Identifying and defining clinical phenotypes in mitochondrial disease

Abstract

Mitochondrial disease is an umbrella term that encompasses many clinically, biochemically and genetically heterogeneous conditions, which develop as a consequence of impaired oxidative phosphorylation. The diagnosis of mitochondrial disease requires coordinated multidisciplinary input, starting with a high index of clinical suspicion and meticulous assessment, followed by systematic biochemical and genetic investigations. More recently, the advent of next generation sequencing has rapidly identified novel disease genes and mechanisms in many previously undiagnosed cases. However, the aspects of natural history, disease progression and prognostication associated with many of these genetic variants require further elucidation. Furthermore, genotype-specific treatment guidance and surveillance strategy for complications are lacking in a routine clinical setting. The MRC Mitochondrial Disease Patient Cohort (UK) is a national collaborative project initiated by three centres of NHS Highly Specialised Service for Rare Mitochondrial Disorders: Newcastle, London and Oxford. Newcastle is the largest centre and has enrolled over 55% of patients (~800), to date. My aim has been to utilise the longitudinal data collected for this national cohort database to facilitate deep phenotyping of common and rare genetic variants, investigate phenotype-genotype correlations and identify treatable complications of mitochondrial disease. In this thesis, I show that sudden adult death syndrome and severe intestinal pseudo-obstruction are two previously under-recognized clinical entities associated with the m.3243A>G mutation, the most common pathogenic heteroplasmic mitochondrial DNA mutation in adult patients. The significant implications of these findings for clinical practice are highlighted. Extrapyramidal movement disorders are identified in 5% of patients followed up in Newcastle. I sought to determine the spectrum of extrapyramidal movement disorders in children and adults, and interrogate the genotype-phenotype correlation that may provide screening guidance for generalists. Mutations in RMND1 (Required for Meiotic Nuclear Division protein 1) and YARS2 (mitochondrial tyrosyl-tRNA synthetase) genes both result in combined mitochondrial respiratory chain deficiencies, but their clinical phenotypes are distinctive. Survival in patients with RMDN1 deficiency is influenced by the presence of kidney disease, as shown in the multi-centre collaborative study that I have drawn together. Myopathy, lactic acidosis and sideroblastic anaemia (MLASA) is a classic syndrome associated with mutations in YARS2. vi However, such a syndromic presentation is not always evident in all patients, and I sought to demonstrate that cardio-respiratory insufficiency is a prominent, potentially treatable, complication in patients who harbour mutations in YARS2 without having the complete MLASA phenotype. Understanding the spectrum of clinical phenotypes and providing appropriate, accurate genetic counselling for heteroplasmic mitochondrial DNA point mutations is challenging under normal circumstances, but this is particularly difficult when the specific mutation is rare and phenotypic data are scant. I sought to perform a detailed analysis of patients harbouring the m.13094T>C mutation in MT-ND5.