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

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.

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

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2021-0672 ◽

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.

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

Human Mutation ◽

10.1002/humu.9187 ◽

2003 ◽

Vol 22 (5) ◽

pp. 417-417 ◽

Cited By ~ 29

Author(s):

Marco Henneke ◽

Nadine Flaschker ◽

Christoph Helbling ◽

Martina Müller ◽

Peter Schadewaldt ◽

...

Keyword(s):

Maple Syrup Urine Disease ◽

Novel Mutations ◽

Maple Syrup ◽

Urine Disease

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

World Journal of Pediatrics ◽

10.1007/s12519-020-00349-1 ◽

2020 ◽

Vol 16 (4) ◽

pp. 401-410 ◽

Cited By ~ 1

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

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

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2017-0305 ◽

2018 ◽

Vol 31 (2) ◽

pp. 205-212 ◽

Cited By ~ 2

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.

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