Primary mitochondrial myopathies diagnosed in adulthood: phenotypic spectrum and long-term outcomes

Primary mitochondrial myopathies (PMM) are frequently recognized in childhood as part of a multisystem disorder, but often overlooked in adults. Herein, we systematically describe the genotypic and phenotypic spectrum, and long-term outcomes of PMM diagnosed in adulthood, in a large single-center cohort. We performed a retrospective chart review of patients diagnosed with PMM at age 18 or older, seen at Mayo Clinic between 2005 and 2021. We identified 94 patients. Median time from symptom onset to diagnosis was 11 years (IQR 4-21). Median age at diagnosis was 48 years (IQR 32-63). A primary genetic defect was identified in mitochondrial (mt) DNA in 48 patients (10 with single large deletion, 38 with point mutations) and nuclear DNA (nDNA) in 29. 5 patients had multiple mtDNA deletions or depletion without nDNA variants. 12 patients had histopathological features of mitochondrial myopathy without molecular diagnosis. Most common phenotypes included a multisystem disorder (n=30), MELAS (14), limb myopathy (13), CPEO (12), and CPEO+ (12). 27% of patients had manifestations isolated to skeletal muscles. 69% had CNS and 21% had cardiac involvement. Most frequent mutations were in MT-TL (m.3243A>G, 27) and POLG (17), however, a wide spectrum of established and novel molecular defects, with overlapping clinical phenotypes, were identified. Skeletal muscle weakness was overall mild and slowly progressive, with decline in strength summated score (SSS) of 0.01/year. 30 patients died during follow-up, with a median survival of 33.4 years from symptom onset and 10.9 years from diagnosis. Cardiac involvement was associated with increased mortality (hazard ratio of 2.36 [1.05, 5.29]). There was no difference in survival or SSS decline based on age at onset or diagnosis, genotype, or phenotype. Despite the wide phenotypic and genotypic spectrum, PMM in adults share similar features with slowly progressive weakness, contrasting with common multi-organ involvement and high mortality. Primary mitochondrial myopathies (PMM) are frequently recognized in childhood as part of a multisystem disorder, but often overlooked in adults. Herein, we systematically describe the genotypic and phenotypic spectrum, and long-term outcomes of PMM diagnosed in adulthood, in a large single-center cohort. We performed a retrospective chart review of patients diagnosed with PMM at age 18 or older, seen at Mayo Clinic between 2005 and 2021. We identified 94 patients. Median time from symptom onset to diagnosis was 11 years (IQR 4-21). Median age at diagnosis was 48 years (IQR 32-63). A primary genetic defect was identified in mitochondrial (mt) DNA in 48 patients (10 with single large deletion, 38 with point mutations) and nuclear DNA (nDNA) in 29. 5 patients had multiple mtDNA deletions or depletion without nDNA variants. 12 patients had histopathological features of mitochondrial myopathy without molecular diagnosis. Most common phenotypes included a multisystem disorder (n=30), MELAS (14), limb myopathy (13), CPEO (12), and CPEO+ (12). 27% of patients had manifestations isolated to skeletal muscles. 69% had CNS and 21% had cardiac involvement. Most frequent mutations were in MT-TL (m.3243A>G, 27) and POLG (17), however, a wide spectrum of established and novel molecular defects, with overlapping clinical phenotypes, were identified. Skeletal muscle weakness was overall mild and slowly progressive, with decline in strength summated score (SSS) of 0.01/year. 30 patients died during follow-up, with a median survival of 33.4 years from symptom onset and 10.9 years from diagnosis. Cardiac involvement was associated with increased mortality (hazard ratio of 2.36 [1.05, 5.29]). There was no difference in survival or SSS decline based on age at onset or diagnosis, genotype, or phenotype. Despite the wide phenotypic and genotypic spectrum, PMM in adults share similar features with slowly progressive weakness, contrasting with common multi-organ involvement and high mortality.