Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 22956686.
- Also identified by DOI 10.1126/science.1224631 and PMC identifier 3704165.
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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.
Medical subject headings
- 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
- 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/administration & dosage
- 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/deficiency
- 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)/genetics
- Adolescent
- Amino Acids, Branched-Chain
- Amino Acids, Branched-Chain/administration & dosage
- Amino Acids, Branched-Chain/blood
- Amino Acids, Branched-Chain/deficiency
- Animals
- Arginine
- Arginine/genetics
- Autistic Disorder
- Autistic Disorder/diet therapy
- Autistic Disorder/enzymology
- Autistic Disorder/genetics
- Base Sequence
- Brain
- Brain/metabolism
- Child
- Child, Preschool
- Diet
- Epilepsy
- Epilepsy/diet therapy
- Epilepsy/enzymology
- Epilepsy/genetics
- Female
- Homozygote
- Humans
- Intellectual Disability
- 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
- RNA, Messenger/metabolism
- Young Adult