Three novel mutations of the BCKDHA, BCKDHB and DBT genes in Chinese children with maple syrup urine disease
Author:
Yang Jianmei1, Xiu Jianjun2, Sun Yan1, Liu Fan1, Shang Xiaohong1, Li Guimei1
Affiliation:
1. Department of Pediatric Endocrinology , Shandong Provincial Hospital affiliated to Shandong First Medical University , Jinan , Shandong , China 2. Radiology Department , Shandong Provincial Hospital affiliated to Shandong First Medical University , Jinan , Shandong , China
Abstract
Abstract
Background
Maple syrup urine disease (MSUD) is a rare metabolic autosomal recessive disorder caused by deficiency of the branched-chain α-ketoacid dehydrogenase complex. Mutations in the BCKDHA, BCKDHB and DBT genes are responsible for MSUD. This study presents the clinical and molecular characterizations of four MSUD patients.
Methods
Clinical data of patients were retrospectively analyzed, and genetic mutations were identified by whole-exome sequencing. CLUSTALX was employed to analyzed cross-species conservation of the mutant amino acid. The impact of the mutations was analyzed with PolyPhen-2 software. The I-TASSER website and PyMOL software were used to predict the protein three-position structure of the novel mutations carried by the patients.
Results
Vomiting, irritability, feeding difficulties, seizures, dyspnoea, lethargy and coma were the main clinical presentations of MSUD. Cranial MRI showed abnormal symmetrical signals in accordance with the presentation of inherited metabolic encephalopathy. Seven mutations were detected in four patients, including three novel pathogenic mutations in the BCKDHA (c.656C>A), BCKDHB (deletion of a single-copy of BCKDHB) and DBT (c.1219dup) genes. Structural changes were compatible with the observed phenotypes.
Conclusions
Different types of MSUD can display heterogeneous clinical manifestations. Exhaustive molecular studies are necessary for a proper differential diagnosis. The newly identified mutation will play a key role in the prenatal diagnosis of MSUD in the future.
Publisher
Walter de Gruyter GmbH
Subject
Endocrinology,Endocrinology, Diabetes and Metabolism,Pediatrics, Perinatology, and Child Health
Reference35 articles.
1. Nellis, MM, Kasinski, A, Carlson, M, Allen, R, Schaefer, AM, Schwartz, EM, et al.. Relationship of causative genetic mutations in maple syrup urine disease with their clinical expression. Mol Genet Metabol 2003;80:189–95. 2. Nellis, MM, Danner, DJ. Gene preference in maple syrup urine disease. Am J Hum Genet 2001;68:232–7. 3. Zinnanti, WJ, Lazovic, J, Griffin, K, Skvorak, KJ, Paul, HS, Homanics, GE, et al.. Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease. Brain : J Neurol 2009;132:903–18. 4. Lin, N, Ye, J, Qiu, W, Han, L, Zhang, H, Gu, X. Application of liquid chromatography-tandem mass spectrometry in the diagnosis and follow-up of maple syrup urine disease in a Chinese population. J Pediatr Endocrinol Metab 2013;26:433–9. 5. Ali, EZ, Ngu, LH. Fourteen new mutations of BCKDHA, BCKDHB and DBT genes associated with maple syrup urine disease (MSUD) in Malaysian population. Mol Genet Metab Rep 2018;17:22–30.
|
|