BCKDK deficiency; autism; branched-chain amino acids; epilepsy; newborn screening; Catalysis; Molecular Biology; Spectroscopy; Computer Science Applications; Physical and Theoretical Chemistry; Organic Chemistry; Inorganic Chemistry; General Medicine
Abstract :
[en] 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 BCKDK. 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.
Disciplines :
Pediatrics
Author, co-author :
BOEMER, François ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
JOSSE, Claire ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale
LUIS, Géraldine ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Di Valentin, Emmanuel ; Université de Liège - ULiège > Département des sciences de la vie > Virologie - Immunologie
Thiry, Jérôme ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Génétique humaine
CELLO, Christophe ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
CABERG, Jean-Hubert ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
DADOUMONT, Caroline ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique ; Department of Pediatrics, CHC MontLégia, 4000 Liege, Belgium
HARVENGT, Julie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Lumaka, Aimé ; Laboratory of Human Genetics, Department of Biomedical and Preclinical Sciences, Groupe Interdisciplinaire de Génoprotéomique Appliquée-Recherche (GIGA-R), University of Liege, 4000 Liege, Belgium
BOURS, Vincent ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique
Harris, R.A.; Joshi, M.; Jeoung, N.H. Mechanisms responsible for regulation of branched-chain amino acid catabolism. Biochem. Biophys. Res. Commun. 2004, 313, 391–396.
Holeček, M. Branched-chain amino acids in health and disease: Metabolism, alterations in blood plasma, and as supplements. Nutr. Metab. 2018, 15, 33. [CrossRef] [PubMed]
Monirujjaman, M.; Ferdouse, A. Metabolic and Physiological Roles of Branched-Chain Amino Acids. Adv. Mol. Biol. 2014, 2014, 1–6. [CrossRef]
Conway, M.E.; Hutson, S.M. BCAA Metabolism and NH3 Homeostasis. In Advances in Neurobiology; Springer: Cham, Switzerland, 2016; Volume 13, pp. 99–132.
Wang, X.L.; Li, C.J.; Xing, Y.; Yang, Y.H.; Jia, J.P. Hypervalinemia and hyperleucine-isoleucinemia caused by mutations in the branched-chain-amino-acid aminotransferase gene. J. Inherit. Metab. Dis. 2015, 38, 855–861. [CrossRef] [PubMed]
Oyarzabal, A.; Martínez-Pardo, M.; Merinero, B.; Navarrete, R.; Desviat, L.R.; Ugarte, M.; Rodríguez-Pombo, P. A Novel Regulatory Defect in the Branched-Chain α-Keto Acid Dehydrogenase Complex Due to a Mutation in the PPM 1 K Gene Causes a Mild Variant Phenotype of Maple Syrup Urine Disease. Hum. Mutat. 2013, 34, 355–362. [CrossRef] [PubMed]
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.; et al. Mutations in BCKD-kinase Lead to a Potentially Treatable Form of Autism with Epilepsy. Science 2012, 338, 394–397. [CrossRef] [PubMed]
García-Cazorla, A.; Oyarzabal, A.; Fort, J.; Robles, C.; Castejón, E.; Ruiz-Sala, P.; Bodoy, S.; Merinero, B.; Lopez-Sala, A.; Dopazo, J.; et al. Two Novel Mutations in the BCKDK (Branched-Chain Keto-Acid Dehydrogenase Kinase) Gene Are Responsible for a Neurobehavioral Deficit in Two Pediatric Unrelated Patients. Hum. Mutat. 2014, 35, 470–477. [CrossRef] [PubMed]
Jayapalan, S.; Natarajan, J. Classification and domain analysis of protein kinases in hominids. Curr. Sci. 2016, 110, 828–838. [CrossRef]
Oyarzabal, A.; Bravo-Alonso, I.; Sánchez-Aragó, M.; Rejas, M.T.; Merinero, B.; García-Cazorla, A.; Artuch, R.; Ugarte, M.; Rodríguez-Pombo, P. Mitochondrial response to the BCKDK-deficiency: Some clues to understand the positive dietary response in this form of autism. Biochim. Biophys. Acta-Mol. Basis Dis. 2016, 1862, 592–600. [CrossRef] [PubMed]
Coll, M.; Oliva, A.; Grassi, S.; Brugada, R.; Campuzano, O. Update on the Genetic Basis of Sudden Unexpected Death in Epilepsy. Int. J. Mol. Sci. 2019, 20, 1979. [CrossRef] [PubMed]
Filee, R.; Schoos, R.; Boemer, F. Evaluation of Physiological Amino Acids Profiling by Tandem Mass Spectrometry. JIMD Rep. 2013, 13, 119–128. [CrossRef] [PubMed]
Chace, D.H.; Kalas, T.A.; Naylor, E.W. Use of Tandem Mass Spectrometry for Multianalyte Screening of Dried Blood Specimens from Newborns. Clin. Chem. 2003, 49, 1797–1817. [CrossRef] [PubMed]
Chace, D.H.; Kalas, T.A.; Naylor, E.W. The application of tandem mass spectrometry to neonatal screening for inherited disorders of intermediary metabolism. Annu. Rev. Genom. Hum. Genet. 2002, 3, 17–45. [CrossRef] [PubMed]
Emi, N.; Friedmann, T.; Yee, J.K. Pseudotype formation of murine leukemia virus with the G protein of vesicular stomatitis virus. J. Virol. 1991, 65, 1202. [CrossRef] [PubMed]
Biasini, M.; Bienert, S.; Waterhouse, A.; Arnold, K.; Studer, G.; Schmidt, T.; Kiefer, F.; Cassarino, T.G.; Bertoni, M.; Bordoli, L.; et al. SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res. 2014, 42, W252-8. [CrossRef] [PubMed]
Waterhouse, A.; Bertoni, M.; Bienert, S.; Studer, G.; Tauriello, G.; Gumienny, R.; Heer, F.T.; De Beer, T.A.P.; Rempfer, C.; Bordoli, L.; et al. SWISS-MODEL: Homology modelling of protein structures and complexes. Nucleic Acids Res. 2018, 46, W296–W303. [CrossRef] [PubMed]
Mariani, V.; Biasini, M.; Barbato, A.; Schwede, T. lDDT: A local superposition-free score for comparing protein structures and models using distance difference tests. Bioinformatics 2013, 29, 2722–2728. [CrossRef] [PubMed]