@article {484,
	title = {Two novel mutations in the BCKDK (branched-chain keto-acid dehydrogenase kinase) gene are responsible for a neurobehavioral deficit in two pediatric unrelated patients.},
	journal = {Hum Mutat},
	volume = {35},
	year = {2014},
	month = {2014 Apr},
	pages = {470-7},
	abstract = {<p>Inactivating mutations in the BCKDK gene, which codes for the kinase responsible for the negative regulation of the branched-chain α-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{\textquoteright} 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. </p>},
	keywords = {Amino Acids, Branched-Chain, Developmental Disabilities, Fibroblasts, Humans, Male, Mutation, Missense, Nervous System Diseases, Pediatrics, Protein Kinases},
	issn = {1098-1004},
	doi = {10.1002/humu.22513},
	author = {Garc{\'\i}a-Cazorla, Angels and Oyarzabal, Alfonso and Fort, Joana and Robles, Concepci{\'o}n and Castej{\'o}n, Esperanza and Ruiz-Sala, Pedro and Bodoy, Susanna and Merinero, Bego{\~n}a and Lopez-Sala, Anna and Dopazo, Joaquin and Nunes, Virginia and Ugarte, Magdalena and Artuch, Rafael and Palac{\'\i}n, Manuel and Rodr{\'\i}guez-Pombo, Pilar and Alcaide, Patricia and Navarrete, Rosa and Sanz, Paloma and Font-Llitj{\'o}s, Mariona and Vilaseca, Ma Antonia and Ormaizabal, Aida and Pristoupilova, Anna and Agull{\'o}, Sergi Beltran}
}
