Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy Journal Article

Author(s): Novarino, Gaia; El-Fishawy, Paul; Kayserili, Hülya; Meguid, Nagwa A; Scott, Eric M; Schroth, Jana; Silhavy, Jennifer L; Kara, Majdi; Khalil, Rehab O; Ben-Omran, Tawfeg I; Ercan-Sencicek, Adife G; Hashish, Adel F; Sanders, Stephan J; Gupta, Abha R; Hashem, Hebatalla S; Matern, Dietrich; Gabriel, Stacey B; Sweetman, Lawrence; Rahimi, Yasmeen; Harris, Robert A; State, Matthew W; Gleeson, Joseph G
Article Title: Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy
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.
Keywords: unclassified drug; 2 oxoisovalerate dehydrogenase (lipoamide); branched chain ketoacid dehydrogenase kinase; cytosine; phosphotransferase; thymine
Journal Title: Science
Volume: 338
Issue 6105
ISSN: 0036-8075
Publisher: American Association for the Advancement of Science  
Date Published: 2012-10-19
Start Page: 394
End Page: 397
DOI: 10.1126/science.1224631
Open access: no