Sarah J Pickett1, John P Grady1, Yi Shiau Ng1, Ian Wilson2, Catherine L Feeney1, Alexandra A Bright1, Andrew M Schaefer1, Grainne S Gorman1,  Heather J Cordell2, Doug M Turnbull1, Robert McFarland1, Robert W Taylor1

1Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK
2 Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is seen in ~15% patients carrying the pathogenic m.3243A>G mitochondrial DNA mutation; remaining cases display a wide range of clinical features, making disease prognosis extremely difficult to predict.

To understand the factors underlying this heterogeneity, we examined the phenotypic profile of 238 m.3243A>G carriers from the UK MRC Mitochondrial Disease Patient Cohort Study using the previously-validated Newcastle Mitochondrial Disease Adult Scale (NMDAS). Seizures, encephalopathy and stroke-like episodes affect 16%-24% of patients; more common phenotypes include hearing impairment, diabetes and cerebellar ataxia. Modelling the role of age, age-adjusted blood heteroplasmy level and sex as risk factors reveals that they are poor predictors of phenotypic severity. Hearing impairment, diabetes and cerebellar ataxia show the strongest associations but pseudo-R2 values are low (0.21-0.25).

As mitochondrial function is under bigenomic control, we examined the role of additive nuclear genetic factors using the SOLAR software package. In our cohort we identified 52 pedigrees (containing 185 m.3243A>G carriers), ranging in size from 2-11 individuals and 2-4 generations. We found a high estimate of heritability for psychiatric disturbance (h2=0.72, P=0.0004) and moderate estimates for cognitive impairment (h2=0.44, P=0.0036), cerebellar ataxia (h2=0.43, P=0.0028), migraine (h2=0.41, P=0.0148) and hearing impairment (h2=0.39, P=0.0062).

Our data provide strong evidence for the presence of nuclear genetic factors influencing several clinical outcomes in m.3234A>G-related disease, paving the way for future work to identify these through large-scale genetic linkage and association studies, increasing our understanding of the cellular and tissue-specific effects in m.3243A>G-related disease and providing improved estimates of disease prognosis to patients.