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EMBO Molecular Medicine Oct 2015Mitochondrial disorders are a group of highly invalidating human conditions for which effective treatment is currently unavailable and characterized by faulty energy... (Review)
Review
Mitochondrial disorders are a group of highly invalidating human conditions for which effective treatment is currently unavailable and characterized by faulty energy supply due to defective oxidative phosphorylation (OXPHOS). Given the complexity of mitochondrial genetics and biochemistry, mitochondrial inherited diseases may present with a vast range of symptoms, organ involvement, severity, age of onset, and outcome. Despite the wide spectrum of clinical signs and biochemical underpinnings of this group of dis-orders, some common traits can be identified, based on both pathogenic mechanisms and potential therapeutic approaches. Here, we will review two peculiar mitochondrial disorders, ethylmalonic encephalopathy (EE) and mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), caused by mutations in the ETHE1 and TYMP nuclear genes, respectively. ETHE1 encodes for a mitochondrial enzyme involved in sulfide detoxification and TYMP for a cytosolic enzyme involved in the thymidine/deoxyuridine catabolic pathway. We will discuss these two clinical entities as a paradigm of mitochondrial diseases caused by the accumulation of compounds normally present in traces, which exerts a toxic and inhibitory effect on the OXPHOS system.
Topics: Brain Diseases, Metabolic, Inborn; Humans; Intestinal Pseudo-Obstruction; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Proteins; Muscular Dystrophy, Oculopharyngeal; Mutation; Nucleocytoplasmic Transport Proteins; Ophthalmoplegia; Purpura; Thymidine Phosphorylase
PubMed: 26194912
DOI: 10.15252/emmm.201505040 -
Chinese Medical Journal Jul 2015Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a progressive, multisystem affected mitochondrial disease associated with a... (Review)
Review
OBJECTIVE
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a progressive, multisystem affected mitochondrial disease associated with a number of disease-related defective genes. MELAS has unpredictable presentations and clinical course, and it can be commonly misdiagnosed as encephalitis, cerebral infarction, or brain neoplasms. This review aimed to update the diagnosis progress in MELAS, which may provide better understanding of the disease nature and help make the right diagnosis as well.
DATA SOURCES
The data used in this review came from published peer review articles from October 1984 to October 2014, which were obtained from PubMed. The search term is "MELAS".
STUDY SELECTION
Information selected from those reported studies is mainly based on the progress on clinical features, blood biochemistry, neuroimaging, muscle biopsy, and genetics in diagnosing MELAS.
RESULTS
MELAS has a wide heterogeneity in genetics and clinical manifestations. The relationship between mutations and phenotypes remains unclear. Advanced serial functional magnetic resonance imaging (MRI) can provide directional information on this disease. Muscle biopsy has meaningful value in diagnosing MELAS, which shows the presence of ragged red fibers and mosaic appearance of cytochrome oxidase negative fibers. Genetic studies have reported that approximately 80% of MELAS cases are caused by the mutation m.3243A>G of the mitochondrial transfer RNA (Leu (UUR)) gene (MT-TL1).
CONCLUSIONS
MELAS involves multiple systems with variable clinical symptoms and recurrent episodes. The prognosis of MELAS patients depends on timely diagnosis. Therefore, overall diagnosis of MELAS should be based on the maternal inheritance family history, clinical manifestation, and findings from serial MRI, muscle biopsy, and genetics.
Topics: Humans; MELAS Syndrome; Magnetic Resonance Imaging
PubMed: 26112726
DOI: 10.4103/0366-6999.159360 -
Journal of Neurology Dec 2022To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM).
OBJECTIVES
To assess natural history and 12-month change of a series of scales and functional outcome measures in a cohort of 117 patients with primary mitochondrial myopathy (PMM).
METHODS
Twelve months follow-up data of 117 patients with PMM were collected. We analysed the 6-min walk test (6MWT), timed up-and-go test (× 3) (3TUG), five-times sit-to-stand test (5XSST), timed water swallow test (TWST), and test of masticating and swallowing solids (TOMASS) as functional outcome measures; the Fatigue Severity Scale and West Haven-Yale Multidimensional pain inventory as patient-reported outcome measures. PMM patients were divided into three phenotypic categories: mitochondrial myopathy (MiMy) without extraocular muscles involvement, pure chronic progressive external ophthalmoplegia (PEO) and PEO&MiMy. As 6MWT is recognized to have significant test-retest variability, we calculated MCID (minimal clinically important difference) as one third of baseline 6 min walking distance (6MWD) standard deviation.
RESULTS
At 12-month follow-up, 3TUG, 5XSST and FSS were stable, while TWST and the perceived pain severity (WHYMPI) worsened. 6MWD significantly increased in the entire cohort, especially in the higher percentiles and in PEO patients, while was substantially stable in the lower percentile (< 408 m) and MiMy patients. This increase in 6MWD was considered not significant, as inferior to MCID (33.3 m). NMDAS total score showed a slight but significant decline at 12 months (0.9 point). The perceived pain severity significantly worsened. Patients with PEO performed better in functional measures than patients with PEO&MiMy or MiMy, and had lower values of NMDAS.
CONCLUSIONS
PMM patients showed a slow global decline valued by NMDAS at 12 months; 6MWT was a more reliable measurement below 408 m, substantially stable at 12 months. PEO patients had better motor performance and lower NMDAS than PEO&MiMy and MiMy also at 12 months of follow-up.
Topics: Humans; Follow-Up Studies; Walk Test; Mitochondrial Myopathies; Ophthalmoplegia, Chronic Progressive External; Time Factors; Walking
PubMed: 35980466
DOI: 10.1007/s00415-022-11324-3 -
Cell Metabolism Aug 2017Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial...
Mitochondrial dysfunction elicits various stress responses in different model systems, but how these responses relate to each other and contribute to mitochondrial disease has remained unclear. Mitochondrial myopathy (MM) is the most common manifestation of adult-onset mitochondrial disease and shows a multifaceted tissue-specific stress response: (1) transcriptional response, including metabolic cytokines FGF21 and GDF15; (2) remodeling of one-carbon metabolism; and (3) mitochondrial unfolded protein response. We show that these processes are part of one integrated mitochondrial stress response (ISRmt), which is controlled by mTORC1 in muscle. mTORC1 inhibition by rapamycin downregulated all components of ISRmt, improved all MM hallmarks, and reversed the progression of even late-stage MM, without inducing mitochondrial biogenesis. Our evidence suggests that (1) chronic upregulation of anabolic pathways contributes to MM progression, (2) long-term induction of ISRmt is not protective for muscle, and (3) rapamycin treatment trials should be considered for adult-type MM with raised FGF21.
Topics: Animals; Fibroblast Growth Factors; Humans; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Middle Aged; Mitochondria, Muscle; Mitochondrial Myopathies; Stress, Physiological
PubMed: 28768179
DOI: 10.1016/j.cmet.2017.07.007 -
Journal of the American College of... Oct 2022The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the...
BACKGROUND
The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the MT-TL1 m.3243A>G mutation of the mitochondrial DNA. Heart transplantation (HTx) is controversial and has rarely been performed with conflicting results.
OBJECTIVES
We analyzed factors preventing HTx in consecutive adult patients with MELAS cardiomyopathy diagnosed and followed during the last 23 years in our HTx referral center.
METHODS
The series consists of 14 unrelated adult probands who were referred for evaluation of cardiomyopathy from 1998 to 2021. None had a suspected diagnosis of MELAS before referral. All patients underwent clinical and genetic visit and counseling, mitochondrial DNA sequencing, cardiovascular investigation (including right heart catheterization and endomyocardial biopsy in 10), multidisciplinary assessment, and biochemical tests. Family screening identified 2 affected relatives.
RESULTS
The cardiac phenotype was characterized by hypertrophic, concentric, nonobstructive cardiomyopathy that often evolved into a dilated cardiomyopathy-like phenotype. Of the 14 probands, 7 were potential candidates for HTx, 2 for heart and kidney Tx, and 1 was on the active HTx list for 3 years. None of the 10 probands underwent HTx. One is currently being evaluated for HTx. All had diabetes, hearing loss, and myopathy, and 10 had chronic kidney disease and progressive encephalomyopathy. During follow-up, 10 died from heart failure associated with multiorgan failure within 5 years of the genetic diagnosis.
CONCLUSIONS
High risk of stroke-like episodes, chronic kidney disease, and wasting myopathy in MELAS patients prevents activation of plans for HTx. As a result, the management of their cardiomyopathy in this syndromic context remains an unmet clinical need.
Topics: Cardiomyopathies; DNA, Mitochondrial; Heart Transplantation; Humans; MELAS Syndrome; Muscular Diseases; Mutation; Renal Insufficiency, Chronic
PubMed: 36202533
DOI: 10.1016/j.jacc.2022.04.067 -
Current Opinion in Clinical Nutrition... Jan 2020We would like to inform clinicians that the systematic administration of oral and intravenous L-arginine is therapeutically beneficial and clinically useful for patients... (Review)
Review
PURPOSE OF REVIEW
We would like to inform clinicians that the systematic administration of oral and intravenous L-arginine is therapeutically beneficial and clinically useful for patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), when they maintain plasma arginine concentration at least 168 μmol/l.
RECENT FINDINGS
MELAS is associated with endothelial dysfunction by decreased plasma L-arginine, nitric oxide (NO), and cyclic guanosine monophosphate. Endothelial dysfunction is also evident using flow-mediated vasodilation measurement by high-resolution Doppler echocardiography in the forearm artery in patients with MELAS. L-arginine is known to be an important precursor of NO to normalize the endothelial function in MELAS. In our clinical trial followed by 7 years follow-up study, the systematic administration of L-arginine to patients with MELAS significantly improved the survival curve of patients compared with natural history. Maintaining plasma arginine concentration at least 168 μmol/l may prevent the ictuses through the putative pathophysiologic mechanism and optimal normalization of endothelial dysfunction.
SUMMARY
Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. Therapeutic regimen of L-arginine on MELAS may be beneficial and clinically useful for patient care with MELAS.
Topics: Administration, Intravenous; Arginine; Clinical Trials as Topic; Follow-Up Studies; Humans; MELAS Syndrome; Treatment Outcome
PubMed: 31693521
DOI: 10.1097/MCO.0000000000000610 -
Neurology Feb 2020To investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy. (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To investigate the safety and efficacy of escalating doses of the semi-synthetic triterpenoid omaveloxolone in patients with mitochondrial myopathy.
METHODS
In cohorts of 8-13, 53 participants were randomized double-blind to 12 weeks of treatment with omaveloxolone 5, 10, 20, 40, 80, or 160 mg, or placebo. Outcome measures were change in peak cycling exercise workload (primary), in 6-minute walk test (6MWT) distance (secondary), and in submaximal exercise heart rate and plasma lactate (exploratory).
RESULTS
No differences in peak workload or 6MWT were observed at week 12 with omaveloxolone treatment vs placebo for all omaveloxolone dose groups. In contrast, omaveloxolone 160 mg reduced heart rate at week 12 by 12.0 ± 4.6 bpm (SE) during submaximal exercise vs placebo, = 0.01, and by 8.7 ± 3.5 bpm (SE) vs baseline, = 0.02. Similarly, blood lactate was 1.4 ± 0.7 mM (SE) lower vs placebo, = 0.04, and 1.6 ± 0.5 mM (SE) lower vs baseline at week 12, = 0.003, with omaveloxolone 160 mg treatment. Adverse events were generally mild and infrequent.
CONCLUSIONS
Omaveloxolone 160 mg was well-tolerated, and did not lead to change in the primary outcome measure, but improved exploratory endpoints lowering heart rate and lactate production during submaximal exercise, consistent with improved mitochondrial function and submaximal exercise tolerance. Therefore, omaveloxolone potentially benefits patients with mitochondrial myopathy, which encourages further investigations of omaveloxolone in this patient group.
CLINICALTRIALSGOV IDENTIFIER
NCT02255422.
CLASSIFICATION OF EVIDENCE
This study provides Class II evidence that, for patients with mitochondrial myopathy, omaveloxolone compared to placebo did not significantly change peak exercise workload.
Topics: Adult; Anti-Inflammatory Agents; Biomarkers; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Exercise Test; Female; Heart Rate; Humans; Lactic Acid; Male; Middle Aged; Mitochondrial Myopathies; NF-E2-Related Factor 2; Treatment Outcome; Triterpenes
PubMed: 31896620
DOI: 10.1212/WNL.0000000000008861 -
Neuromuscular Disorders : NMD Oct 2016Myofibrillar myopathies (MFM) are characterised by focal myofibrillar destruction and accumulation of myofibrillar elements as protein aggregates. They are caused by...
Myofibrillar myopathies (MFM) are characterised by focal myofibrillar destruction and accumulation of myofibrillar elements as protein aggregates. They are caused by mutations in the DES, MYOT, CRYAB, FLNC, BAG3, DNAJB6 and ZASP genes as well as other as yet unidentified genes. Previous studies have reported changes in mitochondrial morphology and cellular positioning, as well as clonally-expanded, large-scale mitochondrial DNA (mtDNA) deletions and focal respiratory chain deficiency in muscle of MFM patients. Here we examine skeletal muscle from patients with desmin (n = 6), ZASP (n = 1) and myotilin (n = 2) mutations and MFM protein aggregates, to understand how mitochondrial dysfunction may contribute to the underlying mechanisms causing disease pathology. We have used a validated quantitative immunofluorescent assay to study respiratory chain protein levels, together with oxidative enzyme histochemistry and single cell mitochondrial DNA analysis, to examine mitochondrial changes. Results demonstrate a small number of clonally-expanded mitochondrial DNA deletions, which we conclude are due to both ageing and disease pathology. Further to this we report higher levels of respiratory chain complex I and IV deficiency compared to age matched controls, although overall levels of respiratory deficient muscle fibres in patient biopsies are low. More strikingly, a significantly higher percentage of myofibrillar myopathy patient muscle fibres have a low mitochondrial mass compared to controls. We concluded this is mechanistically unrelated to desmin and myotilin protein aggregates; however, correlation between mitochondrial mass and muscle fibre area is found. We suggest this may be due to reduced mitochondrial biogenesis in combination with muscle fibre hypertrophy.
Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Cell Cycle Proteins; Cohort Studies; Connectin; DNA, Mitochondrial; Desmin; Female; Humans; LIM Domain Proteins; Male; Microfilament Proteins; Middle Aged; Mitochondria; Muscle, Skeletal; Mutation; Myopathies, Structural, Congenital; Ribonucleotide Reductases
PubMed: 27618136
DOI: 10.1016/j.nmd.2016.08.004 -
CNS Neuroscience & Therapeutics Jul 2021Mitochondrial encephalomyopathies are disorders caused by mitochondrial and nuclear DNA mutations which affect the nervous and muscular systems. Current therapies for... (Review)
Review
Mitochondrial encephalomyopathies are disorders caused by mitochondrial and nuclear DNA mutations which affect the nervous and muscular systems. Current therapies for mitochondrial encephalomyopathies are inadequate and mostly palliative. However, stem cell-derived mitochondria transplantation has been demonstrated to play an key part in metabolic rescue, which offers great promise for mitochondrial encephalomyopathies. Here, we summarize the present status of stem cell therapy for mitochondrial encephalomyopathy and discuss mitochondrial transfer routes and the protection mechanisms of stem cells. We also identify and summarize future perspectives and challenges for the treatment of these intractable disorders based on the concept of mitochondrial transfer from stem cells.
Topics: Animals; DNA, Mitochondrial; Extracellular Vesicles; Humans; Mitochondria; Mitochondrial Encephalomyopathies; Nanotubes; Stem Cell Transplantation; Stem Cells
PubMed: 33538116
DOI: 10.1111/cns.13618 -
Mitochondrion Sep 2021Mitochondrial myopathy (MM) encompasses a clinical heterogenous group of patients that can be difficult to diagnose. The aim of this study was to investigate if changes...
INTRODUCTION/BACKGROUND
Mitochondrial myopathy (MM) encompasses a clinical heterogenous group of patients that can be difficult to diagnose. The aim of this study was to investigate if changes in plasma lactate concentration during a 6-minute submaximal handgrip test (6MHGT) and a 20-minute post-exercise recovery period can be used as a diagnostic test for MM.
METHODS
Twenty-nine patients with MM and nineteen healthy controls (HC) performed an intermittent handgrip exercise test at ½ Hz for 6 min at 50% of maximal voluntary contraction force. We calculated the area under the curve (AUC) of change in plasma lactate during exercise and recovery and compared AUC between groups (MM vs. HC, and between MM subgroups based on disease severity).
RESULTS
The change in plasma lactate during exercise and recovery was similar in MM and HC (p = 0.65 and p = 0.57) and similar between MM subgroups (p ≥ 0.24).
CONCLUSION
Plasma lactate measured during and after a submaximal 6MHGT cannot be used as a diagnostic variable for MM.
Topics: Adult; Aged; Area Under Curve; Case-Control Studies; Exercise; Female; Hand Strength; Humans; Lactates; Male; Middle Aged; Mitochondrial Myopathies; Young Adult
PubMed: 34273558
DOI: 10.1016/j.mito.2021.07.002