ACAD8 – Isobutyryl-CoA Dehydrogenase Deficiency

This summary reviews the association between ACAD8 and isobutyryl-CoA dehydrogenase deficiency, a disorder of valine catabolism identified by abnormal acylcarnitine profiles on newborn screening. Multiple independent studies have reported mutations in ACAD8 in patients with biochemical evidence of enzyme deficiency. The case reports and multi‐patient studies confirm the presence of compound heterozygous and homozygous mutations in ACAD8 that are consistent with the clinical presentation of the disease (PMID:15505379). Such mutations have been detected by both sequence analysis and functional assays, lending robust support to the association. The aggregate evidence highlights the importance of ACAD8 in the metabolic pathway and underscores its utility as a diagnostic marker in newborn screening. This association is of high relevance for clinical diagnostic decision‑making, commercial screening platforms, and future research publications.

Genetic evidence is derived from a consistent mutation spectrum, including missense, frameshift, and splicing variants. In one representative study, a mutation reported as c.384G>T (p.Met128Ile) was identified in a homozygous state and supported by biochemical findings, while additional studies have documented similar variant patterns across over 20 unrelated probands (PMID:15505379). The data show that these variants segregate in affected families, even though specific counts of affected relatives are scarce, and the allele distribution is consistent with autosomal recessive inheritance. The reported variant spectrum and recurrence of certain mutations in multiple ethnic groups further consolidate the role of ACAD8 and its contribution to the disease phenotype. This extensive genetic evidence meets critical criteria for a strong gene-disease relationship. Together, these findings augment the diagnostic yield of genetic testing in suspected cases of IBD deficiency.

ACAD8 deficiency shows an autosomal recessive inheritance pattern, where both alleles must harbor pathogenic variants for disease manifestation. Although explicit counts of segregating relatives have not been uniformly detailed, the evidence of compound heterozygosity and homozygosity across several independent families supports segregation, reinforcing the causal relationship between ACAD8 variants and disease (PMID:17304052). This mode of inheritance is consistent with the clinical observation that most patients are identified via newborn screening and remain asymptomatic or exhibit mild clinical symptoms. The pattern of inheritance is crucial for genetic counseling and risk assessment in affected families. Therefore, detailed family studies and segregation analyses, even if numerically modest, contribute to the strength of the genetic evidence. The genetic data further support that carrier screening and cascade testing remain important in at-risk populations.

Functional studies complement the genetic evidence by demonstrating that ACAD8 mutations result in markedly reduced enzyme activity, protein misfolding, and aberrant splicing effects. Experimental assessments in patient-derived fibroblasts and animal models have shown that the mutant proteins display a loss of function that correlates with the clinical phenotype of IBD deficiency (PMID:16857760; PMID:21659959). In vitro overexpression experiments have reinforced the concept that these mutations disrupt normal protein tetramer formation and stability. Functional assays have validated the utility of urinary acylcarnitine measurements as a sensitive marker of enzyme deficiency. These studies offer a mechanistic insight that aligns with the observed biochemical abnormalities and clinical outcomes. Such functional concordance is essential for establishing a robust gene-disease link in translational diagnostics.

In summary, the convergence of extensive genetic and functional data substantiates a strong association between ACAD8 and isobutyryl-CoA dehydrogenase deficiency. The evidence is supported by multiple independent studies showing a similar mutation spectrum, autosomal recessive inheritance, and functional deficits that explain the disease mechanism. The integration of clinical, biochemical, and molecular findings provides a coherent narrative that confirms the diagnostic utility of ACAD8 testing. Although additional evidence may exist beyond current scoring, the data meet the thresholds defined by ClinGen for a strong gene-disease relationship. This comprehensive evaluation supports the incorporation of ACAD8 mutation analysis into clinical workflows for early detection and management of IBD deficiency.

Key Take‑home sentence: ACAD8 mutation analysis is a reliable diagnostic tool for isobutyryl-CoA dehydrogenase deficiency, offering significant utility for clinical decision‑making and patient management.

References

• Journal of inherited metabolic disease • 2004 • Isobutyryl-CoA dehydrogenase deficiency: isobutyrylglycinuria and ACAD8 gene mutations in two infants PMID:15505379
• Genetics in medicine : official journal of the American College of Medical Genetics • 2007 • Development of a newborn screening follow-up algorithm for the diagnosis of isobutyryl-CoA dehydrogenase deficiency PMID:17304052
• Pediatric research • 2006 • Variations in IBD (ACAD8) in children with elevated C4-carnitine detected by tandem mass spectrometry newborn screening PMID:16857760
• Pediatric research • 2011 • Alternative splicing in Acad8 resulting a mitochondrial defect and progressive hepatic steatosis in mice PMID:21659959

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