Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease in Chinese Han population

Fang, Xiaohua; Zhu, Xuejun; Yin, Feng; Bai, Ying; Zhao, Xuechao; Ning, Liu; Kong, Xiangdong

doi:10.1038/s41598-021-98357-2

Cited by 4 publications

(3 citation statements)

References 36 publications

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“…Similar to previous research reports, as it is a rare disease and the cases in each study are relatively limited, so the relationship between MSUD genotype and phenotype cannot be determined. Generally, most patients with BCKDHA and BCKDHB gene mutations are classical, with BCKDH activity less than 2% (Mitsubuchi et al, 2005;Fang et al, 2021). In our study, three patients with BCKDHB mutations are Classic, and one patient with BCKDHA mutations Intermediate MSUD.…”

Section: Discussionmentioning

confidence: 46%

“…Patients with Thiamineresponsive can improve their tolerance to leucine through thiamine supplementation, and their clinical manifestation is similar to the Intermediate MSUD. E3 deficiency is the rarest type of MSUD and is often associated with severe lactic acidemia and neurological impairment (Flaschker et al, 2007;Frazier et al, 2014;Fang et al, 2021)MSUD has significant racial and geographic variability, with a global incidence of 1/185,000 and a prevalence as high as 1/380 in the Mennonite population (Carleton et al, 2010). MSUD has a complex clinical presentation, with early manifestations mainly consisting of feeding difficulties, vomiting, lethargy, metabolic acidosis, and a peculiar maple sugar odor in urine and sweat during infancy (mainly in the early neonatal period).…”

Section: Introductionmentioning

confidence: 99%

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Identification of gene mutations in six Chinese patients with maple syrup urine disease

Mao²,

Yang³

et al. 2023

Front. Genet.

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Background: Maple syrup urine disease (MSUD) is a rare autosomal recessive amino acid metabolic disease. This study is to identify the pathogenic genetic factors of six cases of MUSD and evaluates the application value of high-throughput sequencing technology in the early diagnosis of MUSD.Methods: Clinical examination was carried out for patients and used blood tandem mass spectrometry (MS/MS), urine gas chromatography-mass spectrometry (GC/MS), and the application of high-throughput sequencing technology for detection. Validate candidate mutations by polymerase chain reaction (PCR)—Sanger sequencing technology. Bioinformatics software analyzed the variants’ pathogenicity. Using Swiss PDB Viewer software to predict the effect of mutation on the structure of BCKDHA and BCKDHB proteins.Result: A total of six MSUD patients were diagnosed, including four males and two females. Nine variants were found in three genes of six MSUD families by high-throughput sequencing, including four missense mutations: c.659C>T(p.A220V), c.818C>T(p.T273I), c.1134C>G(p.D378E), and c.1006G>A(p.G336S); two non-sense mutations: c.1291C>T(p.R431*) and c.331C>T(p.R111*); three deletion mutations: c.550delT (p.S184Pfs*46), c.718delC (p.P240Lfs*14), and c.795delG (p.N266Tfs*64). Sanger sequencing’s results were consistent with the high-throughput sequencing. The bioinformatics software revealed that the mutations were harmful, and the prediction results of Swiss PDB Viewer suggest that variation affects protein conformation.Conclusion: This study identified nine pathogenic variants in the BCKDHA, BCKDHB, and DBT genes in six MSUD families, including two novel pathogenic variants in the BCKDHB gene, which enriched the genetic mutational spectrum of the disease. High-throughput sequencing is essential for the MSUD’s differential diagnosis, early treatment, and prenatal diagnosis.

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Section: Discussionmentioning

confidence: 46%

Section: Introductionmentioning

confidence: 99%

Identification of gene mutations in six Chinese patients with maple syrup urine disease

Mao²,

Yang³

et al. 2023

Front. Genet.

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“…If the NBS results are positive, then follow-up genetic tests are performed using high-throughput genomic sequencing combined with Sanger sequencing for their confirmation and validation [ 12 ]. Notably, NBS and genetic testing have advanced the identification of MSUD cases [ 13 , 14 ], but these approaches have certain limitations that must be resolved. Additionally, genetic testing can be expensive, is occasionally accompanied by delayed results, and detects variants of uncertain significance (VUSs) [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Exploratory Untargeted Metabolomics of Dried Blood Spot Samples from Newborns with Maple Syrup Urine Disease

Alotaibi,

AlMalki,

Al Mogren

et al. 2024

IJMS

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Currently, tandem mass spectrometry-based newborn screening (NBS), which examines targeted biomarkers, is the first approach used for the early detection of maple syrup urine disease (MSUD) in newborns, followed by confirmatory genetic mutation tests. However, these diagnostic approaches have limitations, demanding the development of additional tools for the diagnosis/screening of MUSD. Recently, untargeted metabolomics has been used to explore metabolic profiling and discover the potential biomarkers/pathways of inherited metabolic diseases. Thus, we aimed to discover a distinctive metabolic profile and biomarkers/pathways for MSUD newborns using untargeted metabolomics. Herein, untargeted metabolomics was used to analyze dried blood spot (DBS) samples from 22 MSUD and 22 healthy control newborns. Our data identified 210 altered endogenous metabolites in MSUD newborns and new potential MSUD biomarkers, particularly L-alloisoleucine, methionine, and lysoPI. In addition, the most impacted pathways in MSUD newborns were the ascorbate and aldarate pathways and pentose and glucuronate interconversions, suggesting that oxidative and detoxification events may occur in early life. Our approach leads to the identification of new potential biomarkers/pathways that could be used for the early diagnosis/screening of MSUD newborns but require further validation studies. Our untargeted metabolomics findings have undoubtedly added new insights to our understanding of the pathogenicity of MSUD, which helps us select the appropriate early treatments for better health outcomes.

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Branched-chain amino acids: physico-chemical properties, industrial synthesis and role in signaling, metabolism and energy production

Reifenberg,

Zimmer

2024

Amino Acids

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Branched-chain amino acids (BCAAs)—leucine (Leu), isoleucine (Ile), and valine (Val)—are essential nutrients with significant roles in protein synthesis, metabolic regulation, and energy production. This review paper offers a detailed examination of the physico-chemical properties of BCAAs, their industrial synthesis, and their critical functions in various biological processes. The unique isomerism of BCAAs is presented, focusing on analytical challenges in their separation and quantification as well as their solubility characteristics, which are crucial for formulation and purification applications. The industrial synthesis of BCAAs, particularly using bacterial strains like Corynebacterium glutamicum, is explored, alongside methods such as genetic engineering aimed at enhancing production, detailing the enzymatic processes and specific precursors. The dietary uptake, distribution, and catabolism of BCAAs are reviewed as fundamental components of their physiological functions. Ultimately, their multifaceted impact on signaling pathways, immune function, and disease progression is discussed, providing insights into their profound influence on muscle protein synthesis and metabolic health. This comprehensive analysis serves as a resource for understanding both the basic and complex roles of BCAAs in biological systems and their industrial application.

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Genetic analysis by targeted next-generation sequencing and novel variation identification of maple syrup urine disease in Chinese Han population

Cited by 4 publications

References 36 publications

Identification of gene mutations in six Chinese patients with maple syrup urine disease

Identification of gene mutations in six Chinese patients with maple syrup urine disease

Exploratory Untargeted Metabolomics of Dried Blood Spot Samples from Newborns with Maple Syrup Urine Disease

Branched-chain amino acids: physico-chemical properties, industrial synthesis and role in signaling, metabolism and energy production

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