Exercise training in mitochondrial myopathy: a randomized controlled trial

Patients with mitochondrial myopathies (MM) usually suffer from exercise intolerance due to their impaired oxidative capacity and physical deconditioning. We evaluated the effects of a 12-week supervised randomized rehabilitation program involving endurance training in patients with MM. Twenty MM patients were assigned to a training or control group. For three nonconsecutive days each week, patients combined cycle exercise at 70% of their peak work rate with three upper-body weight-lifting exercises performed at 50% of maximum capacity. Training increased maximal oxygen uptake (28.5%), work output (15.5%), and minute ventilation (40%), endurance performance (62%), walking distance in shuttle walking test (+95 m), and peripheral muscle strength (32%-62%), and improved Nottingham Health Profile scores (21.47%) and clinical symptoms. Control MM patients did not change from baseline. Results show that our exercise program is an adequate training strategy for patients with mitochondrial myopathy.     

Exercise intolerance in mitochondrial myopathy is not related to lactic acidosis

In a double-blinded, placebo-controlled, crossover study in seven mitochondrial myopathy patients (MM), we investigated whether lowering of lactate with dichloroacetate (DCA) can improve exercise tolerance and oxidative capacity in MM. DCA lowered plasma lactate at rest and during exercise (from 10.5 +/- 2.0 to 5.0 +/- 1.6 mM; p = 0.005) but did not improve maximal work load or VO2 in cycle exercise or phosphorous magnetic resonance spectroscopy (31P-MRS)-assessed indices of muscle oxidative metabolism. This indicates that lactate acidosis is not the primary cause of exercise intolerance in MM.     

A case of mitochondrial myopathy in a family with oculo-pharyngeal myopathy

We report the case of a patient with mitochondrial lesions, an old woman belonging by her father and mother to a big family with oculopharyngeal muscular dystrophy. Four patients of this family have typical intranuclear tubulo-filamentous inclusions.     

Vascular involvement in mitochondrial myopathy

Electron microscopic examination of muscle specimens taken at biopsy in 6 patients with complex I deficiency and 1 patient with an unknown primary chemical defect who had the clinical characteristics of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) revealed striking abnormalities in blood vessels in 5. Abnormalities consisted of an increased number of enlarged mitochondria with complicated cristae in the pericytes of capillaries, endothelial cells, and smooth muscle cells of the small arteries, including terminal arterioles and precapillary sphincters, predominantly in smooth muscle cells. On statistical analysis, the number of mitochondria and the ratio of mitochondrial area to the total area of the smooth muscle cells were increased approximately tenfold (p less than 0.001). Although stroke-like episodes were not present, similar mitochondrial abnormalities in blood vessels were found in 1 patient who had the encephalomyopathic form of complex IV deficiency and in 2 patients in whom the primary chemical defects could not be clearly defined. Such abnormalities in small arteries might be responsible for the occasional occurrence of transient cerebral ischemia causing stroke-like episodes and progressive mental deterioration.     

Exercise therapy in patients with myopathy

Common impairments experienced by patients with myopathy include muscle weakness, reduced endurance and cardiovascular fitness. Strength-training programmes, incorporating isometric, isotonic or isokinetic exercise, have been shown to improve muscle strength in the short term, without evidence of increased muscle damage using biochemical markers. However, there is some evidence that eccentric exercise may have adverse effects in patients with myopathy. Aerobic training programmes using cycle ergometers or treadmills have demonstrated an improvement in cardiovascular fitness, muscle strength and endurance, again without evidence of increased muscle damage. Further research is needed to determine the optimum training protocols for patients with various types of myopathy, and in particular to improve the ability of patients to be active and independent in daily life.     

A mitochondrial myopathy in an infant with lactic acidosis

We describe a girl with mitochondrial myopathy, who presented with general muscle weakness, muscle hypotonia and motor retardation. The level of blood lactate and pyruvate was consistently increased. Enzymatic studies showed impairment of NADH-dehydrogenase activity (complex I of the respiratory chain) in skeletal muscle. Electron-microscopy of a muscle biopsy showed abnormalities of a mitochondrial myopathy. The girl, now aged 30 months, has been treated with riboflavine (vitamin B2) since the age of 14 months, and lactate and pyruvate levels have decreased to normal. The patient still shows mild muscle hypotonia and weakness, but good motor progress and normal cognitive development.     

A study of a myopathy presenting as idiopathic scoliosis: Multicore disease or mitochondrial myopathy?

Seven cases from a family with a myopathy categorized as “multicore disease” are presented. The clinical picture is unusual because of the predominant progressive involvement of the axial skeletal muscle, with scoliosis and disproportionate respiratory failure as the major clinical features. The propositus and his cousin have both suffered from scoliosis without limb weakness. There is a possibility that this myopathy may be responsible for some cases regarded as idiopathic scoliosis, especially idiopathic infantile scoliosis.The clinical picture is highly variable, and there are sub-clinical cases. The inheritance pattern is consistent with either autosomal dominant, sex-linked recessive or extra-chromosomally inherited disease.Electron microscopy revealed mitochondrial abnormalities, which may have resulted in the Z-disc pathology.     

脂质代谢性肌病一例:极长链酰基辅酶A脱氢酶缺乏症

患者女性,16岁。主因反复肌无力伴酸痛发作3年余,于2012年2月24日入院。患者自2008年9月至入院时共计6次出现肌无力伴酸痛感,每次发作前均有劳累或受凉史。主要表现为四肢和抬头无力,伴肌肉酸痛感,休息后症状与体征可完全缓解,发作后间歇性"酱油"尿。外院检查血清肌酸激     

A forearm exercise screening test for mitochondrial myopathy

BACKGROUND: The authors hypothesized that impaired oxygen extraction in mitochondrial myopathy (MM) results in a high oxygen saturation in venous effluent blood from working muscle and that this phenomenon can be used as a diagnostic tool for MM. METHODS: Twelve patients with MM, 10 patients with muscular dystrophy, and 12 healthy subjects were studied. All subjects performed intermittent static handgrip exercise (1/2 Hz) at 40% of maximal voluntary contraction (MVC) for 3 minutes. Cubital venous oxygen saturation and brachial artery flow were measured in the exercised arm. RESULTS: Exercise-induced venous oxygen desaturation was smaller in patients with MM (Delta - 7 +/- 5%) than in subjects with muscular dystrophy (Delta - 38 +/- 2%; p = 0.00001) and healthy subjects (Delta - 43 +/- 2%; p = 0.0000002). MVC and exercise blood flow were similar in patients with MM (18 +/- 3 kg; 436 +/- 65 mL/min) and patients with muscular dystrophy (15 +/- 3 kg; 460 +/- 85 mL/min), but were higher in healthy subjects (32 +/- 4 kg; 630 +/- 58 mL/min; p < 0.03). In seven patients with MM and seven patients with McArdle disease, studied with a slightly different protocol, exercise-induced oxygen desaturation was also impaired in MM (Delta - +/- 5%) compared with McArdle disease (Delta - 26 +/- 3%; p = 0.007). CONCLUSION: Oxygen desaturation in venous blood from exercising muscle is markedly lower in patients with mitochondrial myopathy than in subjects with other muscle diseases and healthy subjects, suggesting that a forearm exercise test can be a diagnostic screening tool for mitochondrial myopathy.     

A case of mitochondrial myopathy with mononeuritis multiplex

A case of mitochondrial myopathy with mononeuritis multiplex was described. A 55-year-old man was hospitalized because of blepharoptosis and muscle weakness. His mother also showed blepharoptosis in her elderly stage of life. He had been healthy until 46 years of age, when he first noticed difficulty of speech, followed by bilateral blepharoptosis, weakness of upper limbs, and sensory disturbance in the left occipital, and left upper and lower extremities. These symptoms progressed slowly. On admission, bilateral blepharoptosis was recognized. Slightly to moderate muscle wasting and weakness were observed in the face, neck, trunk, and extremities. Areflexia was observed in the upper extremities. Paresthesia was observed in the left occipital and left hip, and superficial sensation was impaired in the left upper and lower extremities. Electromyographic examination of extremities showed neurogenic changes in the distal muscles and myogenic changes in the proximal muscles. Motor conduction velocities were normal, but sensory conduction velocities decreased in amplitude on the left upper extremity and were not evoked on the left lower extremity. Muscle biopsy specimen revealed numerous "ragged-red" fibers. Cytochrome c oxidase stain showed a decrease in intensity of staining. A sural nerve biopsy showed slight axonal degeneration and slight loss of nerve fibers. Biochemical analysis on biopsy muscle showed partial deficiency of cytochrome c oxidase activity.     

线粒体肌病患者腓肠神经的形态计量学分析

对５例已经肌肉活检病理及生化检测证实的线粒体肌病患者的腓肠神经进行光镜及电镜观察，并用形态计量学方法对其进行分析，结果发现大口径的有髓纤维减少，有髓纤维面数密度减小，有髓纤维轴索直径与纤维外直径之比增大，轴索变性，并可见轴索和雪旺细胞浆中有增多的异常线粒体。     

A5814G mutation in mitochondrial DNA can cause mitochondrial myopathy and cardiomyopathy.

We describe a 5-year-old child with hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis. Mitochondrial DNA analysis showed a heteroplasmic A5814G point mutation in the tRNA(Cys) gene. The mutational load was extremely high (>95%) in muscle, fibroblasts, and blood. This report expands the clinical heterogeneity of the A5814G mutation, which should be considered in the differential diagnosis of hypertrophic cardiomyopathy in childhood.     

Age-related mitochondrial DNA point mutations in patients with mitochondrial myopathy

Mutations in the control region (D-loop) of mitochondrial DNA (mtDNA) have been described in normal old individuals and it is suggested that they originated from oxidative damage. Respiratory chain defects may lead to increased free radical generation, increased susceptibility to oxidative damage and further increased accumulation of age-related mutations. The objective of this study was to verify whether patients with a mitochondrial disease are more predisposed to accumulate the A189G and T408A mutations in the D-loop and confirm their age-associated nature. We evaluated the presence and levels of heteroplasmy of these two mutations in muscle DNA of 52 individuals with different ages (21 age-matched controls and 31 patients with single or multiple mtDNA deletions). The frequency of both mutations was significantly increased with age, but no differences were observed comparing the group of patients with their age-matched controls. We could not observe correlation of levels of heteroplasmy with age. Our results confirm the age-related nature of the A189G and T408A mutations in the D-loop in controls and patients with mitochondrial disease, but do not suggest that patients are more predisposed to the development of age-related point mutations.     

A large-scale deletion of mitochondrial DNA in a case with pure mitochondrial myopathy and neuropathy

Here we report the findings from a male patient with myopathy and neuropathy, who has a large-scale deletion of the mitochondrial genome at nucleotides 6570–14150. In the patient’s history, muscle cramps with intermittent weakness and polyneuropathy with disturbed micturition were the predominant symptoms. Morphological examination of a muscle biopsy sample revealed numerous ragged red fibers and prominent paracrystalline intramitochondrial inclusions. The sural nerve biopsy sample disclosed a chronically progressive neuropathy, predominantly axonal in type with a minor demyelinating component. In previous studies the clinical symptoms mentioned above have been related to point mutations at various positions in the mitochondrial DNA (mtDNA). The present study is the first to describe a large (8 kb) deletion of the mtDNA which had apparently caused myopathy and polyneuropathy without encephalopathy. Received: 27 July 1995 / Revised, accepted: 4 December 1995     

A novel mutation in the mitochondrial tRNA(Phe) gene associated with mitochondrial myopathy

We report a novel heteroplasmic T-->C mutation at nt position 582 within the mitochondrial tRNA(Phe) gene of a 70-year-old woman with mitochondrial myopathy. No other family members were affected, suggesting that our patient was a sporadic case. The muscle showed frequent ragged red fibers and 43% cytochrome c oxidase deficient fibers. The mutation alters a conserved base pairing in the aminoacyl acceptor stem. The mutation load was 70% in muscle homogenate and varied from 0 to 95% in individual muscle fiber segments. Cytochrome c oxidase-negative fibers showed significantly higher levels of mutated mtDNA (>75%) than Cytochrome c oxidase-positive fibers (<55%). This mutation adds to the previously described four pathogenic mutations in the tRNA(Phe) gene.