Mitochondrial tRNA genes are hotspots for mutations in a cohort of patients with exercise intolerance and mitochondrial myopathy

Objective Mitochondrial myopathy (MM) is a relatively rare type of mitochondrial disorder characterized by predominant skeletal muscle involvement. Both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) mutations have been reported as the genetic causes of this disease. Here, we described the clinical and genetic features of a cohort of patients with MM. Methods We conducted a retrospective, single center study enrolling 22 patients with clinically and myopathologically diagnosed MM. The clinical records and results of laboratory examinations were collected and analyzed. The follow-up was conducted by telephone interview in 12 patients. Muscle biopsy and gene analysis was performed in all patients. MtDNA mutation load was quantified in all available tissues. Results Muscle biopsy revealed ragged red fibers and/or cytochrome c oxidase deficient fibers in all patients. Mitochondrial DNA analysis identified pathogenic mutations in 11 patients, including four previously reported mutations (mt-tRNALeu(UUR) m.3243A>G in five patients, mt-tRNALys m.8344A>G in four patients, mt-tRNALeu(UUR) m.3302A>G in one patient, and mt-tRNALeu(UUR) m.3250T>C in one patient) and a novel possible pathogenic variant (MTND1 m.3437G>A) in one patient. The mtDNA mutation load was consistently higher in muscles than in blood. In the remaining 10 patients, there was no pathogenic mutation found either by the Sanger sequencing of entire mitochondrial genome or by the targeted next-generation sequencing which included 238 nuclear genes related to mitochondrial diseases. Clinically, the onset age of these 22 MM patients ranged from 1 to 51 years (mean = 21.1 ± 14.3 years), and the disease duration was between 3 and 44 years (mean = 14.1 ± 9.4 years). Proximal limb weakness with or without exercise intolerance was present in 21 patients, and one patient showed only exercise intolerance. Out of these 22 patients, dysphagia/dysarthria, neck flexor muscle weakness, dyspnea, cardiomyopathy and exercise induced myalgia were observed in five, two, four, one and four patients, respectively. Neither central nervous system manifestation nor brain MRI abnormality was present in these patients. Notably, three of the four patients carrying the m.8344A>G mutation presented with dysarthria. The follow-up of 12 patients revealed symptom improvements in four cases, stable conditions in two cases, and worsened conditions in five cases. The case with the m.3302A>G mutation died of respiratory failure. Conclusions Mitochondrial tRNA genes, as hotspots for mutations, accounted for 50% of MM in this cohort of patients. Patients associated with the m.8344A>G mutation were prone to laryngopharyngeal muscle involvement. The prognosis in our patients is relatively benign except one patient with the m.3302A>G mutation.