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Epilepsia 1999
Review
Topics: Calcium; DNA, Mitochondrial; Epilepsy; Free Radicals; Humans; MELAS Syndrome; MERRF Syndrome; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies; Mutation; Neurotoxins
PubMed: 10446749
DOI: 10.1111/j.1528-1157.1999.tb00897.x -
The Cochrane Database of Systematic... Jul 2013Strength training or aerobic exercise programmes might optimise muscle and cardiorespiratory function and prevent additional disuse atrophy and deconditioning in people... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Strength training or aerobic exercise programmes might optimise muscle and cardiorespiratory function and prevent additional disuse atrophy and deconditioning in people with a muscle disease. This is an update of a review first published in 2004.
OBJECTIVES
To examine the safety and efficacy of strength training and aerobic exercise training in people with a muscle disease.
SEARCH METHODS
We searched the Cochrane Neuromuscular Disease Group Specialized Register (July 2012), CENTRAL (2012 Issue 3 of 4), MEDLINE (January 1946 to July 2012), EMBASE (January 1974 to July 2012), EMBASE Classic (1947 to 1973) and CINAHL (January 1982 to July 2012).
SELECTION CRITERIA
Randomised or quasi-randomised controlled trials comparing strength training or aerobic exercise programmes, or both, to no training, and lasting at least six weeks, in people with a well-described diagnosis of a muscle disease.We did not use the reporting of specific outcomes as a study selection criterion.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed trial quality and extracted the data obtained from the full text-articles and from the original investigators. We collected adverse event data from included studies.
MAIN RESULTS
We included five trials (170 participants). The first trial compared the effect of strength training versus no training in 36 people with myotonic dystrophy. The second trial compared aerobic exercise training versus no training in 14 people with polymyositis and dermatomyositis. The third trial compared strength training versus no training in a factorial trial that also compared albuterol with placebo, in 65 people with facioscapulohumeral muscular dystrophy (FSHD). The fourth trial compared combined strength training and aerobic exercise versus no training in 18 people with mitochondrial myopathy. The fifth trial compared combined strength training and aerobic exercise versus no training in 35 people with myotonic dystrophy type 1.In both myotonic dystrophy trials and the dermatomyositis and polymyositis trial there were no significant differences between training and non-training groups for primary and secondary outcome measures. The risk of bias of the strength training trial in myotonic dystrophy and the aerobic exercise trial in polymyositis and dermatomyositis was judged as uncertain, and for the combined strength training and aerobic exercise trial, the risk of bias was judged as adequate. In the FSHD trial, for which the risk of bias was judged as adequate, a +1.17 kg difference (95% confidence interval (CI) 0.18 to 2.16) in dynamic strength of elbow flexors in favour of the training group reached statistical significance. In the mitochondrial myopathy trial, there were no significant differences in dynamic strength measures between training and non-training groups. Exercise duration and distance cycled in a submaximal endurance test increased significantly in the training group compared to the control group. The differences in mean time and mean distance cycled till exhaustion between groups were 23.70 min (95% CI 2.63 to 44.77) and 9.70 km (95% CI 1.51 to 17.89), respectively. The risk of bias was judged as uncertain. In all trials, no adverse events were reported.
AUTHORS' CONCLUSIONS
Moderate-intensity strength training in myotonic dystrophy and FSHD and aerobic exercise training in dermatomyositis and polymyositis and myotonic dystrophy type I appear to do no harm, but there is insufficient evidence to conclude that they offer benefit. In mitochondrial myopathy, aerobic exercise combined with strength training appears to be safe and may be effective in increasing submaximal endurance capacity. Limitations in the design of studies in other muscle diseases prevent more general conclusions in these disorders.
Topics: Dermatomyositis; Exercise; Humans; Mitochondrial Myopathies; Muscular Diseases; Muscular Dystrophy, Facioscapulohumeral; Myotonic Dystrophy; Physical Fitness; Polymyositis; Randomized Controlled Trials as Topic; Resistance Training
PubMed: 23835682
DOI: 10.1002/14651858.CD003907.pub4 -
Biochimica Et Biophysica Acta May 1995A wide variety of mitochondrial DNA (mtDNA) mutations have recently been identified in degenerative diseases of the brain, heart, skeletal muscle, kidney and endocrine... (Comparative Study)
Comparative Study Review
A wide variety of mitochondrial DNA (mtDNA) mutations have recently been identified in degenerative diseases of the brain, heart, skeletal muscle, kidney and endocrine system. Generally, individuals inheriting these mitochondrial diseases are relatively normal in early life, develop symptoms during childhood, mid-life, or old age depending on the severity of the maternally-inherited mtDNA mutation; and then undergo a progressive decline. These novel features of mtDNA disease are proposed to be the product of the high dependence of the target organs on mitochondrial bioenergetics, and the cumulative oxidative phosphorylation (OXPHOS) defect caused by the inherited mtDNA mutation together with the age-related accumulation mtDNA mutations in post-mitotic tissues.
Topics: Adult; Aged; Aging; Amino Acid Sequence; Animals; Biological Evolution; Child; Conserved Sequence; DNA, Mitochondrial; Energy Metabolism; Female; Humans; Male; Middle Aged; Mitochondria; Mitochondrial Myopathies; Molecular Sequence Data; Mutation; Nervous System Diseases; Optic Atrophies, Hereditary; Oxidative Phosphorylation; Pedigree; Point Mutation; Sequence Homology, Amino Acid
PubMed: 7599200
DOI: 10.1016/0925-4439(95)00021-u -
Journal of Neurology, Neurosurgery, and... Dec 2002
Review
Topics: Charcot-Marie-Tooth Disease; Hereditary Sensory and Motor Neuropathy; Humans; Metabolism, Inborn Errors; Mitochondrial Myopathies; Molecular Diagnostic Techniques; Muscular Diseases; Muscular Dystrophies
PubMed: 12536154
DOI: 10.1136/jnnp.73.suppl_2.ii12 -
American Journal of Medical Genetics.... Jul 2022Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants...
Decompensation of cardiorespiratory function and emergence of anemia during pregnancy in a case of mitochondrial myopathy, lactic acidosis, and sideroblastic anemia 2 with compound heterozygous YARS2 pathogenic variants.
Myopathy, lactic acidosis, and sideroblastic anemia 2 (MLASA2) is an autosomal recessive mitochondrial disorder caused by pathogenic variants in YARS2. YARS2 variants confer heterogeneous phenotypes ranging from the full MLASA syndrome to a clinically unaffected state. Symptom onset is most common in the first decade of life but can occur in adulthood and has been reported following intercurrent illness. Early death can result from respiratory muscle weakness and cardiomyopathy. We report a case of MLASA2 with compound heterozygous YARS2 pathogenic variants; a known pathogenic nonsense variant [NM_001040436.3:c.98C>A (p.Ser33Ter)] and a likely pathogenic missense variant not previously associated with disease [NM_001040436.3:c.948G>T (p.Arg316Ser)]. The proband initially presented with a relatively mild phenotype of myopathy and lactic acidosis. During pregnancy, anemia emerged as an additional feature and in the postpartum period she experienced severe decompensation of cardiorespiratory function. This is the first reported case of pregnancy-related complications in a patient with YARS2-related mitochondrial disease. This case highlights the need for caution and careful counseling when considering pregnancy in mitochondrial disease, due to the risk of disease exacerbation and pregnancy complications.
Topics: Acidosis, Lactic; Adult; Anemia, Sideroblastic; Female; Humans; Mitochondrial Myopathies; Muscular Diseases; Pregnancy; Tyrosine-tRNA Ligase
PubMed: 35393742
DOI: 10.1002/ajmg.a.62755 -
The Journal of Pediatrics Aug 1999Several mutations in mitochondrial DNA have been associated with infantile cardiomyopathy, including a C3303T mutation in the mitochondrial transfer RNA(Leu(UUR)) gene....
OBJECTIVE
Several mutations in mitochondrial DNA have been associated with infantile cardiomyopathy, including a C3303T mutation in the mitochondrial transfer RNA(Leu(UUR)) gene. Although this mutation satisfied generally accepted criteria for pathogenicity, its causative role remained to be confirmed in more families. Our objective was to establish the frequency of the C3303T mutation and to define its clinical presentation.
STUDY DESIGN
Families with cardiomyopathy and maternal inheritance were studied by polymerase chain reaction/restriction fragment length polymorphism analysis looking for the C3303T mutation.
RESULTS
We found the C3303T mutation in 8 patients from 4 unrelated families. In one, the clinical presentation was infantile cardiomyopathy; in the second family, proximal limb and neck weakness dominated the clinical picture for the first 10 years of life, when cardiac dysfunction became apparent; in the third family, 2 individuals presented with isolated skeletal myopathy and 2 others with skeletal myopathy and cardiomyopathy; in the fourth family, one patient had fatal infantile cardiomyopathy and the other had a combination of skeletal myopathy and cardiomyopathy.
CONCLUSIONS
Our findings confirm the pathogenicity of the C3303T mutation and suggest that this mutation may not be rare. The C3303T mutation should be considered in the differential diagnosis of skeletal myopathies and cardiomyopathy, especially when onset is in infancy.
Topics: Adolescent; Adult; Age of Onset; Aged; Cardiomyopathies; Child; DNA, Mitochondrial; Female; Humans; Infant; Male; Middle Aged; Mitochondrial Myopathies; Pedigree; Point Mutation; Polymorphism, Restriction Fragment Length
PubMed: 10431114
DOI: 10.1016/s0022-3476(99)70022-3 -
Annals of Neurology Oct 2021Autosomal recessive human thymidine kinase 2 (TK2) mutations cause TK2 deficiency, which typically manifests as a progressive and fatal mitochondrial myopathy in infants...
OBJECTIVE
Autosomal recessive human thymidine kinase 2 (TK2) mutations cause TK2 deficiency, which typically manifests as a progressive and fatal mitochondrial myopathy in infants and children. Treatment with pyrimidine deoxynucleosides deoxycytidine and thymidine ameliorates mitochondrial defects and extends the lifespan of Tk2 knock-in mouse (Tk2 ) and compassionate use deoxynucleoside therapy in TK2 deficient patients have shown promising indications of efficacy. To augment therapy for Tk2 deficiency, we assessed gene therapy alone and in combination with deoxynucleoside therapy in Tk2 mice.
METHODS
We generated pAAVsc CB6 PI vectors containing human TK2 cDNA (TK2). Adeno-associated virus (AAV)-TK2 was administered to Tk2 , which were serially assessed for weight, motor functions, and survival as well as biochemical functions in tissues. AAV-TK2 treated mice were further treated with deoxynucleosides.
RESULTS
AAV9 delivery of human TK2 cDNA to Tk2 mice efficiently rescued Tk2 activity in all the tissues tested except the kidneys, delayed disease onset, and increased lifespan. Sequential treatment of Tk2 mice with AAV9 first followed by AAV2 at different ages allowed us to reduce the viral dose while further prolonging the lifespan. Furthermore, addition of deoxycytidine and deoxythymidine supplementation to AAV9 + AAV2 treated Tk2 mice dramatically improved mtDNA copy numbers in the liver and kidneys, animal growth, and lifespan.
INTERPRETATION
Our data indicate that AAV-TK2 gene therapy as well as combination deoxynucleoside and gene therapies is more effective in Tk2 mice than pharmacological alone. Thus, combination of gene therapy with substrate enhancement is a promising therapeutic approach for TK2 deficiency and potentially other metabolic disorders. ANN NEUROL 2021;90:640-652.
Topics: Animals; Compassionate Use Trials; DNA, Mitochondrial; Genetic Therapy; Humans; Mice; Mitochondria; Mitochondrial Myopathies; Mutation; Thymidine; Thymidine Kinase
PubMed: 34338329
DOI: 10.1002/ana.26185 -
Brain Pathology (Zurich, Switzerland) Jul 2022Two homoplasmic variants in tRNA (m.14674T>C/G) are associated with reversible infantile respiratory chain deficiency. This study sought to further characterize the...
Expression pattern of mitochondrial respiratory chain enzymes in skeletal muscle of patients with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant.
Two homoplasmic variants in tRNA (m.14674T>C/G) are associated with reversible infantile respiratory chain deficiency. This study sought to further characterize the expression of the individual mitochondrial respiratory chain complexes and to describe the natural history of the disease. Seven patients from four families with mitochondrial myopathy associated with the homoplasmic m.14674T>C variant were investigated. All patients underwent skeletal muscle biopsy and mtDNA sequencing. Whole-genome sequencing was performed in one family. Western blot and immunohistochemical analyses were used to characterize the expression of the individual respiratory chain complexes. Patients presented with hypotonia and feeding difficulties within the first weeks or months of life, except for one patient who first showed symptoms at 4 years of age. Histopathological findings in muscle included lipid accumulation, numerous COX-deficient fibers, and mitochondrial proliferation. Ultrastructural abnormalities included enlarged mitochondria with concentric cristae and dense mitochondrial matrix. The m.14674T>C variant in MT-TE was identified in all patients. Immunohistochemistry and immunoblotting demonstrated pronounced deficiency of the complex I subunit NDUFB8. The expression of MTCO1, a complex IV subunit, was also decreased, but not to the same extent as NDUFB8. Longitudinal follow-up data demonstrated that not all features of the disorder are entirely transient, that the disease may be progressive, and that signs and symptoms of myopathy may develop during childhood. This study sheds new light on the involvement of complex I in reversible infantile respiratory chain deficiency, it shows that the disorder may be progressive, and that myopathy can develop without an infantile episode.
Topics: Cytochrome-c Oxidase Deficiency; DNA, Mitochondrial; Electron Transport; Humans; Mitochondrial Myopathies; Muscle, Skeletal; Mutation
PubMed: 34806237
DOI: 10.1111/bpa.13038 -
BMC Nephrology Mar 2022MtDNA 3243 A > G mutation leads to mitochondrial myopathies with predominant hyperlactatemia. Given the ubiquitous nature of mitochondria, cellular dysfunction can...
BACKGROUND
MtDNA 3243 A > G mutation leads to mitochondrial myopathies with predominant hyperlactatemia. Given the ubiquitous nature of mitochondria, cellular dysfunction can also appear in tissues with high metabolic turnover; thus, there can be cardiac, digestive, ophthalmologic, and kidney complications. MtDNA 3243 A > G mutation has been shown to be with renal involvement in the previous cases of which are FSGS and tubularinterstitial nephritis.
CASE PRESENTATION
We report a case of patient who had the mitochondrial myopathy with mitochondrial DNA (mtDNA) 3243 A > G mutation diagnosed membranous nephropathy by kidney biopsy, which was never reported before. Our patient was found to have chest tightness and shortness of breath with hyperlactatemia and was diagnosed mitochondrial myopathy with mtDNA 3243 A > G mutation 11 months ago. Acute kidney injury occurred with hyperuricemia (urid acid 1011umol/L) which may be associated with mtDNA mutation. Since then, persistent proteinuria was also found and the 24-h urine protein quantitative was around 2 g. Kidney biopsy was performed and the result was consistent with membranous nephropathy, with abnormal mitochondria seen in renal tubules by electron microscopy.
CONCLUSIONS
Patients with mitochondrial myopathy could also have renal presentation of membranous nephropathy. Patients with mtDNA mutation may have various renal manifestations so that more attention should be paid on their kidneys.
Topics: DNA, Mitochondrial; Female; Glomerulonephritis, Membranous; Humans; Hyperlactatemia; Kidney; Male; Mitochondrial Myopathies
PubMed: 35246049
DOI: 10.1186/s12882-022-02710-0 -
Molecular Endocrinology (Baltimore, Md.) Aug 2011The estimated incidence of mitochondrial diseases in humans is approximately 1:5000 to 1:10,000, whereas the molecular mechanisms for more than 50% of human...
The estimated incidence of mitochondrial diseases in humans is approximately 1:5000 to 1:10,000, whereas the molecular mechanisms for more than 50% of human mitochondrial disease cases still remain unclear. Here we report that mice lacking testicular nuclear receptor 4 (TR4(-/-)) suffered mitochondrial myopathy, and histological examination of TR4(-/-) soleus muscle revealed abnormal mitochondrial accumulation. In addition, increased serum lactate levels, decreased mitochondrial ATP production, and decreased electron transport chain complex I activity were found in TR4(-/-) mice. Restoration of TR4 into TR4(-/-) myoblasts rescued mitochondrial ATP generation capacity and complex I activity. Further real-time PCR quantification and promoter studies found TR4 could modulate complex I activity via transcriptionally regulating the complex I assembly factor NDUFAF1, and restoration of NDUFAF1 level in TR4(-/-) myoblasts increased mitochondrial ATP generation capacity and complex I activity. Together, these results suggest that TR4 plays vital roles in mitochondrial function, which may help us to better understand the pathogenesis of mitochondrial myopathy, and targeting TR4 via its ligands/activators may allow us to develop better therapeutic approaches.
Topics: Adenosine Triphosphate; Aminoimidazole Carboxamide; Animals; Cells, Cultured; Electron Transport Complex I; Gene Expression Regulation; Humans; Lactic Acid; Metformin; Mice; Mitochondria; Mitochondrial Myopathies; Muscle Weakness; Muscle, Skeletal; Myoblasts; NADH Dehydrogenase; Physical Conditioning, Animal; Receptors, Steroid; Receptors, Thyroid Hormone; Ribonucleotides
PubMed: 21622535
DOI: 10.1210/me.2010-0455