Phenotypic heterogeneity in m.3243A>G mitochondrial disease: The role of nuclear factors

Objective The pathogenic mitochondrial DNA m.3243A>G mutation is associated with a wide range of clinical features, making disease prognosis extremely difficult to predict. We aimed to understand the cause of this heterogeneity. Methods We examined the phenotypic profile of 238 adult m.3243A>G carriers (patients and asymptomatic carriers) from the UK MRC Mitochondrial Disease Patient Cohort using the Newcastle Mitochondrial Disease Adult Scale. We modeled the role of risk factors for the development of specific phenotypes using proportional odds logistic regression. As mitochondria are under the dual control of their own and the nuclear genome, we examined the role of additive nuclear genetic factors in the development of these phenotypes within 46 pedigrees from the cohort. Results Seizures and stroke‐like episodes affect 25% and 17% of patients, respectively; more common features include hearing impairment, gastrointestinal disturbance, psychiatric involvement, and ataxia. Age, age‐adjusted blood heteroplasmy levels, and sex are poor predictors of phenotypic severity. Hearing impairment, diabetes, and encephalopathy show the strongest associations, but pseudo‐ R 2 values are low (0.14–0.17). We found a high heritability estimate for psychiatric involvement ( h 2 =0.76, P = 0.0003) and moderate estimates for cognition ( h 2 =0.46, P = 0.0021), ataxia ( h 2 = 0.45, P = 0.0011), migraine ( h 2 = 0.41, P = 0.0138), and hearing impairment (h 2 = 0.40, P = 0.0050). Interpretation Our results provide good evidence for the presence of nuclear genetic factors influencing clinical outcomes in m.3234A>G‐related disease, paving the way for future work identifying these through large‐scale genetic linkage and association studies, increasing our understanding of the pathogenicity of m.3243A>G and providing improved estimates of prognosis.