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Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy

Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Science (Impact Factor: 31.48). 09/2012; 338(6105):394-7. DOI: 10.1126/science.1224631
Source: PubMed

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.

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Available from: Joseph Gleeson, Aug 07, 2015
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    • "Recently an inactivating mutation in the branched-chain ketoacid dehydrogenase kinase was described to be associated with autism, epilepsy , and intellectual disability in three families with two children each who were products of first-cousin consanguinity [23]. In this disorder, phosphorylation-mediated inactivation of branched-chain ketoacid dehydrogenase is deficient, leading to abnormally low levels of branchedchain amino acids. "
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    ABSTRACT: Many children with ASD have underlying metabolic conditions.•Metabolic disorders are also commonly associated with epilepsy.•Treating metabolic disorders may optimize seizure management.
    Epilepsy & Behavior 11/2014; DOI:10.1016/j.yebeh.2014.08.134 · 2.06 Impact Factor
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    • ", or there is a need to conserve BCAAs for protein synthesis , BCKD is shifted towards its inactive form , leading to the accumulation of BCAAs . The phosphorylation state of the complex correlates inversely with the level of BCKDK . The recent identification of patients harboring mutations in the PPM1K ( Oyarzabal et al . , 2013 ) or BCKDK gene ( Novarino et al . , 2012 ) highlighted the importance of careful regulation in the oxidative disposal of BCAAs for normal human development ."
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    ABSTRACT: Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain keto-acid dehydrogenase complex (BCKD), have recently been associated with a form of autism in three families. In this work, two novel exonic BCKDK mutations, c.520C>G/p.R174G and c.1166T>C/p.L389P, were identified at the homozygous state in two unrelated children with persistently reduced body fluid levels of branched-chain amino acids (BCAAs), developmental delay, microcephaly and neurobehavioral abnormalities. Functional analysis of the mutations confirmed the missense character of the c.1166T>C change and showed a splicing defect r.[520c>g;521_543del]/p.R174Gfs1*, for c.520C>G due to the presence of a new donor splice site. Mutation p.L389P showed total loss of kinase activity. Moreover, patient-derived fibroblasts showed undetectable (p.R174Gfs1*) or barely detectable (p.L389P) levels of BCKDK protein and its phosphorylated substrate (phospho-E1α), resulting in increased BCKD activity and the very rapid BCAA catabolism manifested by the patients' clinical phenotype. Based on these results, a protein-rich diet plus oral BCAA supplementation was implemented in the patient homozygous for p.R174Gfs1*. This treatment normalized plasma BCAA levels and improved growth, developmental and behavioral variables. Our results demonstrate that BCKDK mutations can result in neurobehavioral deficits in humans and support the rationale for dietary intervention. This article is protected by copyright. All rights reserved.
    Human Mutation 04/2014; 35(4). DOI:10.1002/humu.22513 · 5.05 Impact Factor
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    • "branched chain amino acids Novarino et al . , 2012 NLGN3 Xq13 . 1 heterosynaptic transmission , glutamate receptor - dependent synaptic plasticity , increase or decrease in AMPA - mediated synaptic transmission , altered synaptic branching no Etherton et al . , 2011a ; Etherton et al . , 2011b ; Baudouin et al . , 2012"
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    ABSTRACT: Recent genomic research into autism spectrum disorders (ASD) has revealed a remarkably complex genetic architecture. Large numbers of common variants, copy number variations and single nucleotide variants have been identified, yet each of them individually afforded only a small phenotypic impact. A polygenic model in which multiple genes interact either in an additive or a synergistic way appears the most plausible for the majority of ASD patients. Based on recently identified ASD candidate genes, transgenic mouse models for neuroligins/neurorexins and genes such as Cntnap2, Cntn5, Tsc1, Tsc2, Akt3, Cyfip1, Scn1a, En2, Slc6a4 , and Bckdk have been generated and studied with respect to behavioral and neuroanatomical phenotypes and sensitivity to drug treatments. From these models, a few clues for potential pharmacologic intervention emerged. The Fmr1, Shank2 and Cntn5 knockout mice exhibited alterations of glutamate receptors, which may become a target for pharmacologic modulation. Some of the phenotypes of Mecp2 knockout mice can be ameliorated by administering IGF1. In the near future, comprehensive genotyping of individual patients and siblings combined with the novel insights generated from the transgenic animal studies may provide us with personalized treatment options. Eventually, autism may indeed turn out to be a phenotypically heterogeneous group of disorders (‘autisms’) caused by combinations of changes in multiple possible candidate genes, being different in each patient and requiring for each combination of mutations a distinct, individually tailored treatment.
    Molecular syndromology 06/2013; 4(5):213-226. DOI:10.1159/000350041
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