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.
Funding source: the National Natural Science Foundation of China
Award Identifier / Grant number: 82100920
Funding source: Natural Science Foundation of Shandong Province (CN)
Award Identifier / Grant number: ZR2020MH107, ZR2017MH018
Funding source: China Postdoctoral Science Foundation
Award Identifier / Grant number: 2021M691387
Funding source: Postdoctoral Creative Funding in Shangdong Province
Award Identifier / Grant number: 202103062
Acknowledgments
We are grateful to the patients and their parents for their contribution to the study. We would like to thank MyGenostics (Beijing) Medical Laboratory for technical support.
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Research funding: This work was supported by grants from the National Natural Science Foundation of China (82100920), the Natural Science Foundation of Shandong Province (CN) (ZR2020MH107, ZR2017MH018), the China Postdoctoral Science Foundation (2021M691387) and Postdoctoral Creative Funding in Shangdong Province (202103062).
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Author contribution: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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Ethics approval and consent to participate: This study was performed in accordance with the ethical standards laid down in the Declaration of Helsinki, and Medical Ethics Committee of Shandong Provincial Hospital affiliated to Shandong First Medical University approved all procedures. Patients provided written informed consent before laboratory and clinical examinations.
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Employment or leadership: None declared.
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Honorarium: None declared.
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Template for Ethical and Legal Declarations: This study was performed in accordance with the ethical standards laid down in the Declaration of Helsinki, and Medical Ethics Committee of Shandong Provincial Hospital affiliated to Shandong First Medical University approved all procedures. Patients provided written informed consent before laboratory and clinical examinations.
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