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

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.

Pubmed ID: 22956686


  • 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
  • Gleeson JG


Science (New York, N.Y.)

Publication Data

October 19, 2012

Associated Grants

  • Agency: NIMH NIH HHS, Id: K08 MH087639
  • Agency: NIMH NIH HHS, Id: K08MH087639
  • Agency: NICHD NIH HHS, Id: P01 HD070494
  • Agency: NICHD NIH HHS, Id: P01HD070494
  • Agency: NINDS NIH HHS, Id: P30 NS047101
  • Agency: NINDS NIH HHS, Id: P30NS047101
  • Agency: NINDS NIH HHS, Id: R01 NS041537
  • Agency: NINDS NIH HHS, Id: R01 NS048453
  • Agency: NINDS NIH HHS, Id: R01NS048453
  • Agency: NIMH NIH HHS, Id: R25 MH077823
  • Agency: NIMH NIH HHS, Id: RC2 MH089956
  • Agency: NIMH NIH HHS, Id: RC2MH089956
  • Agency: NIMH NIH HHS, Id: T32MH018268
  • Agency: NHGRI NIH HHS, Id: U54HG003067
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
  • Adolescent
  • Amino Acids, Branched-Chain
  • Animals
  • Arginine
  • Autistic Disorder
  • Base Sequence
  • Brain
  • Child
  • Child, Preschool
  • Diet
  • Epilepsy
  • Female
  • Homozygote
  • Humans
  • Intellectual Disability
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Phosphorylation
  • Protein Folding
  • Protein Structure, Tertiary
  • RNA, Messenger
  • Young Adult