In addition, 4 previously unidentified variants (p.Gly281Arg in BCKDHA gene, p.Ser171Pro, p.Gly95Ala and p.Lys222Thr in BCKDHB gene) were identified. Totally, 13 variants were detected, including 2 variants (p.Ala216Val and p.Gly281Arg) in BCKDHA gene, 10 variants (p.Gly95Ala, p.Ser171Pro, p.Phe175Leu, p.Arg183Trp, p.Lys222Thr, p.Arg285Ter, p.Arg111Ter, p.S184Pfs*46, p.Arg170Cys, p.I160Ffs*25) in BCKDHB gene, 1 variant (p.Arg431Ter) in DBT gene. Targeted NGS revealed 2 pedigrees with MSUD Ia, 5 pedigrees with Ib, 1 pedigree with MSUD II. All the coding regions and exon/intron boundaries of BCKDHA, BCDKHB, DBT and DLD genes were analyzed by targeted NGS in the 8 MSUD pedigrees. In this report, 8 patients (4 females and 4 males) with MSUD from 8 unrelated Chinese Han families were diagnosed at the age of 6 days to 4 months. Only a few cases of MSUD have been documented in Mainland China. The newly identified mutation will play a key role in the prenatal diagnosis of MSUD in the future.ĪbstractMaple syrup urine disease (MSUD) is a rare autosomal recessive disorder that affects the degradation of branched chain amino acids (BCAAs). Exhaustive molecular studies are necessary for a proper differential diagnosis. Structural changes were compatible with the observed phenotypes.ĭifferent types of MSUD can display heterogeneous clinical manifestations. 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. Cranial MRI showed abnormal symmetrical signals in accordance with the presentation of inherited metabolic encephalopathy. Vomiting, irritability, feeding difficulties, seizures, dyspnoea, lethargy and coma were the main clinical presentations of MSUD. The I-TASSER website and PyMOL software were used to predict the protein three-position structure of the novel mutations carried by the patients. The impact of the mutations was analyzed with PolyPhen-2 software. CLUSTALX was employed to analyzed cross-species conservation of the mutant amino acid. This study presents the clinical and molecular characterizations of four MSUD patients.Ĭlinical data of patients were retrospectively analyzed, and genetic mutations were identified by whole-exome sequencing. Mutations in the BCKDHA, BCKDHB and DBT genes are responsible for MSUD. Maple syrup urine disease (MSUD) is a rare metabolic autosomal recessive disorder caused by deficiency of the branched-chain α-ketoacid dehydrogenase complex.
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