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Heart Failure Reviews Jan 2016Heart failure remains an important clinical burden, and mitochondrial dysfunction plays a key role in its pathogenesis. The heart has a high metabolic demand, and... (Review)
Review
Heart failure remains an important clinical burden, and mitochondrial dysfunction plays a key role in its pathogenesis. The heart has a high metabolic demand, and mitochondrial function is a key determinant of myocardial performance. In mitochondrial disorders, hypertrophic remodeling is the early pattern of cardiomyopathy with progression to dilated cardiomyopathy, conduction defects and ventricular pre-excitation occurring in a significant proportion of patients. Cardiac dysfunction occurs in approximately a third of patients with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, a stereotypical example of a mitochondrial disorder leading to a cardiomyopathy. We performed unique comparative ultrastructural and gene expression in a MELAS heart compared with non-failing controls. Our results showed a remarkable increase in mitochondrial inclusions and increased abnormal mitochondria in MELAS cardiomyopathy coupled with variable sarcomere thickening, heterogeneous distribution of affected cardiomyocytes and a greater elevation in the expression of disease markers. Investigation and management of patients with mitochondrial cardiomyopathy should follow the well-described contemporary heart failure clinical practice guidelines and include an important role of medical and device therapies. Directed metabolic therapy is lacking, but current research strategies are dedicated toward improving mitochondrial function in patients with mitochondrial disorders.
Topics: Cardiomyopathies; Heart Failure; Humans; MELAS Syndrome; Metabolism; Mitochondria
PubMed: 26712328
DOI: 10.1007/s10741-015-9524-5 -
Journal of Internal Medicine Jun 2020Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent... (Review)
Review
Mitochondrial medicine is a field that expanded exponentially in the last 30 years. Individually rare, mitochondrial diseases as a whole are probably the most frequent genetic disorder in adults. The complexity of their genotype-phenotype correlation, in terms of penetrance and clinical expressivity, natural history and diagnostic algorithm derives from the dual genetic determination. In fact, in addition to the about 1.500 genes encoding mitochondrial proteins that reside in the nuclear genome (nDNA), we have the 13 proteins encoded by the mitochondrial genome (mtDNA), for which 22 specific tRNAs and 2 rRNAs are also needed. Thus, besides Mendelian genetics, we need to consider all peculiarities of how mtDNA is inherited, maintained and expressed to fully understand the pathogenic mechanisms of these disorders. Yet, from the initial restriction to the narrow field of oxidative phosphorylation dysfunction, the landscape of mitochondrial functions impinging on cellular homeostasis, driving life and death, is impressively enlarged. Finally, from the clinical standpoint, starting from the neuromuscular field, where brain and skeletal muscle were the primary targets of mitochondrial dysfunction as energy-dependent tissues, after three decades virtually any subspecialty of medicine is now involved. We will summarize the key clinical pictures and pathogenic mechanisms of mitochondrial diseases in adults.
Topics: Adult; DNA Repair; DNA, Mitochondrial; Genome, Mitochondrial; Humans; MELAS Syndrome; Mitochondria; Mitochondrial Diseases; Mutation
PubMed: 32463135
DOI: 10.1111/joim.13064 -
Clinical Biochemistry Feb 2023
Topics: Humans; MELAS Syndrome
PubMed: 36402172
DOI: 10.1016/j.clinbiochem.2022.11.007 -
Medicina (Kaunas, Lithuania) May 2022a stroke-like lesion, the morphological equivalent of a stroke-like episode and the hallmark of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes...
OBJECTIVES
a stroke-like lesion, the morphological equivalent of a stroke-like episode and the hallmark of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, have not been reported as manifestations of thiamine deficiency.
CASE REPORT
a 62-year-old man with a history of chronic alcoholism was admitted after a series of epileptic seizures. Upon waking up from the coma, he presented with disorientation, confusion, confabulation, psychomotor agitation, aggressiveness, right hemianopsia, aphasia, and right hemineglect over weeks. Electroencephalography showed a questionable focal status epilepticus over the left hemisphere, responsive to lorazepam and oxcarbazepine. Follow-up electroencephalographies no longer recorded epileptiform discharges. Cerebral magnetic resonance imaging (MRI) revealed T2-/diffusion weighted imaging (DWI) hyperintensity in the left occipito-temporal region that was not congruent to a vascular territory which persisted for at least nine weeks. Since a lactate-peak could be seen in this lesion by magnetic resonance-spectroscopy, this was interpreted as a stroke-like lesion. Since thiamine was reduced, the stroke-like lesion was attributed to thiamine deficiency after the exclusion of differential diseases, including MELAS and status epilepticus. The patient's behavioural and cognitive dysfunctions largely resolved upon vitamin-B1 substitution.
CONCLUSIONS
the case suggests that thiamine deficiency presumably causes mitochondrial dysfunction with cerebrospinal fluid lactic acidosis and a stroke-like lesion mimicking MELAS syndrome. It should be further studied whether nutritional deficits, such as thiamine deficiency, could give rise to secondary stroke-like lesions.
Topics: Acidosis, Lactic; Humans; MELAS Syndrome; Male; Middle Aged; Mitochondrial Encephalomyopathies; Status Epilepticus; Stroke; Thiamine Deficiency; Wernicke Encephalopathy
PubMed: 35630076
DOI: 10.3390/medicina58050660 -
Molecular and Cellular Neurosciences Sep 2023Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways... (Review)
Review
Mitochondrial dysfunction can arise from genetic defects or environmental exposures and impact a wide range of biological processes. Among these are metabolic pathways involved in glutamine catabolism, anabolism, and glutamine-glutamate cycling. In recent years, altered glutamine metabolism has been found to play important roles in the pathologic consequences of mitochondrial dysfunction. Glutamine is a pleiotropic molecule, not only providing an alternate carbon source to glucose in certain conditions, but also playing unique roles in cellular communication in neurons and astrocytes. Glutamine consumption and catabolic flux can be significantly altered in settings of genetic mitochondrial defects or exposure to mitochondrial toxins, and alterations to glutamine metabolism appears to play a particularly significant role in neurodegenerative diseases. These include primary mitochondrial diseases like Leigh syndrome (subacute necrotizing encephalopathy) and MELAS (mitochondrial myopathy with encephalopathy, lactic acidosis, and stroke-like episodes), as well as complex age-related neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. Pharmacologic interventions targeting glutamine metabolizing and catabolizing pathways appear to provide some benefits in cell and animal models of these diseases, indicating glutamine metabolism may be a clinically relevant target. In this review, we discuss glutamine metabolism, mitochondrial disease, the impact of mitochondrial dysfunction on glutamine metabolic processes, glutamine in neurodegeneration, and candidate targets for therapeutic intervention.
Topics: Animals; Glutamine; MELAS Syndrome; Mitochondria; Neurodegenerative Diseases; Mitochondrial Diseases
PubMed: 37586651
DOI: 10.1016/j.mcn.2023.103887 -
Molecular Genetics & Genomic Medicine Jul 2022Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the most well-known mitochondrial diseases, with most cases... (Review)
Review
BACKGROUND
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the most well-known mitochondrial diseases, with most cases attributed to m.3243A>G. MELAS syndrome patients typically present in the first two decades of life with a broad, multi-systemic phenotype that predominantly features neurological manifestations--stroke-like episodes. However, marked phenotypic variability has been observed among paediatric patients, creating a clinical challenge and delaying diagnoses.
METHODS
A literature review of paediatric MELAS syndrome patients and a retrospective analysis in a UK tertiary paediatric neurology centre were performed.
RESULTS
Three children were included in this case series. All patients presented with seizures and had MRI changes not confined to a single vascular territory. Blood heteroplasmy varied considerably, and one patient required a muscle biopsy. Based on a literature review of 114 patients, the mean age of presentation is 8.1 years and seizures are the most prevalent manifestation of stroke-like episodes. Heteroplasmy is higher in a tissue other than blood in most cases.
CONCLUSION
The threshold for investigating MELAS syndrome in children with suspicious neurological symptoms should be low. If blood m.3243A>G analysis is negative, yet clinical suspicion remains high, invasive testing or further interrogation of the mitochondrial genome should be considered.
Topics: Acidosis, Lactic; Child; Humans; MELAS Syndrome; Retrospective Studies; Seizures; Stroke
PubMed: 35474314
DOI: 10.1002/mgg3.1955 -
Journal of Inborn Errors of Metabolism... Jan 2017MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome is a maternally inherited mitochondrial disease with a broad spectrum of...
MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) syndrome is a maternally inherited mitochondrial disease with a broad spectrum of manifestations. In addition to impaired energy production, nitric oxide (NO) deficiency occurs in MELAS syndrome and leads to impaired blood perfusion in microvasculature that can contribute to several complications including stroke-like episodes, myopathy, and lactic acidosis. The supplementation of NO precursors, L-arginine and L-citrulline, increases NO production and hence can potentially have therapeutic utility in MELAS syndrome. L-citrulline raises NO production to a greater extent than L-arginine; therefore, L-citrulline may have a better therapeutic effect. The clinical effect of L-citrulline has not yet been studied and clinical studies on L-arginine, which are limited, only evaluated the stroke-like episodes aspect of the disease. Controlled studies are still needed to assess the clinical effects of L-arginine and L-citrulline on different aspects of MELAS syndrome.
PubMed: 28736735
DOI: 10.1177/2326409817697399 -
Developmental Period Medicine 2015Mitochondrial disorders (MD) represent a clinically, biochemically and genetically heterogeneous group of diseases associated with dysfunction of the oxidative... (Review)
Review
Mitochondrial disorders (MD) represent a clinically, biochemically and genetically heterogeneous group of diseases associated with dysfunction of the oxidative phosphorylation system and pyruvate dehydrogenase complex. Our aim was to illustrate the most common clinical presentation of MD on the example of selected diseases and syndromes. The minimal prevalence of MD is estimated as 1 to 5,000. MD may manifest at any age since birth until late-adulthood with acute manifestation or as a chronic progressive disease. Virtually any organ may be impaired, but the organs with the highest energetic demands are most frequently involved, including brain, muscle, heart and liver. Some MD may manifest as a characteristic cluster of clinical features (e.g. MELAS syndrome, Kearns-Sayre syndrome). Diagnostics includes detailed history, the comprehensive clinical examination, results of specialized examinations (especially cardiology, visual fundus examination, brain imaging, EMG), laboratory testing of body fluids (lactate, aminoacids, organic acids), and analysis of bioptic samples of muscle, skin, and liver, eventually. Normal lactate level in blood does not exclude the possibility of MD. Although the aimed molecular genetic analyses may be indicated in some of mitochondrial diseases, the methods of next generation sequencing come into focus. Examples of treatment are arginine supplementation in MELAS syndrome, ketogenic diet in pyruvate oxidation disorders or quinone analogs in patients with LHON. Conclusion: The clinical suspicion of a mitochondrial disorder is often delayed, or the disease remains undiagnosed. The correct diagnosis and adequate treatment can improve prognosis of the patient. Access to genetic counseling is also of great importance.
Topics: Brain; DNA, Mitochondrial; Electroencephalography; Humans; Kearns-Sayre Syndrome; MELAS Syndrome; MERRF Syndrome; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies
PubMed: 26982751
DOI: No ID Found -
European Journal of Endocrinology Nov 2020Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a very rare condition; it encompasses a diverse group of disorders...
OBJECTIVE
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a very rare condition; it encompasses a diverse group of disorders including diabetes. Phenotypic variability can be attributed to heteroplasmy along with varying proportions of mutant and WT mitochondrial DNA (mtDNA). To examine the clinical relationship between mitochondrial diabetes and mutational load, we analyzed the mtDNA of children and young adolescents with MELAS syndrome using next generation sequencing (NGS).
DESIGN AND METHODS
Of 57 subjects with suspected MELAS syndrome, 32 children and young adolescents were diagnosed as MELAS syndrome with mtDNA A-to-G transition at nucleotide 3243. Mutation load studies and NGS were performed for 25 subjects.
RESULTS
The mean mutation load was 60.4 ± 18.4% (range: 22.5‒100). Of the 25 subjects with NGS results, 15 (60%) were diagnosed with DM and 2 (8%) were diagnosed with impaired glucose tolerance (IGT). The mutational load of subjects inversely correlated with first symptom onset, age at diagnosis of MELAS syndrome, and DM (P < 0.001). However, mutational load did not correlate with the clinical severity or progression of DM/IGT. There was no significant difference in insulin resistance or sensitivity indices between the low- and high-mutation load groups. During the 3.7 years of follow-up, insulin resistance indices were not significantly different between baseline and follow-up.
CONCLUSIONS
We can infer that the mutation load in the MELAS syndrome is significantly associated with the onset of symptoms and associated diseases, including mitochondrial diabetes. However, it may not influence disease progression.
Topics: Adolescent; Child; DNA, Mitochondrial; Diabetes Mellitus; Female; Glucose Intolerance; High-Throughput Nucleotide Sequencing; Humans; MELAS Syndrome; Male; Mitochondria; Mutation
PubMed: 33107434
DOI: 10.1530/EJE-20-0189 -
AJNR. American Journal of Neuroradiology Jan 2020Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder affecting children and young adults....
BACKGROUND AND PURPOSE
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare mitochondrial disorder affecting children and young adults. Stroke-like episodes are often associated with acute cortical lesions in the posterior cerebral cortex and are classically described as asymmetric and transient. In this study we assessed the anatomic distribution of acute cortical lesions, the incidence of symmetry, and the temporal evolution of lesions.
MATERIALS AND METHODS
This was a retrospective cohort study of patients who had a confirmed genetic diagnosis of a pathogenic variant associated with MELAS and MR imaging performed at our center (2006-2018). Each MR imaging study was assessed for new lesions using T1, T2, FLAIR, DWI, ADC, and SWI. The anatomic location, symmetry, and temporal evolution of lesions were analyzed.
RESULTS
Eight patients with the same pathogenic variant of MELAS (MT-TL1 m.3243A>G) with 31 MR imaging studies were included. Forty-one new lesions were identified in 17 of the studies (5 deep, 36 cortical). Cortical lesions most commonly affected the primary visual cortex, the middle-third of the primary somatosensory cortex, and the primary auditory cortex. Thirty of 36 cortical lesions had acute cortical diffusion restriction, of which 21 developed cortical laminar necrosis on subacute imaging. Six of 11 studies with multiple lesions showed symmetric cortical involvement.
CONCLUSIONS
Acute cortical lesions in MELAS most commonly affect the primary visual, somatosensory, and auditory cortices, all regions of high neuronal density and metabolic demand. The most common pattern of temporal evolution is acute cortical diffusion restriction with subacute cortical laminar necrosis and chronic volume loss. Symmetric involvement is more common than previously described.
Topics: Adolescent; Adult; Cohort Studies; Female; Humans; MELAS Syndrome; Magnetic Resonance Imaging; Male; Middle Aged; Retrospective Studies; Stroke; Young Adult
PubMed: 31806591
DOI: 10.3174/ajnr.A6325