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Forecasting stroke-like episodes and outcomes in mitochondrial disease
Yi Shiau Ng1,2,3, Nichola Z Lax1, Alasdair P Blain1
1Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute; NIHR Newcastle Biomedical Research Centre and Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
Brain : a Journal of Neurology
|December 20, 2021
Summary
Mitochondrial stroke-like episodes share features with epilepsy. A new model predicts risk for the m.3243A>G variant, aiding genetic counseling and prognostication.
Area of Science:
- Neurology
- Genetics
- Pathology
Background:
- Mitochondrial diseases, including mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, can manifest with stroke-like episodes.
- Understanding the characteristics and predictors of these episodes is crucial for patient management and prognostication.
- Previous studies have not fully elucidated the clinico-radiopathological correlates and risk factors for mitochondrial stroke-like episodes.
Purpose of the Study:
- To determine the clinical, radiological, EEG, genetic, and neuropathological characteristics of mitochondrial stroke-like episodes.
- To identify associated risk predictors for stroke-like episodes in patients with mitochondrial diseases.
- To develop a multivariable prediction model for forecasting stroke-like episode risk, particularly for the common m.3243A>G variant.
Main Methods:
- Retrospective, multicentre, observational cohort study of 111 patients with genetically determined mitochondrial disease and stroke-like episodes (1998-2018).
- Inclusion of 26 post-mortem cases from the Newcastle Brain Tissue Resource.
- Analysis of clinical, radiological, EEG, genetic, and neuropathological data; development of a multivariable prediction model.
Main Results:
- The m.3243A>G variant was the most common cause (n=66), followed by POLG variants (n=22).
- Stroke-like episodes occurred across a wide age range, with 32% presenting after age 40.
- POLG-related episodes showed more aggressive disease trajectories. Key risk predictors for m.3243A>G variant included BMI, heteroplasmy, hearing loss, and serum lactate. A prediction model showed good discrimination (AUC=0.87).
- Neurodegeneration was more pronounced in mtDNA variant carriers (brain atrophy 90% vs 44%; reduced brain weight).
Conclusions:
- Mitochondrial stroke-like episodes exhibit diverse clinico-radiological and EEG features, often resembling medically refractory epilepsy.
- Early recognition and aggressive treatment of seizures may mitigate neuronal loss and disease burden.
- The developed risk-prediction model for the m.3243A>G variant can enhance genetic counseling and prognostication.
