Three novel mutations of the BCKDHA, BCKDHB and DBT genes in Chinese children with maple syrup urine disease

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Jianmei Yang ◽  
Jianjun Xiu ◽  
Yan Sun ◽  
Fan Liu ◽  
Xiaohong Shang ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
Structural Changes ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Novel Mutations ◽  
Metabolic Encephalopathy ◽  
Maple Syrup ◽  
Feeding Difficulties ◽  
Urine Disease ◽  
The Impact

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.

Four novel mutations of the BCKDHA, BCKDHB and DBT genes in Iranian patients with maple syrup urine disease

2018 ◽  
Vol 31 (2) ◽  
pp. 205-212 ◽  
Author(s):  
Monica Zeynalzadeh ◽  
Alireza Tafazoli ◽  
Azadeh Aarabi ◽  
Morteza Moghaddassian ◽  
Farah Ashrafzadeh ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
Energy Levels ◽  
Clinical Manifestations ◽  
Autosomal Recessive Disorder ◽  
Strong Correlations ◽  
Novel Mutations ◽  
Maple Syrup ◽  
Urine Disease ◽  
Branched Chain ◽  
Ketoacid Dehydrogenase

Abstract Background: Maple syrup urine disease (MSUD) is a rare metabolic autosomal recessive disorder caused by dysfunction of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex. Mutations in the BCKDHA, BCKDHB and DBT genes are responsible for MSUD. The current study analyzed seven Iranian MSUD patients genetically and explored probable correlations between their genotype and phenotype. Methods: The panel of genes, including BCKDHA, BCKDHB and DBT, was evaluated, using routine the polymerase chain reaction (PCR)-sequencing method. In addition, protein modeling (homology and threading modeling) of the deduced novel mutations was performed. The resulting structures were then analyzed, using state-of-the-art bioinformatics tools to better understand the structural and functional effects caused by mutations. Results: Seven mutations were detected in seven patients, including four novel pathogenic mutations in BCKDHA (c.1198delA, c.629C>T), BCKDHB (c.652C>T) and DBT (c.1150A>G) genes. Molecular modeling of the novel mutations revealed clear changes in the molecular energy levels and stereochemical traits of the modeled proteins, which may be indicative of strong correlations with the functional modifications of the genes. Structural deficiencies were compatible with the observed phenotypes. Conclusions: Any type of MSUD can show heterogeneous clinical manifestations in different ethnic groups. Comprehensive molecular investigations would be necessary for differential diagnosis.

Neonatal maple syrup urine disease in China: two novel mutations in the BCKDHB gene and literature review

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Hong‐Hua Jiang ◽  
Yan Guo ◽  
Xian Shen ◽  
Ying Wang ◽  
Ting-Ting Dai ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
Chinese Literature ◽  
Brain Mri ◽  
Classical Type ◽  
Novel Mutations ◽  
Maple Syrup ◽  
Gene Testing ◽  
Urine Disease ◽  
Bckdhb Gene ◽  
Branched Chain

Abstract Objectives To report two novel mutations in the BCKDHB gene with Maple syrup urine disease (MSUD) and compare their data with 52 cases of MSUD reported in the available Chinese literature. Methods Clinical data of a case of a newborn with MSUD was retrospectively studied. Literatures on MSUD in the local medical journals from January 1990 till December 2019 in China were reviewed. Results Two novel BCKDHB mutations c.90_91insCTGGCGCGGGG (p.Phe35TrpfsTer41) and c.80_90del (p.Ala32PhefsTer48) were identified. We found a total of 52 cases of MSUD reports so far. A total of 49 cases had the symptom of poor feeding (94.2%), 50 cases showed poor responses to stimulation (96.2%), 21 cases had odor of maple syrup (40.3%), 29 cases had seizures (55.7%), and 13 cases had respiratory failure (25.0%). The average of the blood ammonia was 127.2 ± 75.0 μmol/L. A total of 18 cases reported the gene testing, among of them 9 cases of BCKDHA mutations, 6 cases of BCKDHB mutations, and 2 cases of DBT mutations. A total of 13 cases (25%) were treated with mechanical ventilation, 50 cases (96.2%) with protein-restricted diet and l-carnitine, 29 cases with thiamine, and only 2 cases were treated with blood purification. Finally, 19 patients (36.5%) were died, 21 cases (40.4%) were improved after treatments. Conclusions The clinical phenotype of neonatal MSUD in China belongs to the classical type currently. Suspected patients should have blood or urine branched-chain amino acid levels tested and brain MRI as early as possible to enable early diagnosis, thus improvement in prognosis.

scholarly journals Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease

2003 ◽  
Vol 22 (5) ◽  
pp. 417-417 ◽  
Author(s):  
Marco Henneke ◽  
Nadine Flaschker ◽  
Christoph Helbling ◽  
Martina Müller ◽  
Peter Schadewaldt ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
Novel Mutations ◽  
Maple Syrup ◽  
Urine Disease

Identification of eight novel mutations in 11 Chinese patients with maple syrup urine disease

2020 ◽  
Vol 16 (4) ◽  
pp. 401-410 ◽  
Author(s):  
Wei-Hua Sun ◽  
Bing-Bing Wu ◽  
Ya-Qiong Wang ◽  
Meng-Yuan Wu ◽  
Xin-Ran Dong ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
Chinese Patients ◽  
Novel Mutations ◽  
Maple Syrup ◽  
Urine Disease

Maple syrup urine disease mutation spectrum in a cohort of 40 consanguineous patients and insilico analysis of novel mutations

2019 ◽  
Vol 34 (4) ◽  
pp. 1145-1156 ◽  
Author(s):  
Maryam Abiri ◽  
Hassan Saei ◽  
Maryam Eghbali ◽  
Razieh Karamzadeh ◽  
Tina Shirzadeh ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
Mutation Spectrum ◽  
Novel Mutations ◽  
Maple Syrup ◽  
Disease Mutation ◽  
Urine Disease

scholarly journals Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease

2021 ◽  
Author(s):  
Xiaohua Fang ◽  
Xiaofan Zhu ◽  
Yin Feng ◽  
Ying Bai ◽  
Xuechao Zhao ◽  
...  
Keyword(s):  
Maple Syrup Urine Disease ◽  
Mainland China ◽  
Autosomal Recessive Disorder ◽  
Maple Syrup ◽  
Targeted Next Generation Sequencing ◽  
Coding Regions ◽  
Targeted Ngs ◽  
Urine Disease ◽  
Bckdhb Gene ◽  
Branched Chain

Abstract Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder that affects the degradation of branched chain amino acids (BCAAs). Only a few cases of MSUD have been documented in Mainland China. In this report, 8 patients (4 girls and 4 boys) with MSUD from 8 unrelated Chinese families were diagnosed at the age of 9 days to 1 year and 8 months. All the coding regions and exon/intron boundaries of BCKDHA, BCDKHB, DBT, DLD genes were analyzed by targeted NGS in the 8 MSUD pedigrees. Targeted NGS revealed 2 pedigrees with MSUD Ia, 5 pedigrees with Ib, 1 pedigree with MSUD II. 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 variants (p.Arg431Ter) in DBT gene. In addition, 4 previously unidentified variants (p.Gly281Arg in BCKDHA gene, p.Ser171Pro, p.Gly95Ala and p.Lys222Thr in BCKDHB gene) were found. NGS plus Sanger sequencing detection is effective and accurate for making gene diagnosis. Computational structural modeling indicated that these novel variations might affect structural stability.

scholarly journals Role of Diffusion Weighted MRI in Maple Syrup Urine Disease: Rare Cause of Neonatal Metabolic Encephalopathy

2013 ◽  
Vol 33 (3) ◽  
pp. 230-233
Author(s):  
Diva Shah ◽  
Apoorv Nirula ◽  
Dwiti Shah
Keyword(s):  
Maple Syrup Urine Disease ◽  
Diffusion Weighted Mri ◽  
Mri Findings ◽  
Metabolic Encephalopathy ◽  
Maple Syrup ◽  
Diffusion Weighted ◽  
Urine Disease ◽  
Classic Form ◽  
Branched Chain

The newborn presenting with neurological symptoms such as seizures or lethargy due to inborn error of metabolism is an important problem. Maple syrup urine disease (MSUD) is an inherited genetic disease, caused by a deficiency of the catalytic components of α-ketoaciddehydrogenase complex, which is responsible for the catabolism of branched-chain amino acids. The purpose of this case report is to show diffusion-weighted imaging (DWI) MRI findings of acute phase of classic form of MSUD in a newborn although this imaging findings are rare but very typical, known as “MSUD oedema”. DOI: http://dx.doi.org/10.3126/jnps.v33i3.8365   J. Nepal Paediatr. Soc. 2013;33(3):230-233

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