1. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.
- Author
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Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J, Silhavy JL, Kara M, Khalil RO, Ben-Omran T, Ercan-Sencicek AG, Hashish AF, Sanders SJ, Gupta AR, Hashem HS, Matern D, Gabriel S, Sweetman L, Rahimi Y, Harris RA, State MW, and Gleeson JG
- Subjects
- 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) deficiency, Adolescent, Amino Acids, Branched-Chain administration & dosage, Amino Acids, Branched-Chain blood, Amino Acids, Branched-Chain deficiency, Animals, Arginine genetics, Autistic Disorder enzymology, Base Sequence, Brain metabolism, Child, Child, Preschool, Diet, Epilepsy enzymology, Female, Homozygote, Humans, Intellectual Disability diet therapy, Intellectual Disability enzymology, Intellectual Disability genetics, Male, Mice, Mice, Knockout, Molecular Sequence Data, Mutation, Pedigree, Phosphorylation, Protein Folding, Protein Structure, Tertiary, RNA, Messenger metabolism, Young Adult, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) administration & dosage, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) genetics, Autistic Disorder diet therapy, Autistic Disorder genetics, Epilepsy diet therapy, Epilepsy genetics
- Abstract
Autism spectrum disorders are a genetically heterogeneous constellation of syndromes characterized by impairments in reciprocal social interaction. Available somatic treatments have limited efficacy. We have identified inactivating mutations in the gene BCKDK (Branched Chain Ketoacid Dehydrogenase Kinase) in consanguineous families with autism, epilepsy, and intellectual disability. The encoded protein is responsible for phosphorylation-mediated inactivation of the E1α subunit of branched-chain ketoacid dehydrogenase (BCKDH). Patients with homozygous BCKDK mutations display reductions in BCKDK messenger RNA and protein, E1α phosphorylation, and plasma branched-chain amino acids. Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation. Thus, autism presenting with intellectual disability and epilepsy caused by BCKDK mutations represents a potentially treatable syndrome.
- Published
- 2012
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