-
Neurologic Clinics Aug 2014Metabolic and mitochondrial myopathies encompass a heterogeneous group of disorders that result in impaired energy production in skeletal muscle. Symptoms of premature... (Review)
Review
Metabolic and mitochondrial myopathies encompass a heterogeneous group of disorders that result in impaired energy production in skeletal muscle. Symptoms of premature muscle fatigue, sometimes leading to myalgia, rhabdomyolysis, and myoglobinuria, typically occur with exercise that would normally depend on the defective metabolic pathway. But in another group of these disorders, the dominant muscle symptom is weakness. This article reviews the clinical features, diagnosis, and management of these diseases with emphasis on the recent literature.
Topics: Adult; Female; Glycogen Storage Disease; Humans; Lipid Metabolism Disorders; Mitochondrial Myopathies; Muscle, Skeletal; Muscular Diseases; Young Adult
PubMed: 25037090
DOI: 10.1016/j.ncl.2014.05.001 -
Annals of Clinical and Laboratory... Mar 2018
Topics: Autoimmunity; DNA, Mitochondrial; Humans; MELAS Syndrome; Mutation; Phenotype
PubMed: 29678857
DOI: No ID Found -
Seizure Aug 2017Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare syndromic mitochondrial disorder (MID) with a broad phenotypic but narrow genotypic heterogeneity.... (Review)
Review
Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare syndromic mitochondrial disorder (MID) with a broad phenotypic but narrow genotypic heterogeneity. One of the predominant phenotypic features in addition to myopathy is epilepsy. The most frequent seizure type in MERRF is generalised myoclonic seizure but also focal myoclonic, focal atonic, generalised tonic-clonic, generalised atonic, generalised myoclonic-atonic, typical absences, or tonic-clonic seizures of unknown onset have been reported. There are no guidelines available for the management of epilepsy in MERRF syndrome but several expert opinions and general recommendations for the treatment of mitochondrial epilepsy have been published. According to these recommendations the antiepileptic drugs (AEDs) of choice are levetiracetam, topiramate, zonisamide, piracetam, and benzodiazepines. Perampanel has not been applied in MERRF patients but is promising in non-mitochondrial myoclonic epilepsy. Mitochondrion-toxic agents, including mitochondrion-toxic AEDs, such as valproate, carbamazepine, phenytoin, and barbiturates, should be avoided as well as AEDs potentially enhancing the frequency of myoclonus, such as phenytoin, carbamazepine, lamotrigine, vigabatrin, tiagabine, gabapentin, pregabalin, and oxcarbazepine.
Topics: Anticonvulsants; Epilepsy; Humans; MERRF Syndrome
PubMed: 28686997
DOI: 10.1016/j.seizure.2017.06.010 -
Nature Reviews. Nephrology May 2016Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are... (Review)
Review
Mitochondria are increasingly recognized as key players in genetic and acquired renal diseases. Most mitochondrial cytopathies that cause renal symptoms are characterized by tubular defects, but glomerular, tubulointerstitial and cystic diseases have also been described. For example, defects in coenzyme Q10 (CoQ10) biosynthesis and the mitochondrial DNA 3243 A>G mutation are important causes of focal segmental glomerulosclerosis in children and in adults, respectively. Although they sometimes present with isolated renal findings, mitochondrial diseases are frequently associated with symptoms related to central nervous system and neuromuscular involvement. They can result from mutations in nuclear genes that are inherited according to classic Mendelian rules or from mutations in mitochondrial DNA, which are transmitted according to more complex rules of mitochondrial genetics. Diagnosis of mitochondrial disorders involves clinical characterization of patients in combination with biochemical and genetic analyses. In particular, prompt diagnosis of CoQ10 biosynthesis defects is imperative because of their potentially reversible nature. In acute kidney injury (AKI), mitochondrial dysfunction contributes to the physiopathology of tissue injury, whereas mitochondrial biogenesis has an important role in the recovery of renal function. Potential therapies that target mitochondrial dysfunction or promote mitochondrial regeneration are being developed to limit renal damage during AKI and promote repair of injured tissue.
Topics: Acute Kidney Injury; Alkyl and Aryl Transferases; Animals; DNA, Mitochondrial; Humans; Kearns-Sayre Syndrome; Kidney Diseases; Mitochondria; Mitochondrial Myopathies; Mutation; Oxidative Phosphorylation; Reactive Oxygen Species; Ubiquinone
PubMed: 26804019
DOI: 10.1038/nrneph.2015.214 -
Neurotherapeutics : the Journal of the... Jan 2024This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach... (Review)
Review
This paper provides an overview of the different types of mitochondrial myopathies (MM), associated phenotypes, genotypes as well as a practical clinical approach towards disease diagnosis, surveillance, and management. nDNA-related MM are more common in pediatric-onset disease whilst mtDNA-related MMs are more frequent in adults. Genotype-phenotype correlation in MM is challenging due to clinical and genetic heterogeneity. The multisystemic nature of many MMs adds to the diagnostic challenge. Diagnostic approaches utilizing genetic sequencing with next generation sequencing approaches such as gene panel, exome and genome sequencing are available. This aids molecular diagnosis, heteroplasmy detection in MM patients and furthers knowledge of known mitochondrial genes. Precise disease diagnosis can end the diagnostic odyssey for patients, avoid unnecessary testing, provide prognosis, facilitate anticipatory management, and enable access to available therapies or clinical trials. Adjunctive tests such as functional and exercise testing could aid surveillance of MM patients. Management requires a multi-disciplinary approach, systemic screening for comorbidities, cofactor supplementation, avoidance of substances that inhibit the respiratory chain and exercise training. This update of the current understanding on MMs provides practical perspectives on current diagnostic and management approaches for this complex group of disorders.
Topics: Humans; Child; Mitochondrial Myopathies; Mitochondria; High-Throughput Nucleotide Sequencing; Mitochondrial Diseases
PubMed: 38241155
DOI: 10.1016/j.neurot.2023.11.001 -
Zhong Nan Da Xue Xue Bao. Yi Xue Ban =... Nov 2023Mitochondrial myopathy is a group of multi-system diseases in which mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) defects lead to structural and functional dysfunction...
Mitochondrial myopathy is a group of multi-system diseases in which mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) defects lead to structural and functional dysfunction of mitochondria. The clinical manifestations of mitochondrial myopathy are complex and varied, and the testing for mtDNA and nDNA is not widely available, so misdiagnosis or missed diagnosis is common. Chronic progressive external ophthalmoplegia (CPEO) is a common type of mitochondrial myopathy, which is characterized by blepharoptosis. Here we report a 38-year-old female with mitochondrial myopathy presented with chronic numbness and weakness of the limbs, accompanied by blepharoptosis that was recently noticed. Laboratory and head magnetic resonance imaging (MRI) examinations showed no obvious abnormalities. Muscle and nerve biopsies showed characteristic ragged red fibers (RRFs) and large aggregates of denatured mitochondria. Testing for mtDNA and nDNA showed a known mutation c.2857C>T (p.R953C) and a novel variant c.2391G>C (p.M797I) in the polymerase gamma ()gene, so the patient was diagnosed as mitochondrial myopathy. Clinicians should pay more attention to long-term unexplained skeletal muscle diseases with recent onset blepharoptosis. Histopathologic examination and genetic testing are of great value in the early diagnosis and therapeutic intervention.
Topics: Female; Humans; Adult; Blepharoptosis; Mitochondrial Myopathies; Ophthalmoplegia, Chronic Progressive External; DNA, Mitochondrial; Mitochondria
PubMed: 38432868
DOI: 10.11817/j.issn.1672-7347.2023.220605 -
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 -
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 -
Mitochondrion Jan 2020We investigated if Growth and Differentiation Factor 15 (GDF-15) can be used as a biomarker to distinguish patients with mitochondrial myopathy from patients with other...
OBJECTIVE
We investigated if Growth and Differentiation Factor 15 (GDF-15) can be used as a biomarker to distinguish patients with mitochondrial myopathy from patients with other myopathies.
METHODS
Serum GDF-15 was measured in 28 patients with mitochondrial disease, 24 with metabolic myopathies, 27 with muscular dystrophy and 21 healthy controls.
RESULTS AND CONCLUSIONS
Our findings indicate that elevated GDF-15 can distinguish patients with mitochondrial myopathy from other myopathies, including metabolic myopathies. This suggests that increases in GDF-15 is specific to respiratory chain dysfunction rather than general metabolic dysfunction or muscle defect.
Topics: Adolescent; Adult; Aged; Biomarkers; Exercise Test; Female; Gene Expression Regulation; Growth Differentiation Factor 15; Humans; Male; Middle Aged; Mitochondrial Myopathies; Oxidative Stress; Pilot Projects; Young Adult
PubMed: 31669236
DOI: 10.1016/j.mito.2019.10.005 -
Fortschritte Der Neurologie-Psychiatrie Sep 2018Mitochondrial diseases (MD) represent a heterogenous group of disorders and syndromes caused either by mutations of the mitochondrial DNA (mtDNA) or the nuclear DNA... (Review)
Review
Mitochondrial diseases (MD) represent a heterogenous group of disorders and syndromes caused either by mutations of the mitochondrial DNA (mtDNA) or the nuclear DNA (nDNA). They belong to the most frequent neurogenetic diseases. The spectrum of clinical manifestations is very broad ranging from mild subclinical presentations to rapidly progressive debilitating conditions with reduced life expectancy. Mitochondrial dysfunction can affect any organ of the body; the clinical presentation is often most severe in tissues with high energy demands. The most common MD are Leber's Hereditary Optic Neuropathy (LHON), Chronic Progressive External Ophthalmoplegia (CPEO), Kearns-Sayre Syndrome (KSS), Mitochondrial Myopathy (MM) and Mitochondrial Encephalomyopathy, Lactic Acidosis and Strokelike episodes (MELAS). In the last couple of years, genetics have become more and more important for the diagnosis of MD. The majority of syndromes presents with a characteristic combination of clinical and laboratory findings which should guide the selection of tissues (blood cells, fibroblasts, urothelial cells or muscle) and methods for targeted genetic testing. Therapeutic approaches to MD include pharmacological stimulation of mitochondrial metabolism, supplementation, symptomatic treatment, assistive devices and physiotherapy. Moreover, strict anti-epileptic therapy and treatment or prevention of stroke-like episodes are very important to prevent complications. In contrast, some medication should be avoided for its direct or indirect depressing effect on mitochondrial function. This article provides an introduction to mitochondrial diseases, an overview of the most common syndromes and an update on established and new therapeutic approaches.
Topics: Genetic Testing; Humans; Mitochondrial Diseases; Mitochondrial Encephalomyopathies
PubMed: 30248691
DOI: 10.1055/a-0621-9255