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We report on two novel mtDNA mutations in patients affected with mitochondrial myopathy. The first patient, a 44-year-old woman, had bilateral eyelid ptosis and the m.8305C>T mutation in the MTTK gene. The second patient, a 56-year-old man, had four-limb muscle weakness and the MTTM gene m.4440G>A mutation. Muscle biopsies in both patients showed ragged red fibers and numerous COX-negative fibers as well as a combined defect of complex I, III and IV activities. The two mutations were heteroplasmic and detected only in muscle tissue, with a higher mutation load in COX-negative fibers. Additionally, both mutations occurred in highly conserved mt-tRNA sites, and were not found by an in silico search in 30,589 human mtDNA sequences. Our report further expands the mutational and phenotypic spectrum of diseases associated with mutations in mitochondrial tRNA genes and reinforces the notion that mutations in mitochondrial tRNAs represent hot spots for mitochondrial myopathies in adults., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Exercise intolerance is one of the clinical hallmarks of late-onset Pompe disease (LOPD). We studied the acute effects of ERT on the physiological variables associated with exercise tolerance in patients chronically ERT treated. Moreover, we assessed the influence of clinical severity on the investigated variables. The day before (B) and the day after (A) ERT injection, 11 LOPD patients performed on a cycle-ergometer an exercise tolerance test to voluntary exhaustion; VO 2 , HR, RPE, and GAA activity were determined in B and A. The disease severity was characterized by Walton scale, 6MWT, and pulmonary function tests. No significant differences in the variables related to exercise tolerance were found in A vs B, despite a significant increase in GAA activity in peripheral lymphocytes. No differences in VO 2 peak were observed between patients with only skeletal muscle impairment and patients with both skeletal and respiratory muscle impairment. Distance walked at 6MWT was significantly higher than VO 2 peak expressed as percentage of normal values. In conclusion, in LOPD patients the exercise tolerance test is not acutely affected by ERT administration; the peripheral muscle component seems more prominent in determining the VO 2 peak decrease than the respiratory component; VO 2 peak might be more sensitive than 6MWT in estimating exercise tolerance in LOPD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

MFN2 is the major gene involved in the axonal form of Charcot-Marie-Tooth disease. It usually has an autosomal dominant pattern of inheritance, but a few cases of homozygous or compound heterozygous mutations have been described. These patients usually present an earlier onset, more severe phenotype and their inheritance pattern can span from autosomal recessive to semidominant. Here we report two unrelated patients carrying two compound heterozygous MFN2 mutations. Both present a pure axonal neuropathy without any additional features. The first patient presents a mild clinical phenotype with onset in the 2nd decade, while the second patient shows a severe, early onset phenotype with loss of independent ambulation. Only a careful clinical examination as well as neurophysiological and genetic studies allowed us to establish the role and the transmission pattern of the identified variants. We discuss practical consequences of this finding in genetic counseling., (Copyright © 2017 Elsevier B.V. All rights reserved.)