Xu Xuebi, Xia Junhui, Xu Fei, Wang Mingshan, Yang Lihong, Chen Xiaoli
Department of Neurology, The First Affiliated Hospital of Wenzhou Medical University, Shangcai Village, Ouhai District, Wenzhou, Zhejiang, China.
Department of Clinical Laboratory, Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Orphanet J Rare Dis. 2025 Aug 18;20(1):439. doi: 10.1186/s13023-025-03962-3.
Mitochondrial neurogastrointestinal encephalopathy (MNGIE) is a rare autosomal recessive disorder caused by variants in the TYMP gene, which encodes thymidine phosphorylase (TP). It is characterized by multisystem involvement, with prominent gastrointestinal, neurological, and systemic manifestations that typically exhibit progressive worsening over time.
We characterized a multigenerational MNGIE family through comprehensive proband analysis, identifying compound heterozygous TYMP variants (c.131G > C, p.Arg44Pro and c.1268T>G, p.Leu423Arg in trans) as the molecular basis of disease. Extended family testing for genetic counseling confirmed no secondary pathogenic variants. Muscle biopsies were analyzed using comprehensive staining techniques. Genomic analysis involved next-generation sequencing (NGS) of the proband's DNA and Sanger sequencing of family members' DNA to confirm variants. In silico analysis utilized bioinformatics tools and protein modeling to predict pathogenicity and assess structural impacts, with variant classification adhering to American College of Medical Genetics and Genomics(ACMG) guidelines. Additionally, a literature review of Chinese MNGIE cases was conducted to contextualize the findings.
The proband exhibited characteristic MNGIE features, including gastrointestinal dysmotility, diffuse leukoencephalopathy on brain MRI (magnetic resonance imaging), and electrophysiologically confirmed peripheral neuropathy. Muscle biopsy revealed ragged red fibers, cytochrome c oxidase-deficient fibers, and enhanced succinate dehydrogenase activity in blood vessels, consistent with mitochondrial dysfunction. Genetic analysis identified a novel TYMP variant (c.1268T > G, p.Leu423Arg) and a known variant (c.131G > C, p.Arg44Pro) in the proband, both classified as likely pathogenic according to ACMG guidelines. Molecular analysis of other 11 family members detected heterozygous carriers of either the c.1268T > G or c.131G > C variant in six asymptomatic individuals. In silico analysis confirmed that both variants are highly conserved and likely pathogenic. Protein modeling revealed that both variants compromise structural integrity and conformation, impairing TP function. Homozygous or compound heterozygous missense variants were identified as the predominant genetic alterations in 16 Chinese MNGIE cases, with gastrointestinal and neurological symptoms being the most common clinical manifestations.
This study enriches the variant spectrum in Chinese patients, highlights the importance of early diagnosis prior to the onset of cachexia and irreversible tissue damage, and enhances the understanding of genetic heterogeneity.
线粒体神经胃肠性脑病（MNGIE）是一种罕见的常染色体隐性疾病，由TYMP基因变异引起，该基因编码胸苷磷酸化酶（TP）。其特征为多系统受累，具有突出的胃肠道、神经和全身表现，通常随时间逐渐恶化。
我们通过对先证者进行全面分析，对一个多代MNGIE家系进行了特征描述，确定复合杂合TYMP变异（反式的c.131G＞C，p.Arg44Pro和c.1268T＞G，p.Leu423Arg）为疾病的分子基础。为进行遗传咨询而对大家庭进行的检测证实没有继发性致病变异。使用全面的染色技术对肌肉活检样本进行分析。基因组分析包括对先证者DNA进行二代测序（NGS）以及对家庭成员DNA进行桑格测序以确认变异。计算机分析利用生物信息学工具和蛋白质建模来预测致病性并评估结构影响，变异分类遵循美国医学遗传学与基因组学学会（ACMG）指南。此外，还对中国MNGIE病例进行了文献综述，以便将研究结果置于背景中。
先证者表现出典型的MNGIE特征，包括胃肠动力障碍、脑部磁共振成像（MRI）显示弥漫性白质脑病以及电生理证实的周围神经病变。肌肉活检显示有破碎红纤维、细胞色素c氧化酶缺陷纤维以及血管中琥珀酸脱氢酶活性增强，与线粒体功能障碍一致。遗传分析在该先证者中鉴定出一个新的TYMP变异（c.1268T＞G，p.Leu423Arg）和一个已知变异（c.131G＞C，p.Arg44Pro），根据ACMG指南，这两个变异均被分类为可能致病。对其他11名家庭成员的分子分析在6名无症状个体中检测到c.1268T＞G或c.131G＞C变异的杂合携带者。计算机分析证实这两个变异高度保守且可能致病。蛋白质建模显示这两个变异均破坏结构完整性和构象，损害TP功能。在16例中国MNGIE病例中，纯合或复合杂合错义变异被确定为主要的遗传改变，胃肠道和神经症状是最常见的临床表现。
本研究丰富了中国患者的变异谱，强调了在恶病质和不可逆组织损伤发生之前进行早期诊断的重要性，并增进了对遗传异质性的理解。
