Natural history study of childhood-onset mitochondrial disorders by using outcome measure assessments

Abstract

This thesis aims to study the natural history of two childhood-onset mitochondrial disorders, Leigh syndrome and RRM2B-related disease. Current studies have not precisely explored the longitudinal aspects of these disorders to outline their trajectories and the utility of outcome measures to objectively characterise their changes over time. Therefore, the natural history of these two disorders needs a better definition. Using the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) in a large cohort of children with Leigh syndrome caused by various genotypes, I discovered that severe disease burden (high NPMDS scores) and rapid disease progression (rate of NPMDS change per annum > 3) were associated with greater rates of mortality. I also identified several factors such as pathogenic variants in the SURF1 gene and certain brain imaging changes, that adversely influence their outcomes. In a separate cohort of patients with autosomal recessive pathogenic variants in their RRM2B gene, I have also objectively determined their disease burden and progression. I have utilised a range of disease rating scales, performance outcome measures (spirometry, nine-hole peg test and muscle dynamometry) and functional tests (six-minute walk, sit-to-stand and water swallow tests) to provide new natural history data of this rare disorder. These patients performed significantly worse than their predicted values. Of note, their lung forced vital capacity (FVC) deteriorated about 5% per annum. To understand the individual impact of the RRM2B-related disorder, I have also explored the use of several patient-reported outcome measures and I found the poor quality of life faced by these patients. All the discoveries in this thesis will serve as robust data for the development of interventional clinical trials in these two conditions where a control arm might not feasible, for the prognostication of disease course in clinical practice, and more importantly, for the provisions of better care for these patients in the future.