ACADSB – 2-Methylbutyryl-CoA Dehydrogenase Deficiency

ACADSB encodes short/branched-chain acyl-CoA dehydrogenase (SBCAD), and biallelic variants cause autosomal recessive 2-methylbutyryl-CoA dehydrogenase deficiency ([MONDO:0012392]). This inborn error of L-isoleucine metabolism presents with variable neurologic features, including athetoid cerebral palsy (HP:0011445) and autism spectrum disorders (HP:0000717).

Inheritance is autosomal recessive. Across two newborn-screening cohorts, 4 affected individuals from 2 Hmong families and 12 non-Hmong probands have been reported with biallelic ACADSB variants, including splice-site and missense alleles ([PMID:12837870], [PMID:20547083]).

Segregation analyses in multiple families demonstrated co-segregation of the IVS3+3A>G (c.303+3A>G) splice mutation with metabolite abnormalities in affected siblings and an asymptomatic carrier mother ([PMID:17883863]).

Functional assays confirm pathogenicity: patient fibroblast enzyme activity is abolished using 2-methylbutyryl-CoA substrate ([PMID:11013134]), minigene splicing assays show exon skipping due to c.303+3A>G ([PMID:16317551]), and bacterial expression of novel missense alleles yields unstable or inactive enzymes.

The clinical spectrum ranges from severe motor delay and cerebral palsy to asymptomatic infancy under dietary management, indicating variable expressivity and incomplete penetrance.

Integration of genetic, segregation, and functional data supports a strong gene–disease relationship. Early detection by tandem mass spectrometry newborn screening enables presymptomatic dietary intervention.

References

• Pediatrics • 2003 • Prospective diagnosis of 2-methylbutyryl-CoA dehydrogenase deficiency in the Hmong population by newborn screening using tandem mass spectrometry. PMID:12837870
• Molecular Genetics and Metabolism • 2010 • Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening. PMID:20547083
• Journal of Medical Case Reports • 2007 • 2-methylbutyryl-CoA dehydrogenase deficiency associated with autism and mental retardation: a case report. PMID:17883863
• American Journal of Human Genetics • 2000 • Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect… PMID:11013134
• Human Genetics • 2006 • Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping. PMID:16317551

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