Abstract
Over 20years ago single clonal deletions were the first mitochondrial DNA (mtDNA) genetic defects described in association with human disease. Since then very large numbers of children and adults harbouring such deletions have been described and it is clear they are an important cause of human mitochondrial disease. However, there still remain many important challenges in relation to our understanding of mechanisms leading to deletion formation and propagation and in relation to the factors determining the complex and varying relationship between genotype and clinical phenotype. Although multidisciplinary team care is essential and can improve quality of life and outcomes for patients, a definitive molecular treatment for single mtDNA deletions remains an important translational research goal. Patients with mtDNA deletions exhibit a very wide range of different clinical phenotypes with marked variation in age at onset and disease severity. Single mtDNA deletions may enter into the differential diagnosis of many different paediatric and adult presentations across a wide range of medical specialties, although neurological presentations are amongst the most common. In this review, we examine the molecular mechanisms underpinning mtDNA replication and we consider the hypotheses proposed to explain the formation and propagation of single large-scale mtDNA deletions. We also describe the range of clinical features associated with single mtDNA deletions, outline a molecular diagnostic approach and discuss current management including the role of aerobic and resistance exercise training programmes.
Highlights
Mitochondria are double membrane-bound intracellular organelles that form large branching reticular networks inside all eukaryotic cells except erythrocytes
Clinical syndromes associated with single mitochondrial DNA (mtDNA) deletions Pearson marrow-pancreas syndrome Kearns–Sayre syndrome Progressive external ophthalmoplegia Isolated anaemia ± lactic acidosis Pancreatic exocrine insufficiency without marrow involvement Pancytopaenia and tubulopathy Tubulopathy and hypoparathyroidism ± encephalopathy Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes Myoclonic epilepsy with ragged red fibres Leigh syndrome Diabetes and deafness
These include subsarcolemmal mitochondrial accumulation demonstrated on routine histochemical staining as “ragged-red fibres” (RRF) in the modified Gomori trichrome stain, or as succinate dehydrogenase (SDH)-positive fibres
Summary
Mitochondria are double membrane-bound intracellular organelles that form large branching reticular networks inside all eukaryotic cells except erythrocytes. It is generally considered that mtDNA deletions arise during replication through slipped-strand mispairing between direct homologous base-pairs (Fig. 1A–D) [36] This mechanism assumes the asynchronous strand displacement model of mtDNA replication, since it is reliant on the presence of long stretches of single-stranded DNA which do not exist in the coupled and RITOLS replication models. If a deleted mtDNA molecule or homoplasmic deleted unit is selected for clonal expansion after the bottleneck, an accumulation of abnormally high levels of deleted mtDNA molecules might occur in a small number of mature oocytes in the unaffected mother This would predict a 5/100,000 risk of offspring inheriting high levels of the pathogenic mtDNA deletion, which roughly corresponds to the incidence of mtDNA deletion disorders in the general population [22]. There is an estimated 4% risk of subsequent transmission from an affected woman [46]
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