TY - JOUR T1 - Two Novel Mutations in the BCKDK Gene (Branched-Chain Keto-Acid Dehydrogenase Kinase) are Responsible of a Neurobehavioral Deficit in two Pediatric Unrelated Patients. JF - Human mutation Y1 - 2014 A1 - García-Cazorla, Angels A1 - Oyarzabal, Alfonso A1 - Fort, Joana A1 - Robles, Concepción A1 - Castejón, Esperanza A1 - Ruiz-Sala, Pedro A1 - Bodoy, Susanna A1 - Merinero, Begoña A1 - Lopez-Sala, Anna A1 - Joaquín Dopazo A1 - Nunes, Virginia A1 - Ugarte, Magdalena A1 - Artuch, Rafael A1 - Palacín, Manuel A1 - Rodríguez-Pombo, Pilar AB - 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. VL - 35 UR - http://onlinelibrary.wiley.com/doi/10.1002/humu.22513/abstract ER -