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

Gaia Novarino, Paul El-Fishawy, Hulya Kayserili, Nagwa A. Meguid, Eric M. Scott, Jana Schroth, Jennifer L. Silhavy, Majdi Kara, Rehab O. Khalil, Tawfeg Ben-Omran, A. G. Ercan-Sencicek, Adel F. Hashish, Stephan J. Sanders, Abha R. Gupta, Hebatalla S. Hashem, Dietrich Matern, Stacey Gabriel, Larry Sweetman, Yasmeen Rahimi, Robert A. HarrisMatthew W. State, Joseph G. Gleeson

Research output: Contribution to journalArticle

148 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)394-397
Number of pages4
JournalScience
Volume338
Issue number6105
DOIs
StatePublished - Oct 19 2012

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3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Autistic Disorder
Epilepsy
Phosphotransferases
Mutation
Intellectual Disability
Phosphorylation
Branched Chain Amino Acids
Interpersonal Relations
Dietary Supplements
Knockout Mice
Proteins
Amino Acids
Messenger RNA
Brain
Genes

ASJC Scopus subject areas

  • General

Cite this

Novarino, G., El-Fishawy, P., Kayserili, H., Meguid, N. A., Scott, E. M., Schroth, J., ... Gleeson, J. G. (2012). Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science, 338(6105), 394-397. https://doi.org/10.1126/science.1224631

Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. / 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. G.; 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.; Gleeson, Joseph G.

In: Science, Vol. 338, No. 6105, 19.10.2012, p. 394-397.

Research output: Contribution to journalArticle

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 2012, 'Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy', Science, vol. 338, no. 6105, pp. 394-397. https://doi.org/10.1126/science.1224631
Novarino G, El-Fishawy P, Kayserili H, Meguid NA, Scott EM, Schroth J et al. Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. Science. 2012 Oct 19;338(6105):394-397. https://doi.org/10.1126/science.1224631
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. G. ; 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. ; Gleeson, Joseph G. / Mutations in BCKD-kinase lead to a potentially treatable form of autism with epilepsy. In: Science. 2012 ; Vol. 338, No. 6105. pp. 394-397.
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AU - Matern, Dietrich

AU - Gabriel, Stacey

AU - Sweetman, Larry

AU - Rahimi, Yasmeen

AU - Harris, Robert A.

AU - State, Matthew W.

AU - Gleeson, Joseph G.

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