1. Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy
- Author
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Novarino, Gaia, El-Fishawy, Paul, Kayserili, Hulya, Meguid, Nagwa A, Scott, Eric M, Schroth, Jana, Silhavy, Jennifer L, Kara, Majdi, Khalil, Rehab O, Ben-Omran, Tawfeg, Ercan-Sencicek, A Gulhan, Hashish, Adel F, Sanders, Stephan J, Gupta, Abha R, Hashem, Hebatalla S, Matern, Dietrich, Gabriel, Stacey, Sweetman, Larry, Rahimi, Yasmeen, Harris, Robert A, State, Matthew W, and Gleeson, Joseph G
- Subjects
Autism ,Pediatric ,Neurodegenerative ,Behavioral and Social Science ,Intellectual and Developmental Disabilities (IDD) ,Brain Disorders ,Neurosciences ,Epilepsy ,Genetics ,Mental Health ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) ,Adolescent ,Amino Acids ,Branched-Chain ,Animals ,Arginine ,Autistic Disorder ,Base Sequence ,Brain ,Child ,Child ,Preschool ,Diet ,Female ,Homozygote ,Humans ,Intellectual Disability ,Male ,Mice ,Mice ,Knockout ,Molecular Sequence Data ,Mutation ,Pedigree ,Phosphorylation ,Protein Folding ,Protein Structure ,Tertiary ,RNA ,Messenger ,Young Adult ,General Science & Technology - 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