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: 33.61). 09/2012; 338(6105):394-7. DOI: 10.1126/science.1224631
Source: PubMed


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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    • "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: Autism spectrum disorder (ASD) affects a significant number of individuals in the United States, with the prevalence continuing to grow. A significant proportion of individuals with ASD have comorbid medical conditions such as epilepsy. In fact, treatment-resistant epilepsy appears to have a higher prevalence in children with ASD than in children without ASD, suggesting that current antiepileptic treatments may be suboptimal in controlling seizures in many individuals with ASD. Many individuals with ASD also appear to have underlying metabolic conditions. Metabolic conditions such as mitochondrial disease and dysfunction and abnormalities in cerebral folate metabolism may affect a substantial number of children with ASD, while other metabolic conditions that have been associated with ASD such as disorders of creatine, cholesterol, pyridoxine, biotin, carnitine, γ-aminobutyric acid, purine, pyrimidine, and amino acid metabolism and urea cycle disorders have also been associated with ASD without the prevalence clearly known. Interestingly, all of these metabolic conditions have been associated with epilepsy in children with ASD. The identification and treatment of these disorders could improve the underlying metabolic derangements and potentially improve behavior and seizure frequency and/or severity in these individuals. This paper provides an overview of these metabolic disorders in the context of ASD and discusses their characteristics, diagnostic testing, and treatment with concentration on mitochondrial disorders. To this end, this paper aims to help optimize the diagnosis and treatment of children with ASD and epilepsy. This article is part of a Special Issue entitled "Autism and Epilepsy".
    Full-text · Article · Nov 2014 · Epilepsy & Behavior
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    • "Recent studies have suggested that ASD is associated with impairments in basic physiological processes such as redox (16) and mitochondrial (9) metabolism as well as abnormalities in regulating essential metabolites such as folate (17), tetrahydrobiopterin (18–20), glutathione (21–23), cholesterol (24), carnitine (25–28), and branch chain amino acids (29). Although many of these studies have based their findings on peripheral markers of abnormal metabolism, many studies have documented some of these same abnormalities in the brain of individuals with ASD, including mitochondrial dysfunction and oxidative stress (30) and one study has demonstrated a link between oxidative stress, inflammation, and mitochondrial dysfunction in the brain of individuals with ASD (23). "
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    ABSTRACT: Recent studies point to the effectiveness of novel treatments that address physiological abnormalities associated with autism spectrum disorder (ASD). This is significant because safe and effective treatments for ASD remain limited. These physiological abnormalities as well as studies addressing treatments of these abnormalities are reviewed in this article. Treatments commonly used to treat mitochondrial disease have been found to improve both core and associated ASD symptoms. Double-blind, placebo-controlled (DBPC) studies have investigated l-carnitine and a multivitamin containing B vitamins, antioxidants, vitamin E, and co-enzyme Q10 while non-blinded studies have investigated ubiquinol. Controlled and uncontrolled studies using folinic acid, a reduced form of folate, have reported marked improvements in core and associated ASD symptoms in some children with ASD and folate related pathway abnormities. Treatments that could address redox metabolism abnormalities include methylcobalamin with and without folinic acid in open-label studies and vitamin C and N-acetyl-l-cysteine in DBPC studies. These studies have reported improved core and associated ASD symptoms with these treatments. Lastly, both open-label and DBPC studies have reported improvements in core and associated ASD symptoms with tetrahydrobiopterin. Overall, these treatments were generally well-tolerated without significant adverse effects for most children, although we review the reported adverse effects in detail. This review provides evidence for potentially safe and effective treatments for core and associated symptoms of ASD that target underlying known physiological abnormalities associated with ASD. Further research is needed to define subgroups of children with ASD in which these treatments may be most effective as well as confirm their efficacy in DBPC, large-scale multicenter studies.
    Full-text · Article · Jun 2014 · Frontiers in Pediatrics
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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.
    Full-text · Article · Apr 2014 · Human Mutation
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