Gaia Novarino and colleagues have identified mutations in the BCKDK gene as the cause of a potentially treatable recessive syndrome characterized by autism, intellectual disability and epilepsy (Science, published online 6 September 2012; doi:10.1126/science.1224631). The authors performed exome sequencing in two consanguineous families, each presenting with two siblings with autism and other neurodevelopmental phenotypes and a segregation pattern consistent with autosomal recessive inheritance. In both families, they found that the affected siblings harbored homozygous loss-of-function mutations in BCKDK. Further analyses of in-house exome data led to the identification of a third consanguineous family with two affected siblings harboring a homozygous missense mutation in BCKDK. The kinase encoded by BCKDK acts as a negative regulator of the branched-chain ketoacid dehydrogenase complex, which catalyzes the degradation of branched-chain amino acids. Consistent with the human findings, adult Bckdk-knockout mice developed neurological phenotypes, including tremors and seizures, accompanied by reduced levels of branched-chain amino acids in the brain and other tissues. Notably, placing these knockout mice on a diet enriched in branched-chain amino acids reversed these neurological phenotypes, suggesting that humans with BCKDK mutations could benefit from similar dietary supplementation.
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Vogan, K. New recessive autism syndrome. Nat Genet 44, 1079 (2012). https://doi.org/10.1038/ng.2430
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DOI: https://doi.org/10.1038/ng.2430