Mitochondrial Encephalopathy Lactic Acidosis Research Articles

Psihijatrijski aspekti sindroma MELAS

MELAS (Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like episodes) syndrome is a condition characterized by mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. It is a rare, inherited, neurodegenerative disorder caused by mitochondrial dysfunction that leads to energy production disturbances. The disease most commonly begins at a younger age, before the age of 40, with episodes resembling strokes, and psychiatric symptoms can also occur in the early stages of the disease. Later on, encephalopathy may develop, which is accompanied by epileptic seizures and/ or dementia. Psychiatric disorders in MELAS syndrome are present but insufficiently studied, which should be considered during diagnosis to prevent th disease from going unrecognized. Early diagnosis of any disease, including MELAS, is crucial as timely initiation of treatment significantly contributes to a more favorable course and better prognosis of the disease. When diagnosing MELAS, attention should be paid to the potential presence of psychiatric disorders.

Current Understanding on the Genetic Basis of Key Metabolic Disorders: A Review.

Simple SummaryMetabolic disorders (MD) are a challenge to healthcare systems; the emergence of the modern socio-economic system has led to a profound change in lifestyles in terms of dietary habits, exercise regimens, and behavior, all of which complement the genetic factors associated with MD. Diabetes Mellitus and Familial hypercholesterolemia are two of the 14 most widely researched MD, as they pose the greatest challenge to the public healthcare system and have an impact on productivity and the economy. Research findings have led to the development of new therapeutic molecules for the mitigation of MD as well as the invention of experimental strategies, which target the genes themselves via gene editing and RNA interference. Although these approaches may herald the emergence of a new toolbox to treat MD, the current therapeutic approaches still heavily depend on substrate reduction, dietary restrictions based on genetic factors, exercise, and the maintenance of good mental health. The development of orphan drugs for the less common MD such as Krabbe, Farber, Fabry, and Gaucher diseases, remains in its infancy, owing to the lack of investment in research and development, and this has driven the development of personalized therapeutics based on gene silencing and related technologies.Advances in data acquisition via high resolution genomic, transcriptomic, proteomic and metabolomic platforms have driven the discovery of the underlying factors associated with metabolic disorders (MD) and led to interventions that target the underlying genetic causes as well as lifestyle changes and dietary regulation. The review focuses on fourteen of the most widely studied inherited MD, which are familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, Maple syrup urine disease, Metachromatic leukodystrophy, Mitochondrial encephalopathy lactic acidosis stroke-like episodes (MELAS), Niemann-Pick disease, Phenylketonuria (PKU), Porphyria, Tay-Sachs disease, Wilson’s disease, Familial hypertriglyceridemia (F-HTG) and Galactosemia based on genome wide association studies, epigenetic factors, transcript regulation, post-translational genetic modifications and biomarker discovery through metabolomic studies. We will delve into the current approaches being undertaken to analyze metadata using bioinformatic approaches and the emerging interventions using genome editing platforms as applied to animal models.

Mitochondrial Disease Masquerading as Recurrent Encephalopathy

A young male who was a diabetic presented with gradually progressive hearing loss, recurrent episodic behavioral abnormality, easy fatigability, proximal weakness, and seizures. The patient was evaluated in detail to find out the etiology of encephalitis. The serum autoimmune encephalitis panel was negative. On magnetic resonance imaging of the Brain, there was temporoparietal T2 and fluid-attenuated inversion recovery hyperintensity. In the magnetic resonance spectroscopy study, a lactate peak was found. So, the patient was evaluated for mitochondrial illness mitochondrial encephalopathy lactic acidosis with stroke-like symptoms) and it was confirmed by a genetic study. This case illustrates that though it is a rare disease, always a strong clinical index of suspicion is required for the diagnosis of mitochondrial disorders in case of multisystem involvement so that diagnosis would not be missed.

Glutamate-Induced Deregulation of Krebs Cycle in Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-Like Episodes (MELAS) Syndrome Is Alleviated by Ketone Body Exposure.

(1) Background: The development of mitochondrial medicine has been severely impeded by a lack of effective therapies. (2) Methods: To better understand Mitochondrial Encephalopathy Lactic Acidosis Syndrome Stroke-like episodes (MELAS) syndrome, neuronal cybrid cells carrying different mutation loads of the m.3243A > G mitochondrial DNA variant were analysed using a multi-omic approach. (3) Results: Specific metabolomic signatures revealed that the glutamate pathway was significantly increased in MELAS cells with a direct correlation between glutamate concentration and the m.3243A > G heteroplasmy level. Transcriptomic analysis in mutant cells further revealed alterations in specific gene clusters, including those of the glutamate, gamma-aminobutyric acid pathways, and tricarboxylic acid (TCA) cycle. These results were supported by post-mortem brain tissue analysis from a MELAS patient, confirming the glutamate dysregulation. Exposure of MELAS cells to ketone bodies significantly reduced the glutamate level and improved mitochondrial functions, reducing the accumulation of several intermediate metabolites of the TCA cycle and alleviating the NADH-redox imbalance. (4) Conclusions: Thus, a multi-omic integrated approach to MELAS cells revealed glutamate as a promising disease biomarker, while also indicating that a ketogenic diet should be tested in MELAS patients.

Whole Mitochondrial Genome Analysis in Turkish Patients with Mitochondrial Diseases

Background:Mitochondrial diseases are a clinically heterogeneous group of rare hereditary disorders that are defined by a genetic defect predominantly affecting mitochondrial oxidative phosphorylation. Mitochondrial diseases are caused by mutations of genes encoded by either nuclear DNA or mitochondrial DNA. Hundreds of different mitochondrial DNA point mutations and large-scale mitochondrial DNA rearrangements have been shown to cause mitochondrial diseases including Kearns–Sayre syndrome, Leber’s hereditary optic neuropathy, Leigh syndrome, myoclonic epilepsy with ragged-red fibers, mitochondrial encephalopathy lactic acidosis stroke.Aims:To investigate new variants that could be associated with mitochondrial diseases and to determine the effect of mitochondrial DNA mutations on the clinical spectrum.Study Design:Cross-sectional study.Methods:We screened whole mitochondrial DNA genome using next-generation sequencing in 16 patients who are considered to have mitochondrial disease. CentoGene and Mikrogen Genetic Diseases Diagnostic Center’s database were used to investigate sequence variants. Detected variants were evaluated in bioinformatic databases to determine pathogenicity and were classified as class 1 (pathogenic), class 2 (likely pathogenic), and class 3 (variant of uncertain significance) according to CentoGene-ACMG database.Results:As a result of the study, 2 patients were diagnosed with Leigh syndrome as previously reported class 1 mutations in MT-ATP6 and MT-ND5 genes. Four variants were identified for the first time in literature and 2 variants, previously reported but with uncertain pathogenic effect, are thought to be associated with mitochondrial disease.Conclusion:Mitochondrial DNA screening should be among the primary clinical tests in patients with suspected mitochondrial disease to rule out DNA-associated mutations.

Effect of rapamycin on mitochondria and lysosomes in fibroblasts from patients with mtDNA mutations.

Maintaining mitochondrial function and dynamics is crucial for cellular health. In muscle, defects in mitochondria result in severe myopathies where accumulation of damaged mitochondria causes deterioration and dysfunction. Importantly, understanding the role of mitochondria in disease is a necessity to determine future therapeutics. One of the most common myopathies is mitochondrial encephalopathy lactic acidosis stroke-like episodes (MELAS), which has no current treatment. Recently, patients with MELAS treated with rapamycin exhibited improved clinical outcomes. However, the cellular mechanisms of rapamycin effects in patients with MELAS are currently unknown. In this study, we used cultured skin fibroblasts as a window into the mitochondrial dysfunction evident in MELAS cells, as well as to study the mechanisms of rapamycin action, compared with control, healthy individuals. We observed that mitochondria from patients were fragmented, had a threefold decline in the average speed of motility, a twofold reduced mitochondrial membrane potential, and a 1.5- to 2-fold decline in basal respiration. Despite the reduction in mitochondrial function, mitochondrial import protein Tim23 was elevated in patient cell lines. MELAS fibroblasts exhibited increased MnSOD levels and lysosomal function when compared with healthy controls. Treatment of MELAS fibroblasts with rapamycin for 24 h resulted in increased mitochondrial respiration compared with control cells, a higher lysosome content, and a greater localization of mitochondria to lysosomes. Our studies suggest that rapamycin has the potential to improve cellular health even in the presence of mtDNA defects, primarily via an increase in lysosomal content.

Mitophagy: An Emerging Target in Ocular Pathology.

Mitochondrial function is essential for the viability of aerobic eukaryotic cells, as mitochondria provide energy through the generation of adenosine triphosphate (ATP), regulate cellular metabolism, provide redox balancing, participate in immune signaling, and can initiate apoptosis. Mitochondria are dynamic organelles that participate in a cyclical and ongoing process of regeneration and autophagy (clearance), termed mitophagy specifically for mitochondrial (macro)autophagy. An imbalance in mitochondrial function toward mitochondrial dysfunction can be catastrophic for cells and has been characterized in several common ophthalmic diseases. In this article, we review mitochondrial homeostasis in detail, focusing on the balance of mitochondrial dynamics including the processes of fission and fusion, and provide a description of the mechanisms involved in mitophagy. Furthermore, this article reviews investigations of ocular diseases with impaired mitophagy, including Fuchs endothelial corneal dystrophy, primary open-angle glaucoma, diabetic retinopathy, and age-related macular degeneration, as well as several primary mitochondrial diseases with ocular phenotypes that display impaired mitophagy, including mitochondrial encephalopathy lactic acidosis stroke, Leber hereditary optic neuropathy, and chronic progressive external ophthalmoplegia. The results of various studies using cell culture, animal, and human tissue models are presented and reflect a growing awareness of mitophagy impairment as an important feature of ophthalmic disease pathology. As this review indicates, it is imperative that mitophagy be investigated as a targetable mechanism in developing therapies for ocular diseases characterized by oxidative stress and mitochondrial dysfunction.

Commentary: Neuromuscular and Muscle Metabolic Functions in MELAS Before and After Resistance Training: A Case Study.

Treatment of myopathy in MELAS relies on the application of antioxidants, co-factors, vitamins, the ketogenic diet, and physical exercise. Systematic studies of muscle training in mitochondrial disorders (MIDs) has been only rarely carried out (Porcelli et al., 2016) but a beneficial effect has been reported in most of these studies (Cade et al., 2017). In a recent study article published in Frontiers in Physiology, Venturelli et al. (2019) reported a 21 years old Caucasian male with mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS) syndrome who profited from resistance training at 85% of one repetition maximum by increasing the body mass by 1.4 kg during a training period of 12 weeks. The study raised the following comments and concerns.

Different mitochondrial genetic defects exhibit the same protein signature of metabolism in skeletal muscle of PEO and MELAS patients: A role for oxidative stress

A major challenge in mitochondrial diseases (MDs) is the identification of biomarkers that could inform of the mechanisms involved in the phenotypic expression of genetic defects. Herein, we have investigated the protein signature of metabolism and of the antioxidant response in muscle biopsies of clinically and genetically diagnosed patients with Progressive External Ophthalmoplegia due to single large-scale (PEO-sD) or multiple (PEO-mD) deletions of mtDNA and Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like episode (MELAS) syndrome, and healthy donors. A high-throughput immunoassay technique that quantitates the expression of relevant proteins of glycolysis, glycogenolysis, pentose phosphate pathway, oxidative phosphorylation, pyruvate and fatty acid oxidation, tricarboxylic acid cycle and the antioxidant response in two large independent and retrospectively collected cohorts of PEO-sD, PEO-mD and MELAS patients revealed that despite the heterogeneity of the genetic alterations, the three MDs showed the same metabolic signatures in both cohorts of patients, which were highly divergent from those of healthy individuals. Linear Discriminant Analysis and Support Vector Machine classifier provided a minimum of four biomarkers to discriminate healthy from pathological samples. Regardless of the induction of a large number of enzymes involved in ameliorating oxidative stress, the down-regulation of mitochondrial superoxide dismutase (SOD2) and catalase expression favored the accumulation of oxidative damage in patients’ proteins. Down-regulation of SOD2 and catalase expression in MD patients is not due to relevant changes in the availability of their mRNAs, suggesting that oxidative stress regulates the expression of the two enzymes post-transcriptionally. We suggest that SOD2 and catalase could provide specific targets to improve the detoxification of reactive oxygen species that affects muscle proteins in these patients.

Outcome of epilepsy in patients with mitochondrial disorders: Phenotype genotype and magnetic resonance imaging correlations

ObjectivesStudies exploring the outcome of epilepsy in patients with mitochondrial disorders are limited. This study examined the outcome of epilepsy in patients with mitochondrial disorders and its relation with the clinical phenotype, genotype and magnetic resonance imaging findings. Patients and methodsThe cohort was derived from the database of 67 patients with definite genetic diagnosis of mitochondrial disorders evaluated over a period of 11years (2006–2016). Among this, 27 had epilepsy and were included in final analysis. Data were analyzed with special reference to clinical phenotypes, genotypes, epilepsy characteristics, EEG findings, anti epileptic drugs used, therapeutic response, and magnetic resonance imaging findings. Patients were divided into three groups according to the seizure frequency at the time of last follow up: Group I- Seizure free; Group II- Infrequent seizures; Group III- uncontrolled seizures. For each group the clinical phenotype, genotype, magnetic resonance imaging and duration of epilepsy were compared. ResultsThe phenotypes & genotypes included Mitochondrial Encephalopathy Lactic Acidosis and Stroke like episodes (MELAS) & m.3243A>G mutation (n = 10), Myoclonic Epilepsy Ragged Red Fiber syndrome (MERRF) & m.8344A>G mutation (n = 4), Chronic Progressive External Ophthalmoplegia plus &POLG1 mutation (CPEO, n = 6), episodic neuroregression due to nuclear mutations (n = 6; NDUFV1 (n = 3), NDUFA1, NDUFS2, MPV17-1 one each), and one patient with infantile basal ganglia stroke syndrome, mineralizing angiopathy &MT-ND5 mutations. Seven patients (25.9%) were seizure free; seven had infrequent seizures (25.9%), while thirteen (48.1%) had frequent uncontrolled seizures. Majority of the subjects in seizure free group had episodic neuroregression & leukoencephalopathy due to nuclear mutations (85.7%). Patients in group II with infrequent seizures had CPEO, POLG1 mutation and a normal MRI (71%) while 62% of the subjects in group III had MELAS, m.3243A>G mutation and stroke like lesions on MRI. ConclusionsA fair correlation exists between the outcome of epilepsy, clinical phenotypes, genotypes and magnetic resonance imaging findings in patients with mitochondrial disorders. The recognition of these patterns is important clinically because of the therapeutic and prognostic implications.

Birds of a feather flock together: Maternally inherited diabetes and Deafness AND Mitochondrial encephalopathy lactic acidosis and stroke like episodes

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Clinical presentation, etiology, and outcome of stroke in children: A hospital-based study

AimTo describe clinical presentations, etiologies, and outcomes of stroke in Jordanian children. Patients and methodsWe retrospectively reviewed the medical records of children diagnosed with ischemic stroke who presented to our clinic from January 2001 to June 2014. Patients with onset of stroke in the neonatal period were excluded. ResultsTwenty-four children (12 boys and 12 girls, with a male to female ratio of 1:1) were included in this study. The follow-up period ranged from 1month to 9years. Age at onset of the first stroke ranged from 1month to 13years. The most common initial clinical presentation was hemiparesis (58.3%). A known etiology was identified in 58.3% of patients. The most common etiologies were metabolic disorders, such as mitochondrial encephalopathy lactic acidosis and stroke (MELAS) and homocystinuria (25%), cardiac disorders (17%), and coagulopathy, such as a homozygous mutation in the MTHFR gene and a factor V Leiden mutation (17%). Recurrence of both clinical and silent strokes occurred in 46% of patients, residual motor weakness occurred in 58.3%, and residual epilepsy occurred in 29.2%. ConclusionMetabolic disorders, cardiac disorders, and coagulopathy are the causes of strokes in Jordanian children. Our results emphasized the importance of inherited disorders in Jordan.

Improvement in symptoms of the syndrome of mitochondrial encephalopathy, lactic acidosis, and stroke-like symptoms (MELAS) following treatment with sympathomimetic amines – possible implications for improving fecundity in women of advanced reproductive age

Purpose: To evaluate the efficacy of sympathomimetic amine therapy on a mitochondrial abnormality known as the mitochondrial encephalopathy lactic acidosis and stroke-like symptoms syndrome (MELAS syndrome). Materials and Methods: Dextroamphetamine sulfate 15 mg extended release capsule was prescribed to a woman with a 25 year history of MELAS syndrome refractory to most other therapies. Results: Within one month of therapy the woman noticed considerable improvement in her chronic fatigue, pain, and edema. Conclusions: The MELAS syndrome is thus another condition to add to the list of various chronic refractory disorders that improve considerably after dextroamphetamine therapy. This is the first mitochondrial disorder shown to improve with sympathomimetic amines which could suggest that dextroamphetamine could prove useful in decreasing the risk of aneuploidy in women of advanced reproductive age.

MELAS: A Multigenerational Impact of the MTTL1 A3243G MELAS Mutation

the maternally inherited MTTL1 A3243G mutation in the mitochondrial genome causes MelaS (Mitochondrial encephalopathy lactic acidosis with Stroke-like episodes), a condition that is multisystemic but affects primarily the nervous system. Significant intra-familial variation in phenotype and severity of disease is well recognized. retrospective and ongoing study of an extended family carrying the MTTL1 A3243G mutation with multiple symptomatic individuals. tissue heteroplasmy is reviewed based on the clinical presentations, imaging studies, laboratory findings in affected individuals and pathological material obtained at autopsy in two of the family members. there were seven affected individuals out of thirteen members in this three generation family who each carried the MTTL1 A3243G mutation. the clinical presentations were varied with symptoms ranging from hearing loss, migraines, dementia, seizures, diabetes, visual manifestations, and stroke like episodes. three of the family members are deceased from MelaS or to complications related to MelaS. the results of the clinical, pathological and radiological findings in this family provide strong support to the current concepts of maternal inheritance, tissue heteroplasmy and molecular pathogenesis in MelaS. neurologists (both adult and paediatric) are the most likely to encounter patients with MelaS in their practice. genetic counselling is complex in view of maternal inheritance and heteroplasmy. newer therapeutic options such as arginine are being used for acute and preventative management of stroke like episodes.

The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation—implications for diagnosis and management

BackgroundPopulation-based studies suggest the m.3243A>G mutation in MTTL1 is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people. The m.3243A>G mutation is associated with...

Microangiopathy in the cerebellum of patients with mitochondrial DNA disease

Neuropathological findings in mitochondrial DNA disease vary and are often dependent on the type of mitochondrial DNA defect. Many reports document neuronal cell loss, demyelination, gliosis and necrotic lesions in post-mortem material. However, previous studies highlight vascular abnormalities in patients harbouring mitochondrial DNA defects, particularly in those with the m.3243A>G mutation in whom stroke-like events are part of the mitochondrial encephalopathy lactic acidosis and stroke-like episodes syndrome. We investigated microangiopathic changes in the cerebellum of 16 genetically and clinically well-defined patients. Respiratory chain deficiency, high levels of mutated mitochondrial DNA and increased mitochondrial mass were present within the smooth muscle cells and endothelial cells comprising the vessel wall in patients. These changes were not limited to those harbouring the m.3243A>G mutation frequently associated with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes, but were documented in patients harbouring m.8344A>G and autosomal recessive polymerase (DNA directed), gamma (POLG) mutations. In 8 of the 16 patients, multiple ischaemic-like lesions occurred in the cerebellar cortex suggestive of vascular smooth muscle cell dysfunction. Indeed, changes in vascular smooth muscle and endothelium distribution and cell size are indicative of vascular cell loss. We found evidence of blood–brain barrier breakdown characterized by plasma protein extravasation following fibrinogen and IgG immunohistochemistry. Reduced immunofluorescence was also observed using markers for endothelial tight junctions providing further evidence in support of blood–brain barrier breakdown. Understanding the structural and functional changes occurring in central nervous system microvessels in patients harbouring mitochondrial DNA defects will provide an important insight into mechanisms of neurodegeneration in mitochondrial DNA disease. Since therapeutic strategies targeting the central nervous system are limited, modulating vascular function presents an exciting opportunity to lessen the burden of disease in these patients.

Atypical Strokes in a Young African American Male: A Case of Mitochondrial Encephalopathy Lactic Acidosis and Stroke-Like Episodes (MELAS) Syndrome

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare but important cause of stroke-like symptoms which can often be missed Thambisetty and Newman 2004. We describe a case of a young male presenting with stroke-like episodes, later diagnosed with MELAS in an attempt to improve the understanding about diagnosing MELAS in the appropriate clinical context.

Introduction: Euromit VII – summarizing 50 years of research on mitochondrial disease

Introduction: Euromit VII – summarizing 50 years of research on mitochondrial disease

A transgenic model to study the pathogenesis of somatic mtDNA mutation accumulation in β‐cells

Low levels of somatic mutations accumulate in mitochondrial DNA (mtDNA) as we age; however, the pathogenic nature of these mutations is unknown. In contrast, mutational loads of >30% of mtDNA are associated with electron transport chain defects that result in mitochondrial diseases such as mitochondrial encephalopathy lactic acidosis and stroke-like episodes. Pancreatic beta-cells may be extremely sensitive to the accumulation of mtDNA mutations, as insulin secretion requires the mitochondrial oxidation of glucose to CO(2). Type 2 diabetes arises when beta-cells fail to compensate for the increased demand for insulin, and many type 2 diabetics progress to insulin dependence because of a loss of beta-cell function or beta-cell death. This loss of beta-cell function/beta-cell death has been attributed to the toxic effects of elevated levels of lipids and glucose resulting in the enhanced production of free radicals in beta-cells. mtDNA, localized in close proximity to one of the major cellular sites of free radical production, comprises more than 95% coding sequences such that mutations result in changes in the coding sequence. It has long been known that mtDNA mutations accumulate with age; however, only recently have studies examined the influence of somatic mtDNA mutation accumulation on disease pathogenesis. This article will focus on the effects of low-level somatic mtDNA mutation accumulation on ageing, cardiovascular disease and diabetes.

Clinical and genetic uniqueness in an individual with MELAS

Mitochondrial encephalopathy lactic acidosis stroke like episodes (MELAS) is a progressive neurodegenerative disorder with varying age of onset. It is a clinically and genetically heterogeneous disease. Molecular etiology of MELAS is not known in several cases. We have identified a unique individual with late onset MELAS at the age of 55 years. We have analyzed the complete mitochondrial genome of the tissue and blood samples of the patient. One novel heteroplasmic mutation (C13565A) in NADH dehydrogenase 5 subunit (ND5) gene was found only in the tissue sample but not in the blood. This mutation is missense causing a change of amino acid serine to tyrosine at position 410. This mutation was found neither in controls nor in world populations. This study has also confirmed ND5 as a hotspot for the mitochondrial diseases. This will be of great help for the clinicians in the diagnosis of MELAS.