observed universally, and isobutyrylglycinuria was a common but not invariable urinary marker. Of these 172 individuals, 146 were asymptomatic at follow-up, whereas 26 presented with diverse, non-specific manifestations, including motor delay, failure to thrive, muscular hypotonia, speech delay, developmental delay, and anemia-the latter being the most frequently reported abnormality. Biallelic pathogenic variants in ACAD8 were identified in most cases with available genetic information, with c.286G > A p.(Gly96Ser) emerging as the most prevalent variant, predominantly among individuals of Chinese origin. Notably, altered biochemical markers of liver function were reported in 19 individuals, including 18 with isolated elevations of serum transaminases and γ-glutamyl transferase. One 11-year-old boy exhibited hepatomegaly and ultrasound findings suggestive of hepatic steatosis, along with markedly elevated transaminase levels. Hepatic steatosis has also been observed in an IBDD mouse model, suggesting a potential link between IBDD and liver involvement.

Most individuals with IBDD remain asymptomatic following detection through newborn screening, yet a minority develop heterogeneous clinical features. Our overview highlights that some liver enzyme abnormalities and hepatic steatosis may occur in some individuals with IBDD. These findings suggest that further research is warranted to clarify possible hepatic implications of IBDD and to determine whether long-term monitoring of affected individuals should be considered, particularly in light of ongoing discussions about the appropriateness of IBDD as a target condition in newborn screening programs.