Clinical and genotypic aspects of mitochondrial disease

Abstract

Mitochondrial myopathies are a clinically multifarious group of genetic disorders that affect the central nervous system and skeletal muscles and other organs heavily dependent on aerobic metabolism. They are typically characterised by multi-system involvement and have extensive phenotypic and disease burden variability. These diseases are often relentlessly progressive with high morbidity and mortality. The biochemical and molecular basis of many of the common mitochondrial myopathies has been elucidated over the last decade, yet the association between mitochondrial gene mutations and clinical symptoms, requires further elucidation. I propose to clearly define the clinico-pathological and molecular features of adults with mitochondrial disease and evaluate if there is a clear correlation between clinical phenotype and the underlying genetic defect. Identifying clear clinical features should help guide genetic diagnosis and enable tailored counselling regarding potential disease progression. Unfortunately, to date, there are few effective treatments and no known cure for patients with mitochondrial myopathies. Exercise has been shown to hold significant positive effects upon skeletal muscle function and perceived health- related quality of life in patients with mitochondrial myopathies. The molecular basis of many of the common mitochondrial disorders has been elucidated over the last decade and although there is a vast spectrum of phenotypic expression throughout different genotypes, common symptoms are reported. Perceived fatigue is often a prominent symptom in patients with mitochondrial disease but to date, its prevalence, severity and aetiology is poorly understood. I wish to determine the prevalence and nature of perceived fatigue in a large, genetically heterogeneous group of patients with mitochondrial disease and systematically assess potential covariates of fatigue compared to healthy controls and patients with Myalgic Encephalopathy /Chronic Fatigue Syndrome. Health-related quality of life is important for understanding the impact and progression of chronic disease and is increasingly recognised as a fundamental patient-based outcome measure in both clinical intervention and research. Generic outcome measures have been extensively validated to assess health-related quality of life across populations and different disease states. However, due to their inclusive construct, it is acknowledged that not all relevant aspects of a specific illness may be captured. Hence there is a need to develop a disease-specific health-related quality of life measures that centre on symptoms characteristic of a specific disease or condition and their impact. SF-36 and its abbreviated version SF-12 are currently the only tools used routinely for measuring patient-reported outcomes in our patients with mitochondrial myopathies. I wish to explore the conceptualisation, development and preliminary psychometric evaluation (validity and reliability) of a mitochondrial disease -specific health-related quality of life measure, which may be used both in research and clinical settings. Indeed, in a condition where the natural history of the disease is poorly understood and therapeutic options are limited, long-term preservation of health-related quality of life in patients with mitochondrial disease poses a real challenge.