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.
authors.affiliation: Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. gnovarino@ucsd.edu
authors.forename: Gaia
authors.initials: G
authors.lastname: Novarino
authors.forename: Paul
authors.initials: P
authors.lastname: El-Fishawy
authors.forename: Hulya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Nagwa A
authors.initials: NA
authors.lastname: Meguid
authors.forename: Eric M
authors.initials: EM
authors.lastname: Scott
authors.forename: Jana
authors.initials: J
authors.lastname: Schroth
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Silhavy
authors.forename: Majdi
authors.initials: M
authors.lastname: Kara
authors.forename: Rehab O
authors.initials: RO
authors.lastname: Khalil
authors.forename: Tawfeg
authors.initials: T
authors.lastname: Ben-Omran
authors.forename: A Gulhan
authors.initials: AG
authors.lastname: Ercan-Sencicek
authors.forename: Adel F
authors.initials: AF
authors.lastname: Hashish
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.forename: Abha R
authors.initials: AR
authors.lastname: Gupta
authors.forename: Hebatalla S
authors.initials: HS
authors.lastname: Hashem
authors.forename: Dietrich
authors.initials: D
authors.lastname: Matern
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.forename: Larry
authors.initials: L
authors.lastname: Sweetman
authors.forename: Yasmeen
authors.initials: Y
authors.lastname: Rahimi
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harris
authors.forename: Matthew W
authors.initials: MW
authors.lastname: State
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Gleeson
mesh_terms: D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) / Q000008:administration & dosage* / Q000172:deficiency / Q000235:genetics*; D000293:Adolescent; D000597:Amino Acids, Branched-Chain / Q000008:administration & dosage / Q000097:blood / Q000172:deficiency; D000818:Animals; D001120:Arginine / Q000235:genetics; D001321:Autistic Disorder / Q000178:diet therapy* / Q000201:enzymology / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D004032:Diet; D004827:Epilepsy / Q000178:diet therapy* / Q000201:enzymology / Q000235:genetics*; D005260:Female; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000178:diet therapy / Q000201:enzymology / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010766:Phosphorylation; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D000597:Amino Acids, Branched-Chain; D012333:RNA, Messenger; D001120:Arginine; D042942:3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)