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
Highlights
The Newcastle Mitochondrial Centre is among only 3 highly specialized, national referral centers for mitochondrial disease in the United Kingdom. Those individuals with pathogenic mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) mutations, or those with unidentified nuclear mutations, but pathological multiple mtDNA deletions evident in muscle, who were alive at the midyear period of 2011, were identified. Those with multiple mtDNA deletions in muscle were only included when there was no evidence of other muscle pathology, the mtDNA deletions had been independently verified using 2 different techniques, and the clinical and biochemical (>3% cyclooxygenase-deficient fibers) features were consistent with a diagnosis of mitochondrial disease
Prevalence of Pathogenic Mutations of Either mtDNA or nDNA The minimum point prevalence of clinically affected adults with mitochondrial disease attributable to either the mitochondrial or nuclear genome is 12.5 in 100,000 (95% confidence interval (CI) 5 11.1–14.1 3 1025), whereas the prevalence of all pathogenic mutations in both nDNA and mtDNA is 23 in 100,000 (1 in 4,300; 95% CI 5 14.6–34.5 3 1025)
Recessive mutations in SPG7 and dominant mutations in PEO1 were the most common pathogenic nDNA mutations identified in clinically affected individuals (SPG7: minimum prevalence 5 0.8 3 1025, 95% CI 5 0.5–1.3 3 1025; PEO1: minimum prevalence 5 0.7 3 1025, 95% CI 5 0.4-1.2 3 1025)
Summary
Adult cases (>16 years old) with suspected mitochondrial disease were ascertained following referral to a single specialist mitochondrial center in the North East of England between 1990 and 2011. The Newcastle Mitochondrial Centre is among only 3 highly specialized, national referral centers for mitochondrial disease in the United Kingdom Those individuals with pathogenic mtDNA or nDNA mutations, or those with unidentified nuclear mutations, but pathological multiple mtDNA deletions evident in muscle, who were alive at the midyear period of 2011, were identified. Those with multiple mtDNA deletions in muscle were only included when there was no evidence of other muscle pathology, the mtDNA deletions had been independently verified using 2 different techniques (long-range polymerase chain reaction [PCR], Southern blot or real-time PCR), and the clinical and biochemical (>3% cyclooxygenase-deficient fibers) features were consistent with a diagnosis of mitochondrial disease. In contrast to our previous study,[3] improvements in noninvasive testing[4,5] have allowed us to include elderly individuals, beyond working age, where a positive genetic diagnosis was confirmed
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