Novel Loss of Function Variant in BCKDK Causes a Treatable Developmental and Epileptic Encephalopathy

• Published in: International journal of molecular sciences 2022-02, Vol.23 (4), p.2253
• Main Authors: Boemer, François, Josse, Claire, Luis, Géraldine, Di Valentin, Emmanuel, Thiry, Jérôme, Cello, Christophe, Caberg, Jean-Hubert, Dadoumont, Caroline, Harvengt, Julie, Lumaka, Aimé, Bours, Vincent, Debray, François-Guillaume
• Format: Article
• Language: English
• Subjects: 3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide) - genetics; Amino Acid Sequence; Amino Acids, Branched-Chain - genetics; Autism; Autism Spectrum Disorder - genetics; Autism Spectrum Disorder - pathology; BCKDK deficiency; Brain - pathology; Brain Diseases - genetics; Brain Diseases - pathology; branched-chain amino acids; Catabolism; Catalysis; Cell Line; Cerebrospinal fluid; Chain branching; Chains; Computer Science Applications; Convulsions & seizures; Dehydrogenases; Diet; Encephalopathy; Enzymes; Epilepsy; Epilepsy, Generalized - genetics; Female; Functional testing; Gene deletion; General Medicine; Genes; HEK293 Cells; Homeostasis; Human health sciences; Humans; Hyperactivity; Inorganic Chemistry; Kinases; Loss of Function Mutation - genetics; Male; Medical screening; Metabolic disorders; Metabolism; Microencephaly; Molecular Biology; Mutation; Neurotransmission; newborn screening; Organic Chemistry; Patients; Pediatrics; Pharmacokinetics; Phosphorylation; Phosphorylation - genetics; Physical and Theoretical Chemistry; Plasma; Protein biosynthesis; Protein synthesis; Proteins; Pédiatrie; Retrospective Studies; Sciences de la santé humaine; Seizures; Siblings; Spectroscopy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms23042253

Branched-chain amino acids (BCAA) are essential amino acids playing crucial roles in protein synthesis and brain neurotransmission. Branched-chain ketoacid dehydrogenase (BCKDH), the flux-generating step of BCAA catabolism, is tightly regulated by reversible phosphorylation of its E1α-subunit. BCKDK is the kinase responsible for the phosphorylation-mediated inactivation of BCKDH. In three siblings with severe developmental delays, microcephaly, autism spectrum disorder and epileptic encephalopathy, we identified a new homozygous in-frame deletion (c.999_1001delCAC; p.Thr334del) of . Plasma and cerebrospinal fluid concentrations of BCAA were markedly reduced. Hyperactivity of BCKDH and over-consumption of BCAA were demonstrated by functional tests in cells transfected with the mutant BCKDK. Treatment with pharmacological doses of BCAA allowed the restoring of BCAA concentrations and greatly improved seizure control. Behavioral and developmental skills of the patients improved to a lesser extent. Importantly, a retrospective review of the newborn screening results allowed the identification of a strong decrease in BCAA concentrations on dried blood spots, suggesting that BCKDK is a new treatable metabolic disorder probably amenable to newborn screening programs.