背景:枫糖浆尿病(MSUD)是一种常染色体隐性代谢紊乱,起源于由BCKDHA编码的支链α-酮酸脱氢酶(BCKDH)复合物的缺陷,BCKDHB,还有DBT。这种情况表现出一系列症状和潜在的致命结果。尽管已经发现了许多与MSUD相关的BCKDH复合物基因的突变,特定基因型之间的关系仍有待完全阐明。
目的:我们的目的是预测这些基因突变的致病性,并建立基因型改变和MSUD临床表型之间的潜在联系。
方法:基于人群的回顾性队列。
方法:我们分析了浙江大学医学院附属儿童医院的20名MSUD患者(杭州,中国),记录于2010年1月至2023年5月。通过新生儿筛查,通过脚跟棒收集患者的血液样本,和氨基酸谱通过串联质谱法测量。采用计算机模拟方法评估致病性,稳定性,和生物物理特性。各种计算工具被用于评估,即PredictSNP,MAGPIE,iStable,对齐GVGD,ConSurf和SNP效应。
结果:我们检测到25个不同的突变,包括12个新的突变.与BCKDHA基因(20.0%)和DBT基因(26.7%)相比,BCKDHB基因最常受到影响(53.3%)。在计算机上,网络服务器预测所有新的突变都是致病的。
结论:这项研究强调了MSUD的遗传复杂性,并强调了早期发现和干预的重要性。将新生儿筛查与先进的测序方法相结合对于确保MSUD的精确诊断和有效管理至关重要。从而显著改善患有这种疾病的个体的预后。
BACKGROUND: Maple Syrup Urine Disease (MSUD) is an autosomal recessive metabolic disorder originating from defects in the branched-chain α-ketoacid dehydrogenase (BCKDH) complex encoded by BCKDHA, BCKDHB, and DBT. This condition presents a spectrum of symptoms and potentially fatal outcomes. Although numerous mutations in the BCKDH complex genes associated with MSUD have been identified, the relationship between specific genotypes remains to be fully elucidated.
OBJECTIVE: Our objective was to predict the pathogenicity of these genetic mutations and establish potential links between genotypic alterations and the clinical phenotypes of MSUD.
METHODS: Retrospective population-based cohort.
METHODS: We analyzed 20 MSUD patients from the Children\'s Hospital at Zhejiang University School of Medicine (Hangzhou, China), recorded from January 2010 to May 2023. Patients\' blood samples were collected by heel-stick through neonatal screening, and amino acid profiles were measured by tandem mass spectrometry. In silico methods were employed to assess the pathogenicity, stability, and biophysical properties. Various computation tools were utilized for assessment, namely PredictSNP, MAGPIE, iStable, Align GVGD, ConSurf and SNP effect.
RESULTS: We detected 25 distinct mutations, including 12 novel mutations. The BCKDHB gene was the most commonly affected (53.3%) compared to the BCKDHA gene (20.0%) and DBT gene (26.7%). In silico webservers predicted all novel mutations were disease-causing.
CONCLUSIONS: This study highlights the genetic complexity of MSUD and underscores the importance of early detection and intervention. Integrating neonatal screening with advanced sequencing methodologies is pivotal in ensuring precise diagnosis and effective management of MSUD, thereby significantly improving the prognosis for individuals afflicted with this condition.