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Genes Oct 2021Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected...
Mitochondrial stroke-like episodes (SLEs) are a hallmark of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). They should be suspected in anyone with an acute/subacute onset of focal neurological symptoms at any age and are usually driven by seizures. Suggestive features of an underlying mitochondrial pathology include evolving MRI lesions, often originating within the posterior brain regions, the presence of multisystemic involvement, including diabetes, deafness, or cardiomyopathy, and a positive family history. The diagnosis of MELAS has important implications for those affected and their relatives, given it enables early initiation of appropriate treatment and genetic counselling. However, the diagnosis is frequently challenging, particularly during the acute phase of an event. We describe four cases of mitochondrial strokes to highlight the considerable overlap that exists with other neurological disorders, including viral and autoimmune encephalitis, ischemic stroke, and central nervous system (CNS) vasculitis, and discuss the clinical, laboratory, and imaging features that can help distinguish MELAS from these differential diagnoses.
Topics: Adult; Brain; Cardiomyopathies; Central Nervous System; Deafness; Diabetes Mellitus; Diagnosis, Differential; Female; Humans; MELAS Syndrome; Magnetic Resonance Imaging; Male; Middle Aged; Mitochondrial Encephalomyopathies; Vasculitis, Central Nervous System
PubMed: 34681037
DOI: 10.3390/genes12101643 -
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 -
Acta Neurologica Taiwanica Mar 2024A 13-year and 4-month-old girl was brought to the emergency department due to fever, dizziness,vomiting, and blurred vision. Laboratory data revealed hyperglycemia with...
A 13-year and 4-month-old girl was brought to the emergency department due to fever, dizziness,vomiting, and blurred vision. Laboratory data revealed hyperglycemia with an HbA1C of 7.3 percent, ketonuria, and lactic acidosis. The initial impression was diabetic ketoacidosis. During admission, recurrent focal impaired awareness seizures were noted, and magnetic resonance imaging of the brain revealed multiple brain infarctions in the bilateral cerebrum. Mitochondrial gene report showed A3243 G with 64 percent heteroplasmy, and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes was diagnosed. At 16 years and 7 months old, recurrence of vomiting and onset of right hemianopia and mild right limb weakness were observed and follow-up T2 images showed massive edema in her left parieto-occipital region. At 16 years and 10 months old, she developed clonus in her left hand associated with an unsteady gait and blurred vision. MRI of the brain revealed recurrent brain infarction, and T2 images showed massive edema of the right parieto-occipital region. MELAS is a rare disease entity and occasionally comorbid with mitochondrial diabetes in childhood. Characteristic radiological features of MELAS include infarction-like lesions over the parieto-occipital or parieto-temporal areas, which help distinguish MELAS from childhood ischemic stroke.
Topics: Humans; Female; Infant; MELAS Syndrome; Diabetic Ketoacidosis; Stroke; Acidosis, Lactic; Ketosis; Edema; Vomiting; Diabetes Mellitus
PubMed: 37853548
DOI: No ID Found -
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 -
Journal of the American Society of... Nov 2023Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the...
SIGNIFICANCE STATEMENT
Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the diagnostic workup of patients with electrolyte disorders. In this systematic review, we investigated the presence of electrolyte disorders in patients with mitochondrial cytopathies to determine the relevance of mitochondrial mutation screening in this population. Our analysis demonstrates that electrolyte disorders are commonly reported in mitochondrial cytopathies, often as presenting symptoms. Consequently, more clinical attention should be raised for mitochondrial disease as cause for disturbances in electrolyte homeostasis. Further prospective cohort studies are required to determine the exact prevalence of electrolyte disorders in mitochondrial cytopathies.
BACKGROUND
Electrolyte reabsorption in the kidney has a high energy demand. Proximal and distal tubular epithelial cells have a high mitochondrial density for energy release. Recently, electrolyte disorders have been reported as the primary presentation of some mitochondrial cytopathies. However, the prevalence and the pathophysiology of electrolyte disturbances in mitochondrial disease are unknown. Therefore, we systematically investigated electrolyte disorders in patients with mitochondrial cytopathies.
METHODS
We searched PubMed, Embase, and Google Scholar for articles on genetically confirmed mitochondrial disease in patients for whom at least one electrolyte is reported. Patients with a known second genetic anomaly were excluded. We evaluated 214 case series and reports (362 patients) as well as nine observational studies. Joanna Briggs Institute criteria were used to evaluate the quality of included studies.
RESULTS
Of 362 reported patients, 289 had an electrolyte disorder, with it being the presenting or main symptom in 38 patients. The average number of different electrolyte abnormalities per patient ranged from 2.4 to 1.0, depending on genotype. Patients with mitochondrial DNA structural variants seemed most affected. Reported pathophysiologic mechanisms included renal tubulopathies and hormonal, gastrointestinal, and iatrogenic causes.
CONCLUSIONS
Mitochondrial diseases should be considered in the evaluation of unexplained electrolyte disorders. Furthermore, clinicians should be aware of electrolyte abnormalities in patients with mitochondrial disease.
Topics: Humans; Mitochondrial Myopathies; Kearns-Sayre Syndrome; Mitochondrial Diseases; Mitochondria; DNA, Mitochondrial; Water-Electrolyte Imbalance
PubMed: 37678265
DOI: 10.1681/ASN.0000000000000224 -
Mitochondrion Sep 2023Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper... (Review)
Review
Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper understanding of how tissue-specific mitochondrial dysfunction result in multi-systemic disease. Here, we summarize how the m.3243G mtDNA mutation affects mitochondrial function in different tissues using iPSC and iPSC-differentiated cell type disease models and what significant findings have been replicated in the independent studies. Through this brief review and with a focus on mitochondrial dysfunction in iPSC-differentiated cell types, namely fibroblast, neuron, and retinal pigment epithelium cells, we aim to bring awareness of hiPSC as a robust mitochondrial disease model even if many unanswered questions remain.
Topics: Humans; MELAS Syndrome; Induced Pluripotent Stem Cells; Acidosis, Lactic; Cell Differentiation; Mitochondria
PubMed: 37633406
DOI: 10.1016/j.mito.2023.08.003 -
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