Clinical Spectrum, Heteroplasmy‐Phenotype Correlation, and Prognosis of the MT‐ND3 m.10191 T > C Mutation
Zimeng He, Huafang Jiang, Tongyue Li, Yang Liu, Ying Zou, Chaolong Xu, Zhimei Liu, Danmin Shen, Ruoyu Duan, Minhan Song, Yunxi Zhang, Zixuan Zhang, Mingxi Sun, Rui Shen, Hong Xue, Fang FangABSTRACT
Aim
To systematically characterize the phenotypic spectrum, neuroimaging features, heteroplasmy‐phenotype correlation, and prognosis of the m.10191 T > C mutation.
Methods
We collected and analyzed data from 52 patients (14 newly recruited; 38 from literature). Phenotypes were pre‐classified as Leigh syndrome (LS), Leigh‐like syndrome (LLS), MELAS/LS overlap syndrome, and MELAS‐like syndrome. Neuroimaging data were subjected to statistical analysis to explore inter‐lesional associations and lesion‐symptom correlations. Heteroplasmy level underwent k‐means clustering and latent class analysis (LCA) to define data‐driven subgroups and model genotype–phenotype correlations. Prognostic factors were evaluated through Bayesian logistic regression, and survival analysis was conducted.
Results
The cohort exhibited phenotypic heterogeneity, dominated by LS (46.2%). Key features included epilepsy, developmental delay, and dystonia. Globus pallidus involvement frequently co‐occurred with midbrain and pontine lesions. Heteroplasmy level differed significantly across phenotypes. LCA identified three classes corresponding to clinical phenotypes. High heteroplasmy level, medullary involvement, and severe hyperlactatemia were associated with disease progression. Survival analysis indicated a 5 year survival rate of 80.0%, with high heteroplasmy level, hypotonia, and cerebellar lesions predicting poorer survival.
Interpretation
The m.10191 T > C mutation is linked to a continuous clinical spectrum correlated with heteroplasmy level. Specific clinical and neuroimaging features serve as valuable biomarkers for phenotypic classification and prognostic assessment.