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Disorders of mitochondrial DNA (mtDNA) maintenance are a major cause of sporadic and inherited neurologic disease,1 but the underlying nuclear gene defects have yet to be identified in many patients. Following the recent description of multiple mtDNA deletions in seven families with mutations in OPA1 ,2–4 we determined the frequency of OPA1 mutations in adult patients with multiple mtDNA deletions who did not have mutations in POLG1, POLG2, SLC25A4, and PEO1 . ### Methods. OPA1 and exon-intron boundaries was sequenced in 21 probands with a mosaic defect of cytochrome c oxidase (COX) and multiple deletions of mtDNA in skeletal muscle (table; e-methods on the Neurology ® Web site at www.neurology.org). View this table: Table Clinical, histochemical, and genetic findings in 21 probands ### Results. Eighteen patients had synonymous substitutions in OPA1 , or single nucleotide polymorphisms (SNPs) present in >1% of the control population (tables e-1 and e-2). c.575C>T was detected in 3.5% of 144 matched population controls (95% CI = 1.8–6.4). Pathogenic variants were detected in three subjects (14.2% of the 21): c.1334G>A/p.R445H in patients 16 and 20 …

International audience; Mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance cause a wide range of clinical phenotypes associated with the secondary accumulation of multiple mtDNA deletions in affected tissues. The majority of families with autosomal dominant progressive external ophthalmoplegia (PEO) harbour mutations in genes encoding one of three well-characterized proteins—polγ, Twinkle or Ant 1. Here we show that a heterozygous mis-sense mutation in OPA1 leads to multiple mtDNA deletions in skeletal muscle and a mosaic defect of cytochrome c oxidase (COX). The disorder presented with visual failure and optic atrophy in childhood, followed by PEO, ataxia, deafness and a sensory-motor neuropathy in adult life. COX-deficient skeletal muscle fibres contained supra-threshold levels of multiple mtDNA deletions, and genetic linkage, sequencing and expression analysis excluded POLG1, PEO1 and SLC25A4, the gene encoding Ant 1, as the cause. This demonstrates the importance of OPA1 in mtDNA maintenance, and implicates OPA1 in diseases associated with secondary defects of mtDNA.

Defects of the mitochondrial respiratory chain give rise to a wide range of clinical disorders ranging from isolated myopathy to multisystem disease. These conditions are now being increasingly recognized, especially among the young, and are significant causes of morbidity and mortality. Our understanding of both respiratory-chain function and the disorders which result from its failure has grown enormously since Luft and colleagues described the first case in 1962 (Luft et al, 1962). However, owing to the complexity of the system we still have a great deal yet to learn. This chapter attempts to provide a general understanding of this unique and vital pathway in energy metabolism. We explore how its dysfunction may produce both local and systemic defects and what is known about the inheritance of these disorders. The last two sections deal exclusively with the methods used for investigation and describe some of the clinical presentations associated with defects of each individual complex.

Background: In clinical practice, mitochondrial disease is seldom considered until a variable combination of seizures, alteration in tone, muscle weakness, and developmental problems is evident. However, it is not uncommon for one symptom to occur in isolation and dominate the clinical phenotype. We report six patients from two families where dystonia was the principal clinical manifestation. A mitochondrial etiology was considered in each case because of the association of dystonia with other less prominent clinical features such as epilepsy. Methods: Histochemical and biochemical analyses were undertaken in skeletal muscle biopsies from individuals in both families. Sequencing of skeletal muscle mtDNA was also performed and suspected mutations were quantified by hot last cycle PCR-RFLP or primer extension assay. Functional consequences of one of the mutations were investigated by measurement of steady state levels of mitochondrial tRNA. Results: Two distinct mitochondrial pathologies were identified: a novel, homoplasmic mitochondrial tRNA Cys ( MTTC ) mutation and the primary, m.11778G>A Leber hereditary optic neuropathy (LHON) mutation. The mild nature of both mutations has permitted very high levels of mutated mtDNA to accumulate. Patients with the mutation in the MTTC gene have no wild type mtDNA detectable and although the LHON mutation is heteroplasmic in the patients we report, it is commonly observed to be homoplasmic. Conclusions: The mitochondrial etiology identified in these patients emphasizes the pathologic potential of homoplasmic mutations and has important implications for the investigation and genetic counseling of families where dystonia is the principal clinical feature. We advocate that mitochondrial disease should be given serious consideration in patients with familial, progressive dystonia, particularly when additional neurologic features such as epilepsy are present.

Mitochondrial DNA (mtDNA) disease is an important genetic cause of neurological disability. A variety of different clinical features are observed and one of the most common phenotypes is MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes). The majority of patients with MELAS have the 3243A>G mtDNA mutation. The neuropathology is dominated by multifocal infarct-like lesions in the posterior cortex, thought to underlie the stroke-like episodes seen in patients. To investigate the relationship between mtDNA mutation load, mitochondrial dysfunction and neuropathological features in MELAS, we studied individual neurones from several brain regions of two individuals with the 3243A>G mutation using dual cytochrome c oxidase (COX) and succinate dehydrogenase (SDH) histochemistry, and Polymerase Chain Reaction Restriction Fragment Lenght Polymorphism (PCR-RFLP) analysis. We found a low number of COX-deficient neurones in all brain regions. There appeared to be no correlation between the threshold level for the 3243A>G mutation to cause COX deficiency within single neurones and the degree of pathology in affected brain regions. The most severe COX deficiency associated with the highest proportion of mutated mtDNA was present in the walls of the leptomeningeal and cortical blood vessels in all brain regions. We conclude that vascular mitochondrial dysfunction is important in the pathogenesis of the stroke-like episodes in MELAS patients. As migraine is a commonly encountered feature in MELAS, we propose that coupling of the vascular mitochondrial dysfunction with cortical spreading depression (CSD) might underlie the selective distribution of ischaemic lesions in the posterior cortex in these patients.

Publisher Summary This chapter describes the current and future prospects for the treatment of mitochondrial disorders. Whether the primary genetic lesion occurs in the mitochondrial genome (mitochondrial DNA [mtDNA]) or a nuclear gene, all mitochondrial disorders result from the progressive decline in the ability to supply cellular energy demands in the form of available adenosine triphosphate (ATP). The pivotal role occupied by the respiratory chain in cellular metabolism consequently poses acute difficulties in trying to overcome the respiratory defect. Biochemical strategies to increase the production of ATP have sought to bypass the block in electron transfer using artificial electron acceptors, enhance residual enzyme activity, or minimize the free radical-induced damage that occurs as a result of a defective respiratory chain. As mitochondrial dysfunction can present with problems in different systems, it is vital that diverse clinical problems be managed correctly through appropriate supportive medical care. Although these aids are no substitutes for treatment per se, particular supportive measures may significantly improve an individual's quality of life and help to counteract the progressive, disabling course of these disorders.

Although the association between celiac disease and progressive myoclonic ataxia is well recognized, in each of the reported cases the neurologic features began in middle adult life and usually in patients who had clinical or laboratory evidence of malabsorption. We report a case of progressive myoclonic ataxia and epilepsy (Ramsay Hunt syndrome) that began in childhood. In this patient there were no features suggestive of gluten intolerance. The presence of antigliadin antibodies in the serum and CSF suggested celiac disease was the cause of the patient's neurologic syndrome. Duodenal morphologic abnormalities reversed with treatment but no major changes were noted in the patient. Celiac disease should be considered in the differential diagnosis of myoclonic ataxia at any age, even in the absence of clinical evidence of gluten-sensitive enteropathy.

Background Cardiomyopathy is an independent predictor of morbidity and early mortality in mitochondrial DNA disease, and occurs in 20%–40% of adult patients harbouring the common m.3243A>G mutation, usually with a hypertrophic phenotype. Pathogenetic mechanisms are unclear yet no detailed study of myocardial structure, function and bioenergetics has been performed in m.3243A>G mutation carriers to identify early markers of cardiac involvement. Methods Cardiac MRI was performed in 20 adult patients (10 males, mean age 38.7±13.1 years) harbouring the m.3243A>G mutation, without clinical evidence of cardiac involvement on routine ECG and echocardiographic screening, and 20 age- and gender-matched healthy controls (10 males, 38.4±14.2 years): (1) phosphorus-31 magnetic resonance spectroscopy, (2) cine imaging (3), cardiac tagging, and (4) late gadolinium enhancement (LGE) imaging on a Philips Intera Achieva 3 Tesla scanner. Clinical disease burden was determined using: (1) the Newcastle Mitochondrial Disease Adult Scale (NMDAS), a 29-domain validated scoring system with a single cardiac domain, and (2) urinary mutation load, the best predictor of overall clinical outcome in m.3243A>G mutation carriers. Results Compared to control subjects and following Bonferroni correction for multiple comparisons, patients had increased left ventricular mass index (LVMI), LV mass to end-diastolic volume ratio (M/V ratio), LV radial wall thicknesses (all p Conclusions Concentric remodelling and subendocardial dysfunction are prevalent in m.3243A>G mutation carriers without clinical cardiac disease. Assessment of myocardial deformation may be useful in monitoring disease progression or response to early intervention. Patients with higher urinary mutation loads and disease burden may be at increased risk of cardiac involvement.

Background Mitochondrial respiratory chain disorders are the most prevalent group of inherited neurometabolic diseases. Treatment is supportive, although some treatments report disease-modifying efficacy in isolated cases and small trials. This review evaluates the efficacy of these treatments. Objectives To identify any objective evidence to support the use of current treatments for mitochondrial disease. Methods We searched various clinical trials registers and medical literature databases up to the end of 2009, for clinical trials in mitochondrial disease. Studies with a high risk of bias were excluded. Interventions included any pharmacological agent, dietary modification, nutritional supplement, exercise therapy or other treatment. Results 1335 abstracts were reviewed, and from this 19 abstracts were identified for further review. Upon detailed review, ten studies fulfilled the entry criteria. Three trials used creatine monohydrate. One trial studied the effects of a combination of coenzyme Q10, creatine monohydrate, and lipoic acid. Some of these demonstrated improvement in surrogate markers but no clinical benefit. Five trials studied the effects of dichloroacetate: three trials in children (improvement in biochemical markers only) and two trials in adults (long-term study terminated early due to peripheral nerve toxicity). One trial using dimethylglycine showed no significant effect. Excluded trials are also discussed. Conclusions There is currently no clear evidence supporting the use of any intervention in mitochondrial disorders. Further research is needed to establish the role of a wide range of therapeutic approaches.

Mitochondrial disease is a debilitating and often life-threatening condition that affects at least 1 in 5000 people in the UK. Clinical descriptions of the natural history of mitochondrial disease are largely anecdotal and there have been no systematic attempts to study disease progression in a tightly defined patient cohort. The MRC has funded the Mitochondrial Cohort Study, a collaborative project involving the MRC Centre for Neuromuscular Diseases in London and Newcastle. It aims to create a national database of patients with genetically confirmed mitochondrial disease, make detailed clinico-pathological description of phenotype and correlate this with underlying genotype. The data will be crucial in providing accurate prognostic advice to patients and are prerequisite for assessing efficacy of clinical interventions. The cohort will help facilitate phase IIb and phase III drug trials and assessment of novel treatment strategies such as sequential resistance-endurance exercise. It will also provide the opportunity to assess various prevention strategies including those for cardiomyopathy, stroke-like episodes, migraine and epilepsy. The unprecedented access to family data including genotyping will also permit definitive studies on the transmission of mitochondrial DNA mutations and the effects of mitochondrial disease on female fertility and pregnancy.

Introduction Rapid progress has been made in relation to our understanding of the molecular and genetic basis of many mitochondrial disorders. Yet despite this, avenues for therapeutic intervention are limited. Low levels of habitual physical activity have been recognised to have a strong negative relationship with muscle mitochondrial capacity, disease development and mortality. The aims of this study were to systematically assess habitual physical activity in a cohort of mitochondrial patients. Methods One hundred patients were enrolled in the study. Habitual physical activity was measured by a multisensor array and by completion of a self-report questionnaire. Disease severity was assessed using the Newcastle Mitochondrial Disability Adult Scale (NMDAS). Results Low levels of habitual physical activity were common. Seventy-eight per cent of the patients achieved less than nationally advised levels of physical activity (10 000 steps per day) and almost half had an average daily energy expenditure of less than 1.4 METS. Higher physical activity was associated with lower BMI and lower clinical disease burden. Conclusion Low levels of physical activity are prominent and constitute a significant and important modifiable risk factor in mitochondrial disease. These findings advocate the promotion of increased physical activity irrespective of genotype.

Introduction Mitochondrial diseases are a clinically multifarous group of genetic disorders with extensive phenotypic and disease burden variability. Health related quality of life (HRQoL) is increasingly recognised as a fundamental patient-based outcome measure in both clinical intervention and research. Generic HRQoL outcome measures have been extensively validated across populations and different disease states. Due to their inclusive construct not all relevant aspects of a specific illness may be captured. It is acknowledged that there is a need to develop disease-specific HRQoL measures that centre on symptoms characteristic of a specific disease or condition. This study presents the conceptualisation, development and assessment of a disease-specific HRQoL measure (Mito-QoL) for patients with mitochondrial cytopathies. Methods Domain and item content for the Mito-QoL was derived from semi-structured key-informant interviews and modified following piloting of the questionnaire by post. Items were eliminated with the use of standard psychometric criteria. Construct validity was assessed by comparing domain scores with similar Short Form 36 domains. Results Mito-QoL consists of 63 items within 16 unidimensional domains demonstrating excellent internal reliability (Cronbach9s α>0.74) and construct validity. Conclusion Mito-QoL is a valid and reliable disease-specific HRQoL measure which may be of use in clinical practice and research.

Genetic factors are important in the aetiology of the two most common neurodegenerative diseases: Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB).1,2 Individuals with AD are more likely to have a similarly affected mother than a similarly affected father,3 raising the possibility of a maternally transmitted susceptibility factor. Patients with AD accumulate cytochrome c oxidase deficient neurones at a faster rate than age matched controls,4 and although contentious, abnormal mitochondrial function has been documented in the brains of patients with AD. Cybrid studies suggest that the biochemical abnormality is due to a defect of the mitochondrial genome (mtDNA).5 Different mtDNA sequence variants have been associated with AD and DLB, but there have been no consistent findings, and a maternally transmitted susceptibility factor remains elusive. The 16.5 kb mtDNA molecule codes for 13 essential respiratory chain subunits and the 24 RNAs required for intramitochondrial protein synthesis. Transcription and translation of mtDNA is controlled by the short 1 kb non-coding D-loop. In the wild-type genome, a thymidine residue at nucleotide position (np) 16189 interrupts a tract of cytosine residues between np 16184 and 16193, close to the origin of heavy strand replication (OH).6 The presence of a cytosine residue at np 16189 generates a homopolymeric C tract which appears to be unstable. It is thought …