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Neurology India 2023Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant,...
OBJECTIVES
Clinical spectrum of mitochondrial myopathy extends beyond chronic progressive external ophthalmoplegia (CPEO). While information on encephalomyopathies is abundant, clinical data on predominant myopathic presentation of mitochondrial disorders are lacking.
MATERIALS AND METHODS
Clinical, electrophysiological, biochemical, and follow-up data of patients with predominant myopathic presentation and muscle biopsy confirmed primary mitochondrial myopathy was obtained. We excluded known syndromes of mitochondrial cytopathies and encephalomyopathies.
RESULTS
Among 16 patients, 7 had CPEO, 4 had CPEO with limb-girdle muscle weakness (LGMW), and 5 had isolated LGMW. Systemic features included seizures with photosensitivity (n = 3), diabetes (n = 1), cardiomyopathy (n = 1), and sensorineural hearing loss (n = 1) and were more common in isolated LGMW. Elevated serum creatine kinase (CK) and lactate levels and electromyography (EMG) myopathic potentials were more frequent with LGMW. During follow-up, LGMW had more severe progression of weakness.
CONCLUSION
We identified three subsets of mitochondrial myopathy with distinct clinical features and evolutionary patterns. Isolated LGMW was seen in 30% of patients and would represent severe end of the spectrum.
Topics: Humans; Mitochondrial Myopathies; Kearns-Sayre Syndrome; Ophthalmoplegia, Chronic Progressive External; Electromyography; Biopsy
PubMed: 38174457
DOI: 10.4103/0028-3886.391399 -
Yonsei Medical Journal Dec 2018To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease.
PURPOSE
To evaluate the classification, diagnosis, and natural course of ophthalmoplegia associated with mitochondrial disease.
MATERIALS AND METHODS
Among 372 patients with mitochondrial disease who visited our hospital between January 2006 and January 2016, 21 patients with ophthalmoplegia were retrospectively identified. Inclusion criteria included onset before 20 years of age, pigmentary retinopathy, and cardiac involvement. The 16 patients who were finally included in the study were divided into three groups according to disease type: Kearns-Sayre syndrome (KSS), KSS-like, and chronic progressive external ophthalmoplegia (CPEO).
RESULTS
The prevalences of clinical findings were as follows: ptosis and retinopathy, both over 80%; myopathy, including extraocular muscles, 75%; lactic acidosis, 71%; and elevated levels of serum creatine kinase, 47%. Half of the patients had normal magnetic resonance imaging findings. A biochemical enzyme assay revealed mitochondrial respiratory chain complex I defect as the most common (50%). The prevalence of abnormal muscle findings in light or electron microscopic examinations was 50% each, while that of large-scale mitochondrial DNA (mtDNA) deletions in a gene study was 25%. We compared the KSS and KSS-like groups with the CPEO patient group, which showed pigmentary retinopathy (<0.001), cardiac conduction disease (=0.013), and large-scale mtDNA deletions (=0.038). KSS and KSS-like groups also had gastrointestinal tract disorders such as abnormal gastrointestinal motility (=0.013) unlike the CPEO group.
CONCLUSION
Patients with KSS had gastrointestinal symptoms, which may indicate another aspect of systemic involvement. The presence of large-scale mtDNA deletions was an objective diagnostic factor for KSS and a gene study may be helpful for evaluating patients with KSS.
Topics: Adult; DNA, Mitochondrial; Female; Gene Deletion; Humans; Kearns-Sayre Syndrome; Magnetic Resonance Imaging; Male; Middle Aged; Ophthalmoplegia; Ophthalmoplegia, Chronic Progressive External; Prevalence; Republic of Korea; Retinal Diseases; Retrospective Studies; Young Adult
PubMed: 30450853
DOI: 10.3349/ymj.2018.59.10.1190 -
Mitochondrion Mar 2021Mitochondrial disorders are a group of heterogeneous diseases characterized by biochemical disturbances in oxidative phosphorylation (OXPHOS). Mutations in mitochondrial...
BACKGROUND
Mitochondrial disorders are a group of heterogeneous diseases characterized by biochemical disturbances in oxidative phosphorylation (OXPHOS). Mutations in mitochondrial transfer RNA (mt-tRNA) genes are the most frequently in mitochondrial disease. However, few studies have detailed the molecular mechanisms behind these mutations.
METHODS
We performed clinical evaluation, genetic analysis, muscle histochemistry, and molecular and biochemical investigations in muscle tissue and proband-derived cybrid cell lines.
RESULTS
We found a mitochondrial tRNA mutation (m.7453G>A) in a 15-year-old patient with severe mitochondrial myopathy. We demonstrated that this mutation caused impairment of mitochondrial translation, respiratory deficiency, overproduction of reactive oxygen species (ROS), and decreased mitochondrial membrane potential (MMP), which ultimately led to severe mitochondrial myopathy.
CONCLUSION
Our findings offer valuable new insights into the tRNA m.7453G>A mutation for both the pathogenic mechanism and functional consequences.
Topics: Adolescent; Cell Line; Female; Genome, Mitochondrial; High-Throughput Nucleotide Sequencing; Humans; Membrane Potential, Mitochondrial; Mitochondrial Myopathies; Models, Molecular; Nucleic Acid Conformation; Polymorphism, Single Nucleotide; Protein Biosynthesis; RNA, Transfer, Ser; Reactive Oxygen Species; Sequence Analysis, DNA
PubMed: 33279600
DOI: 10.1016/j.mito.2020.11.015 -
Biochimica Et Biophysica Acta. General... Mar 2021Increasing evidence from pathological and biochemical investigations suggests that mitochondrial metabolic impairment and oxidative stress play a crucial role in the... (Review)
Review
BACKGROUND
Increasing evidence from pathological and biochemical investigations suggests that mitochondrial metabolic impairment and oxidative stress play a crucial role in the pathogenesis of mitochondrial diseases, such as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, and various neurodegenerative disorders. Recent advances in molecular imaging technology with positron emission tomography (PET) and functional magnetic resonance imaging (MRI) have accomplished a direct and non-invasive evaluation of the pathophysiological changes in living patients.
SCOPE OF REVIEW
In this review, we focus on the latest achievements of molecular imaging for mitochondrial metabolism and oxidative stress in mitochondrial diseases and neurodegenerative disorders.
MAJOR CONCLUSIONS
Molecular imaging with PET and MRI exhibited mitochondrial metabolic changes, such as enhanced glucose utilization with lactic acid fermentation, suppressed fatty acid metabolism, decreased TCA-cycle metabolism, impaired respiratory chain activity, and increased oxidative stress, in patients with MELAS syndrome. In addition, PET imaging clearly demonstrated enhanced cerebral oxidative stress in patients with Parkinson's disease or amyotrophic lateral sclerosis. The magnitude of oxidative stress correlated well with clinical severity in patients, indicating that oxidative stress based on mitochondrial dysfunction is associated with the neurodegenerative changes in these diseases.
GENERAL SIGNIFICANCE
Molecular imaging is a promising tool to improve our knowledge regarding the pathogenesis of diseases associated with mitochondrial dysfunction and oxidative stress, and this would facilitate the development of potential antioxidants and mitochondrial therapies.
Topics: Acidosis, Lactic; Brain Diseases; Electron Transport; Fatty Acids; Glucose; Humans; Lactic Acid; MELAS Syndrome; Magnetic Resonance Imaging; Mitochondria; Mitochondrial Myopathies; Molecular Imaging; Neurodegenerative Diseases; Oxidative Stress; Positron-Emission Tomography; Severity of Illness Index
PubMed: 33358866
DOI: 10.1016/j.bbagen.2020.129832 -
Cells Mar 2022Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial...
Endonuclease G (ENDOG) is a nuclear-encoded mitochondrial-localized nuclease. Although its precise biological function remains unclear, its proximity to mitochondrial DNA (mtDNA) makes it an excellent candidate to participate in mtDNA replication, metabolism and maintenance. Indeed, several roles for ENDOG have been hypothesized, including maturation of RNA primers during mtDNA replication, splicing of polycistronic transcripts and mtDNA repair. To date, has been deemed as a determinant of cardiac hypertrophy, but no pathogenic variants or genetically defined patients linked to this gene have been described. Here, we report biallelic variants identified by NGS in a patient with progressive external ophthalmoplegia, mitochondrial myopathy and multiple mtDNA deletions in muscle. The absence of the ENDOG protein in the patient's muscle and fibroblasts indicates that the identified variants are pathogenic. The presence of multiple mtDNA deletions supports the role of ENDOG in mtDNA maintenance; moreover, the patient's clinical presentation is very similar to mitochondrial diseases caused by mutations in other genes involved in mtDNA homeostasis. Although the patient's fibroblasts did not present multiple mtDNA deletions or delay in the replication process, interestingly, we detected an accumulation of low-level heteroplasmy mtDNA point mutations compared with age-matched controls. This may indicate a possible role of ENDOG in mtDNA replication or repair. Our report provides evidence of the association of variants with mitochondrial myopathy.
Topics: DNA, Mitochondrial; Endodeoxyribonucleases; Endonucleases; Humans; Mitochondria; Mitochondrial Myopathies
PubMed: 35326425
DOI: 10.3390/cells11060974 -
European Journal of Pediatrics Apr 2015Defects in peroxisomes such as those associated with Zellweger syndrome (ZS) can influence diverse intracellular metabolic pathways, including mitochondrial functioning.... (Review)
Review
Defects in peroxisomes such as those associated with Zellweger syndrome (ZS) can influence diverse intracellular metabolic pathways, including mitochondrial functioning. We report on an 8-month-old female infant and a 6-month-old female infant with typical clinical, radiological and laboratory features of Zellweger syndrome; light microscopic and ultrastructural evidence of mitochondrial pathology in their muscle biopsies; and homozygous pathogenic mutations of the PEX16 gene (c.460 + 5G > A) and the PEX 12 gene (c.888_889 del p.Leu297Thrfs*12), respectively. Additionally, mitochondrial respiratory chain enzymology analysis in the first girl showed a mildly low activity in complexes II-III and IV. We also review five children previously reported in the literature with a presumptive diagnosis of ZS and additional mitochondrial findings in their muscle biopsies. In conclusion, this is the first study of patients with a molecularly confirmed peroxisomal disorder with features of a concomitant mitochondrial myopathy and underscores the role of secondary mitochondrial dysfunction in Zellweger syndrome, potentially contributing to the clinical phenotype.
Topics: Female; Homozygote; Humans; Infant; Magnetic Resonance Imaging; Mitochondria; Mitochondrial Myopathies; Mutation; Zellweger Syndrome
PubMed: 25287621
DOI: 10.1007/s00431-014-2431-2 -
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 -
Pediatric Nephrology (Berlin, Germany) Jan 2021Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria.... (Review)
Review
Kidneys have a high energy demand to facilitate the reabsorption of the glomerular filtrate. For this reason, renal cells have a high density of mitochondria. Mitochondrial cytopathies can be the result of a mutation in both mitochondrial and nuclear DNA. Mitochondrial dysfunction can lead to a variety of renal manifestations. Examples of tubular manifestations are renal Fanconi Syndrome, which is often found in patients diagnosed with Kearns-Sayre and Pearson's marrow-pancreas syndrome, and distal tubulopathies, which result in electrolyte disturbances such as hypomagnesemia. Nephrotic syndrome can be a glomerular manifestation of mitochondrial dysfunction and is typically associated with focal segmental glomerular sclerosis on histology. Tubulointerstitial nephritis can also be seen in mitochondrial cytopathies and may lead to end-stage renal disease. The underlying mechanisms of these cytopathies remain incompletely understood; therefore, current therapies focus mainly on symptom relief. A better understanding of the molecular disease mechanisms is critical in order to improve treatments.
Topics: DNA, Mitochondrial; Humans; Kearns-Sayre Syndrome; Mitochondria; Mitochondrial Myopathies; Mutation; Nephritis, Interstitial
PubMed: 31925537
DOI: 10.1007/s00467-019-04404-6 -
Journal of Neuromuscular Diseases 2022Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders.... (Review)
Review
Defects in the replication, maintenance, and repair of mitochondrial DNA (mtDNA) constitute a growing and genetically heterogeneous group of mitochondrial disorders. Multiple genes participate in these processes, including thymidine kinase 2 (TK2) encoding the mitochondrial matrix protein TK2, a critical component of the mitochondrial nucleotide salvage pathway. TK2 deficiency (TK2d) causes mtDNA depletion, multiple deletions, or both, which manifest predominantly as mitochondrial myopathy. A wide clinical spectrum phenotype includes a severe, rapidly progressive, early onset form (median survival: < 2 years); a less severe childhood-onset form; and a late-onset form with a variably slower rate of progression. Clinical presentation typically includes progressive weakness of limb, neck, facial, oropharyngeal, and respiratory muscle, whereas limb myopathy with ptosis, ophthalmoparesis, and respiratory involvement is more common in the late-onset form. Deoxynucleoside monophosphates and deoxynucleosides that can bypass the TK2 enzyme defect have been assessed in a mouse model, as well as under open-label compassionate use (expanded access) in TK2d patients, indicating clinical efficacy with a favorable side-effect profile. This treatment is currently undergoing testing in clinical trials intended to support approval in the US and European Union (EU). In the early expanded access program, growth differentiation factor 15 (GDF-15) appears to be a useful biomarker that correlates with therapeutic response. With the advent of a specific treatment and given the high morbidity and mortality associated with TK2d, clinicians need to know how to recognize and diagnose this disorder. Here, we summarize translational research about this rare condition emphasizing clinical aspects.
Topics: Animals; Child; DNA, Mitochondrial; Humans; Mice; Mitochondrial Myopathies; Muscular Diseases; Thymidine Kinase
PubMed: 35094997
DOI: 10.3233/JND-210786 -
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