Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease

Abstract

ObjectiveThe 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.MethodsAdults 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.ResultsThe 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.InterpretationCombined, 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

Pseudo‐obstruction, stroke, and mitochondrial dysfunction: A lethal combination

“…Furthermore, review of our patient cohort and the literature would suggest that this late gastrointestinal complication may occur in other primary mtDNA25, 26, 27, 28, 29 and nuclear mutations (up to 3% in POLG ‐related mitochondrial disease30, but is extremely rare. Thus, given that IPO appears relatively common in this cohort of patients (and with the m.3243A>G mtDNA mutation responsible for almost one third of all forms of adult mitochondrial disease)2, it is imperative for neurologists to be aware of this condition and its cardinal findings.…”

“…Thirteen percent of our patient cohort presented with severe gastrointestinal dysmotility symptoms with almost one third concomitantly presenting during an acute stroke‐like episode. Mid‐point 2014 census population data for the North East of England, as specified by the Office for National Statistics, UK (2,618,710),22 were used to estimate the prevalence rate of IPO in m.3243A>G‐related mitochondrial disease, as described previously 2. The minimum prevalence rate of IPO in clinically manifesting m.3243A>G carriers was estimated as 1 in 200,000 or 0.53 per 100,000 (95% confidence interval [CI]: 0.3–0.9 per 100,000), which is comparable to the previously published point prevalence of all‐cause chronic IPO (0.9 per 100,000) 23, 24.…”

Recent Advances in Mitochondrial Disease

“…A good example of the latter is Leigh syndrome, a progressive neurodegenerative disorder of childhood and the most common clinical phenotype seen in pediatric mitochondrial disease, which can be caused by mutations in almost 80 different genes (53). The most detailed estimate of mitochondrial disease prevalence in adults is based on a cohort study in northeast England that revealed that the prevalence of mitochondrial disease is 2.9 cases per 100,000 individuals for nDNA mutations and 9.6 cases per 100,000 individuals for mtDNA mutations, with a further 10.8 per 100,000 individuals at risk of developing symptoms in later life or transmitting a pathogenic mutation (30). The frequency of mtDNA mutations in the population is much higher, with ∼1 in 200 healthy individuals thought to carry a pathogenic mtDNA mutation at low levels of heteroplasmy (18).…”

Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders

“…Approximately 1 in 5,000 individuals (Gorman et al, 2015) suffers from deleterious mtDNA mutations that can cause metabolic disorders and typically lead to dysfunctions of the nervous system (Carelli and Chan, 2014). Recent breakthroughs in the field of mitochondrial medicine might yield methods to prevent the transmission of pathogenic mtDNA mutations in the future (Mitalipov and Wolf, 2014;Reddy et al, 2015); but, currently no cures or effective interventional therapies are available for patients who have already inherited the mutations and are subject to such disorders (Pfeffer et al, 2013).…”