Disease progression in patients with single, large-scale mitochondrial DNA deletions

Grady, John P.; Campbell, Georgia; Ratnaike, Thiloka; Blakely, Emma L.; Falkous, Gavin; Nesbitt, Victoria; Schaefer, Andrew M.; McNally, Richard J.Q.; Gorman, Gráinne; Taylor, Robert W.; Turnbull, Doug M.; McFarland, Robert

doi:10.1093/brain/awt321

Cited by 105 publications

(77 citation statements)

References 59 publications

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“…We have studied a limited number of patients in detail and, except for 1 patient, all had a CPEO phenotype. Previous studies from our cohort have used statistical modeling to demonstrate that a variety of outcome measures such as age at onset of symptoms and progression of disease burden, as measured by the Newcastle Mitochondrial Disease Adult Scale, are significantly correlated ( p < 0.05) with the size of the deletion, the mtDNA deletion level in skeletal muscle, and the position of the mtDNA deletion within the genome 16. With this new information about the presence of different biochemical profiles associated with different deletions, it will be of interest to determine whether there is any link between the biochemical defect and the clinical phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…Larger mtDNA deletions have been associated with more severe disease and earlier disease onset 15, 16, 17, 18, 19. Whereas a highly significant,20 significant,15, 16, 21, 22 weak,18, 23 or no24 correlation has been reported between the percentage of COX‐deficient fibers and the degree of mtDNA heteroplasmy, most studies found no correlation between the biochemical defects and the nature of the deletion (the number of protein‐encoding genes and the complexes affected by the deletion) or deletion size alone 4, 15, 20, 22, 25. Interestingly, a higher proportion of COX‐deficient ragged‐red fibers was found in patients with deletions encompassing the 3 mtDNA‐encoded COX genes,26, 27 whereas an isolated complex I deficiency was reported in patients with smaller mtDNA deletions removing only complex I genes 26…”

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confidence: 99%

“…Therefore, fibers exhibiting high levels of deficiency involving other respiratory chain complexes might be missed. Despite few exceptions,16, 17, 19, 26 patients were also often evaluated as one group, without discriminating deletions of different sizes and locations. Such an analysis cannot determine whether the nature of the deletion influences biochemical and clinical profiles.…”

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Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Rocha

Rosa

Grady

et al. 2018

Annals of Neurology

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ObjectiveSingle, large‐scale deletions in mitochondrial DNA (mtDNA) are a common cause of mitochondrial disease. This study aimed to investigate the relationship between the genetic defect and molecular phenotype to improve understanding of pathogenic mechanisms associated with single, large‐scale mtDNA deletions in skeletal muscle.MethodsWe investigated 23 muscle biopsies taken from adult patients (6 males/17 females with a mean age of 43 years) with characterized single, large‐scale mtDNA deletions. Mitochondrial respiratory chain deficiency in skeletal muscle biopsies was quantified by immunoreactivity levels for complex I and complex IV proteins. Single muscle fibers with varying degrees of deficiency were selected from 6 patient biopsies for determination of mtDNA deletion level and copy number by quantitative polymerase chain reaction.ResultsWe have defined 3 “classes” of single, large‐scale deletion with distinct patterns of mitochondrial deficiency, determined by the size and location of the deletion. Single fiber analyses showed that fibers with greater respiratory chain deficiency harbored higher levels of mtDNA deletion with an increase in total mtDNA copy number. For the first time, we have demonstrated that threshold levels for complex I and complex IV deficiency differ based on deletion class.InterpretationCombining genetic and immunofluorescent assays, we conclude that thresholds for complex I and complex IV deficiency are modulated by the deletion of complex‐specific protein‐encoding genes. Furthermore, removal of mt‐tRNA genes impacts specific complexes only at high deletion levels, when complex‐specific protein‐encoding genes remain. These novel findings provide valuable insight into the pathogenic mechanisms associated with these mutations. Ann Neurol 2018;83:115–130

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Section: Discussionmentioning

confidence: 99%

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Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Rocha

Rosa

Grady

et al. 2018

Annals of Neurology

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“…However, recent studies also suggest a correlation among deletion size, heteroplasmy, and clinical severity (Grady et al, 2014).…”

Section: Deletionsmentioning

confidence: 99%

Mitochondrial DNA-related disorders: emphasis on mechanisms and heterogeneity

Cagin¹,

Enrı́quez²

2015

Turk J Biol

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IntroductionMitochondria are the organelles with the main responsibility for energy production in cells, generated in the form of ATP by oxidative phosphorylation (OXPHOS). Mitochondria are additionally involved in many other important processes, including apoptosis and calcium homeostasis (Pozzan et al., 2000;Newmeyer and Ferguson-Miller, 2003). Furthermore, mitochondria are the main site of the production of reactive oxygen species (ROS). The tricarboxylic acid (TCA) cycle, which in addition to its contribution to ATP production also generates several important metabolic intermediates, occurs in mitochondria (Boveris et al., 1972).Mitochondria contain their own genetic material, called mitochondrial DNA (mtDNA), a 16,569-bp-long, doublestranded, circular molecule containing just 37 genes. Only 13 of these genes encode proteins, all of them contributing to the formation of OXPHOS complexes through association with nuclear DNA (nDNA)-encoded proteins. The remaining genes encode 22 tRNAs and 2 rRNAs (Anderson et al., 1981). The copy number of mtDNA varies depending on the cell type and energy demand of the tissue.Replication of mtDNA is dependent on proteins encoded by nDNA and imported to mitochondria. Therefore, mtDNArelated diseases can be caused not only by mutations in mtDNA but also by defects in nDNA-encoded factors required for mtDNA replication (Figure 1). This dualdependence of mtDNA integrity is largely responsible for the heterogeneous nature of mtDNA-related diseases.The history of research on mtDNA-related diseases is relatively short, with the first disease-causing mtDNA mutations reported in 1988 (Holt et al., 1988;Wallace et al., 1988). These two ground-breaking studies paved the way to the discovery and characterization of a large number of mtDNA mutations, and at least 300 pathogenic mtDNA mutations have now been identified (www.mitomap.org). Due to the high degree of heterogeneity in mtDNA-related diseases, it is very hard to quantify their prevalence. Studies have been conducted to define the severity of mtDNA mutations in specific populations; however, a worldwide study in this field is missing. A study based in northeastern England reported that mtDNA-related diseases occurred at a frequency of 1 in 10,000 in working-age adults with a further 1 in 6000 people (below retirement age) at Abstract: Mitochondrial diseases are a heterogeneous group of disorders that are currently the focus of intense research. The many cell functions performed by mitochondria include ATP production, calcium homeostasis, and apoptosis. One of the unique properties of mitochondria is the existence of a separate mitochondrial genome (mitochondrial DNA, mtDNA) found in varying copy numbers and containing 37 genes, 13 of them encoding proteins. All 13 mitochondrially encoded proteins form part of oxidative phosphorylation complexes through combination with approximately 100 nuclear DNA-encoded proteins. Coregulation of nDNA and mtDNA is therefore essential for mitochondrial function, and this coregulation contributes t...

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“…Nevertheless, some clinical features are more common in certain genotypes. Thus, for example, central nervous system (CNS) involvement is common in the m.3243A>G and m.8344A>G point mutations,5 but relatively rare in patients with single mtDNA deletions 6…”

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Epilepsy in adults with mitochondrial disease: A cohort study

Whittaker

Devine

Gorman

et al. 2015

Annals of Neurology

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ObjectiveThe aim of this work was to determine the prevalence and progression of epilepsy in adult patients with mitochondrial disease.MethodsWe prospectively recruited a cohort of 182 consecutive adult patients attending a specialized mitochondrial disease clinic in Newcastle upon Tyne between January 1, 2005 and January 1, 2008. We then followed this cohort over a 7‐year period, recording primary outcome measures of occurrence of first seizure, status epilepticus, stroke‐like episode, and death.ResultsOverall prevalence of epilepsy in the cohort was 23.1%. Mean age of epilepsy onset was 29.4 years. Prevalence varied widely between genotypes, with several genotypes having no cases of epilepsy, a prevalence of 34.9% in the most common genotype (m.3243A>G mutation), and 92.3% in the m.8344A>G mutation. Among the cohort as a whole, focal seizures, with or without progression to bilateral convulsive seizures, was the most common seizure type. Conversely, all of the patients with the m.8344A>G mutation and epilepsy experienced myoclonic seizures. Patients with the m.3243A>G mutation remain at high risk of developing stroke‐like episodes (1.16% per year). However, although the standardized mortality ratio for the entire cohort was high (2.86), this ratio did not differ significantly between patients with epilepsy (2.96) and those without (2.83).InterpretationEpilepsy is a common manifestation of mitochondrial disease. It develops early in the disease and, in the case of the m.3243A>G mutation, often presents in the context of a stroke‐like episode or status epilepticus. However, epilepsy does not itself appear to contribute to the increased mortality in mitochondrial disease. Ann Neurol 2015;78:949–957

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Disease progression in patients with single, large-scale mitochondrial DNA deletions

Cited by 105 publications

References 59 publications

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Pathological mechanisms underlying single large‐scale mitochondrial DNA deletions

Mitochondrial DNA-related disorders: emphasis on mechanisms and heterogeneity

Epilepsy in adults with mitochondrial disease: A cohort study

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