Mitochondrial tRNA genes are hotspots for mutations in a cohort of patients with exercise intolerance and mitochondrial myopathy
Introduction
Mitochondrial disorders are characterized by variable clinical manifestations usually involving multiple tissues and organs, such as skeletal muscle, brain and pancreas, with a significant energy demand. In most well defined phenotypes, such as mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF) and chronic progressive external ophthalmoplegia/Kearns-Sayre syndrome (CPEO/KSS), limb muscle weakness occurs, associated with encephalopathies, seizures, diabetes mellitus or ophthalmoplegia ([1], [2]). Mitochondrial myopathy (MM), characterized by isolated or predominant skeletal muscle involvement, however, is relatively rare and frequently misdiagnosed as limb-girdle muscular dystrophy or lipid storage myopathy [39], [40]. For such patients, muscle biopsy can provide great value in the diagnostic work-up, showing ragged red fibers (RRFs) and/or cytochrome c oxidase (COX) deficient fibers ([1], [3]).
MM is heterogeneous in genetics. With the widespread availability of molecular genetic tests, both primary alterations of the mitochondrial DNA (mtDNA) and mutations in mitochondria-related nuclear DNA (nDNA) have been identified as genetic causes of MM [1]. Human mtDNA is a 16,569-kb circular, double-stranded molecule, encoding 13 subunits of the respiratory chain enzymes, 22 tRNA and two rRNA genes [4]. Although mutations in the mitochondrial-encoded cytochrome b gene have been defined as hot spot mutations in exercise intolerance or MM, other mtDNA mutations have also been reported ([5], [6], [7], [12]). Here, we present the clinical and genetic features of a cohort of patients with exercise intolerance and MM.
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Patients
We retrospectively enrolled 22 patients with clinically and myopathologically suspected MM (8 female and 14 male) who were referred to the Department of Neurology, Peking University First Hospital from 2008 to 2015. All patients were Han Chinese and unrelated. Their clinical records and results of laboratory examinations were retrospectively collected and analyzed. All patients were interviewed and examined by at least two neurologists. Follow up data were available in 12 patients by telephone
Patients
The age of onset ranged from 1 to 51 years (mean = 21.1 ± 14.3 years). The disease duration ranged from 3 to 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. None of the patients showed ptosis, diplopia, epilepsy, dementia, stroke-like episodes, or other central nervous system symptoms. Physical examination showed proximal weakness in both upper and lower limbs in 15 patients and
Discussion
In 1973, H. Shibasaki first described a 60-year-old man with a 2-year history of proximal muscle weakness and atrophy with numerous giant and elongated mitochondria in muscle fibers under electron microscopy, indicating MM [10]. In 1999, Hirata K described seven patients with predominant proximal muscle weakness and atrophy caused by a mtDNA m.8291A > G mutation and suggested the concept of limb-girdle mitochondrial myopathy [11]. In the present study, we described 22 patients clinically
Conflicts of interest
The authors declared that they have no conflicts of interest to this work. Prof. Jan Smeitink is the founding CEO of Khondrion (www.khondrion.com).
Acknowledgments
The authors would like to thank the patients and their parents for cooperation. We thank Prof. Yinan Ma and Mrs. Ying Zhang for technical assistance in doing PCR-RFLP. This work was financially supported by grants from the Ministry of Science and Technology of China (No. 2011ZX09307-001-07) and Beijing Municipal Science and Technology Commission (No. Z151100003915126).
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