Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy
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A Fine Balance: Intellectual and neurological disabilities can arise from diverse developmental aberrations. Novarino et al. (p. 394 , published online 6 September; see the Perspective by Beaudet ) have now determined the genetic basis for one such disorder for a small group of patients. Exome sequencing led to identification of mutations in a kinase BCKDK ( Branched Chain Ketoacid Dehydrogenase Kinase ) that regulates metabolism of branched-chain amino acids such as valine, leucine, and isoleucine. Mice with homozygous mutations in the BCKDK gene showed developmental and neurological abnormalities resembling those in certain mouse autism models. Analysis of transport mechanisms responsible for carrying amino acids across the blood-brain barrier revealed competition between the branched-chain amino acids and large neutral amino acids. Nutritional supplementation with extra branched-chain amino acids in the diet of mice carrying homozygous mutations in the BCKDK gene normalized their phenotype.
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Disruption of BCAA levels by branched chain ketoacid dehydrogenase kinase and SLC7A5 mutations has extensive implications for survival and function of several neuronal circuits.
“Further, disruption of BCAA levels by branched chain ketoacid dehydrogenase kinase and SLC7A5 mutations has been shown to have extensive implications for survival and function of several neuronal circuits (Novarino et al., 2012).”
From The Microbiota-Gut-Brain Axis (2019) · cites this paper as Novarino et al., 2012
The indexed paper’s Abstract (page unavailable) reports that BCKDK mutations lower BCAA levels and are associated with neurological deficits in patients and mice. It describes SLC7A5 as a blood–brain-barrier transporter, not as a mutated gene in this study. It does not establish effects on the survival or function of several neuronal circuits; its cultured-cell experiments found no genotype-dependent difference in cell survival. (LLM, conf=0.90)
Experimental — accuracy not yet measuredBckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation.
“Bckdk knockout mice show abnormal brain amino acid profiles and neurobehavioral deficits that respond to dietary supplementation.”
From Getting to the cores of autism (2019) · cites this paper as Novarino et al., 2012
Inactivating BCKDK mutations were identified in consanguineous families with autism, epilepsy, and intellectual disability.
“For example Novarino et al identified inactivating mutations in the gene Branched Chain Ketoacid Dehydrogenase Kinase (BCKDK) in consanguineous families with autism, epilepsy, and intellectual disability (Novarino et al., 2012).”
From Getting to the cores of autism (2019) · cites this paper as Novarino et al., 2012
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- Authors
- Novarino, G., El-Fishawy, P., Kayserili, H., Meguid, N. A., Scott, E. M., Schroth, J., Silhavy, J. L., Kara, M., Khalil, R. O., Ben-Omran, T., Ercan-Sencicek, A. G., Hashish, A. F., Sanders, S. J., Gupta, A. R., Hashem, H. S., Matern, D., Gabriel, S., Sweetman, L., Rahimi, Y., Harris, R. A., State, M. W., & Gleeson, J. G.
- Affiliations
- Howard Hughes Medical Institute (US)
- Yale University (US)
- Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, 34093 Faith/Istanbul, Turkey.
- National Research Centre (EG)
- Pediatric Department, Tripoli Children’s Hospital, Tripoli, Libya.
- Clinical and Metabolic Genetics Division, Department of Pediatrics, Hamad Medical Corporation, Doha, Qatar.
- Program on Neurogenetics, Child Study Center, Department of Psychiatry and Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA.
- Mayo Clinic (US)
- Broad Institute (US)
- Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX 75226, USA.
- Richard L. Roudebush VA Medical Center (US)
- Corresponding author
- Novarino, Gaia
- El-Fishawy, Paul
- Gleeson, Joseph G.
- ORCID
- Venue
- Science
- Published
- 2012-10-19
- Volume
- 338
- Issue
- 6105
- Pages
- 394-397
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3704165
- OpenAlex
- W2005809131
- Cited by
- 320
- References
- 30
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 19 · 2023: 20 · 2022: 26 · 2021: 26 · 2020: 28 · 2019: 19 · 2018: 32 · 2017: 23 · 2016: 18 · 2015: 22 · 2014: 23 · 2013: 31 · 2012: 5
- FWCI
- 13.28
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Eli Lilly and Company
- Pfizer
- Yale University
- Broad Institute (U54HG003067)
- Halozyme
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- University of California, San Diego (P30 NS047101)
- Pfizer Pharmaceuticals
- National Institute of Mental Health (RC2MH089956, K08MH087639, R25MH077823, T32MH018268)
- National Human Genome Research Institute (U54HG003067)
- National Institute of Neurological Disorders and Stroke (R01NS041537, R01NS048453, P30NS047101)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P01HD070494)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Keywords
- BCKDK, autism spectrum disorder, epilepsy, intellectual disability, consanguineous family, branched-chain amino acids, branched-chain ketoacid dehydrogenase, dietary supplementation, neurobehavioral deficits, brain amino acid metabolism
- MeSH terms
- Adolescent, Amino Acids, Branched-Chain, Animals, Arginine, Autistic Disorder, Base Sequence, Brain, Child, Child, Preschool, Diet, Epilepsy, Female, Homozygote, Humans, Male, Intellectual Disability, Molecular Sequence Data, Mutation, Pedigree, Phosphorylation, RNA, Messenger, Protein Structure, Tertiary, Protein Folding, Mice, Knockout, 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide), Mice, Young Adult
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