The clinical features and genetic characteristics of MT-ATP6-related mitochondrial disease: a national, observational study

Importance: Mutations in the mitochondrial MT-ATP6 gene are an important cause of mitochondrial disease. Phenotypes related to these mutations include Leigh syndrome (LS), and the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP); however, there are also reports of other and intermediate phenotypes. Objective: To characterise the phenotypic and genotypic spectrum of the MT-ATP6 related mitochondrial disease in a large and well-defined mitochondrial disease cohort. Design: A retrospective, observational cohort study. Setting: Three national diagnostic and clinical centres for mitochondrial disorders in Newcastle upon Tyne, Oxford and London; patients were recruited to the Mitochondrial Disease Patient Cohort, UK. Participants: Eighty-eight patients with clinically and genetically defined mitochondrial disease due to mutations in the MT-ATP6 gene that were included in this study. Data from 36 clinically unaffected carriers of MT-ATP6 mutations were also analysed. Main Outcomes and Measures: All patients were interviewed and examined. All available medical notes and clinical, radiological, and genetic investigations were reviewed. Results: We identified 88 clinically affected individuals and 36 asymptomatic family members from 60 pedigrees. Among the patients of whom the respective data were available, 57 of 69 (83%) had cerebellar ataxia, 42 of 57 (74%) had peripheral neuropathy, and 40 of 59 (68%) had some degree of cognitive dysfunction or learning disability. Thirty-two patients (36%) had a presentation compatible with LS, whereas just seven patients (8%) had the complete neuropathy, ataxia, and retinitis pigmentosa phenotype without LS. We observed meaningful differences between the clinical features associated with the common MT-ATP6 mutations. Of interest, four adult patients developed unexpected, subacute brainstem dysfunction akin to Leigh-like crisis, one patient had a stroke-like episode, and three patients exhibited symptoms similar to episodic ataxia. Conclusions and Relevance: The majority of patients with genetic defects of MT-ATP6 have cerebellar ataxia and peripheral neuropathy, and some degree of cognitive dysfunction seems relatively common among these patients. Moreover, some patients experience sudden exacerbations that are suggestive of a mitochondrial energy crisis and mandate active supportive treatment. These findings may be useful in the diagnostics and care of patients with MT-ATP6 related mitochondrial disease.