Objective: The prevalence of mitochondrial disease has proven difficult to establish, predominantly as a result of clinical and genetic heterogeneity. The phenotypic spectrum of mitochondrial disease has expanded significantly since the original reports that associated classic clinical syndromes with mitochondrial DNA (mtDNA) rearrangements and point mutations. The revolution in genetic technologies has allowed interrogation of the nuclear genome in a manner that has dramatically improved the diagnosis of mitochondrial disorders. We comprehensively assessed the prevalence of all forms of adult mitochondrial disease to include pathogenic mutations in both nuclear and mtDNA.Methods: Adults with suspected mitochondrial disease in the North East of England were referred to a single neurology center from 1990 to 2014. For the midyear period of 2011, we evaluated the minimum prevalence of symptomatic nuclear DNA mutations and symptomatic and asymptomatic mtDNA mutations causing mitochondrial diseases.Results: The minimum prevalence rate for mtDNA mutations was 1 in 5,000 (20 per 100,000), comparable with our previously published prevalence rates. In this population, nuclear mutations were responsible for clinically overt adult mitochondrial disease in 2.9 per 100,000 adults.Interpretation: Combined, our data confirm that the total prevalence of adult mitochondrial disease, including pathogenic mutations of both the mitochondrial and nuclear genomes (≈1 in 4,300), is among the commonest adult forms of inherited neurological disorders. These figures hold important implications for the evaluation of interventions, provision of evidence‐based health policies, and planning of future services. Ann Neurol 2015 Ann Neurol 2015;77:753–759

Mitochondria are double‐membrane‐bound organelles that are present in all nucleated eukaryotic cells and are responsible for the production of cellular energy in the form of ATP. Mitochondrial function is under dual genetic control – the 16.6‐kb mitochondrial genome, with only 37 genes, and the nuclear genome, which encodes the remaining ∼1300 proteins of the mitoproteome. Mitochondrial dysfunction can arise because of defects in either mitochondrial DNA or nuclear mitochondrial genes, and can present in childhood or adulthood in association with vast clinical heterogeneity, with symptoms affecting a single organ or tissue, or multisystem involvement. There is no cure for mitochondrial disease for the vast majority of mitochondrial disease patients, and a genetic diagnosis is therefore crucial for genetic counselling and recurrence risk calculation, and can impact on the clinical management of affected patients. Next‐generation sequencing strategies are proving pivotal in the discovery of new disease genes and the diagnosis of clinically affected patients; mutations in >250 genes have now been shown to cause mitochondrial disease, and the biochemical, histochemical, immunocytochemical and neuropathological characterization of these patients has led to improved diagnostic testing strategies and novel diagnostic techniques. This review focuses on the current genetic landscape associated with mitochondrial disease, before focusing on advances in studying associated mitochondrial pathology in two, clinically relevant organs – skeletal muscle and brain. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Defects of the mitochondrial respiratory chain have emerged as the most common cause of childhood and adult neurometabolic disease, with an estimated prevalence of 1 in 5000 live births.¹ Clinically they can present at any time of life, are often seen in association with neurological impairment, and cause chronic disability and premature death.² Major advances in understanding the molecular basis of mitochondrial disease have been mirrored by a complex, expanding phenotypic spectrum. Although some genetic defects appear to be seen in association with specific clinical features, this is not usually the case, and a systematic multidisciplinary approach is required to make a diagnosis.³ Biochemical and molecular genetic investigations are time consuming, expensive, and highly specialized, often involving a biopsy of an affected tissue or organ. With a growing list of mitochondrial diseases caused by different nuclear gene defects,⁴ achieving a comprehensive molecular diagnosis is now more labor-intensive than ever. This can compromise clinical management through protracted and often repeated investigations, impeding reliable genetic counseling and prenatal diagnosis.

Mitochondrial disease associated with the pathogenic m.3243A>G variant is a common, clinically heterogeneous, neurogenetic disorder. Using multiple linear regression and linear mixed modelling, we evaluated which commonly assayed tissue (blood N = 231, urine N = 235, skeletal muscle N = 77) represents the m.3243A>G mutation load and mitochondrial DNA (mtDNA) copy number most strongly associated with disease burden and progression. m.3243A>G levels are correlated in blood, muscle and urine ( R ² = 0.61–0.73). Blood heteroplasmy declines by ~2.3%/year; we have extended previously published methodology to adjust for age. In urine, males have higher mtDNA copy number and ~20% higher m.3243A>G mutation load; we present formulas to adjust for this. Blood is the most highly correlated mutation measure for disease burden and progression in m.3243A>G‐harbouring individuals; increasing age and heteroplasmy contribute ( R ² = 0.27, P < 0.001). In muscle, heteroplasmy, age and mtDNA copy number explain a higher proportion of variability in disease burden ( R ² = 0.40, P < 0.001), although activity level and disease severity are likely to affect copy number. Whilst our data indicate that age‐corrected blood m.3243A>G heteroplasmy is the most convenient and reliable measure for routine clinical assessment, additional factors such as mtDNA copy number may also influence disease severity.

Mitochondrial disease is a challenging area of genetics because two distinct genomes can contribute to disease pathogenesis. It is also challenging clinically because of the myriad of different symptoms and, until recently, a lack of a genetic diagnosis in many patients. The last five years has brought remarkable progress in this area. We provide a brief overview of mitochondrial origin, function, and biology, which are key to understanding the genetic basis of mitochondrial disease. However, the primary purpose of this review is to describe the recent advances related to the diagnosis, genetic basis, and prevention of mitochondrial disease, highlighting the newly described disease genes and the evolving methodologies aimed at preventing mitochondrial DNA disease transmission.