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Iranian Journal of Public Health Dec 2022We discuss the involvement of nuclear genetic variants correlating to observed phenotype in this case study. In January 2020, the 19-year-old boy from Nantong, Jiangsu...
We discuss the involvement of nuclear genetic variants correlating to observed phenotype in this case study. In January 2020, the 19-year-old boy from Nantong, Jiangsu Province, China with epilepsy symptom was identified to have myelin loss in the motor and sensory nerves in the electromyogram examination. Brain magnetic resonance imaging (MRI) demonstrated high-intensity areas of small multifocal gray matter regions in the bilateral temporal, parietal, and occipital lobes. In the serum of the patient, the levels of lactate dehydrogenase (LDH) and lactic acid were higher than the normal range values in multiple tests. By subsequent whole exome sequencing (WES) including analysis of the mitochondrial genome, the patient was revealed to carry an m.3243A>G mutation in mitochondria gene which was confirmed by direct Sanger sequencing analysis. Thus, disease of the patient was diagnosed as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. According to WES analysis, the patient also carried multiple homozygous variants, which correlating to myelinloss and epilepsy in nuclear genes. The peripheral neuropathy of the patient carrying single mitochondrial m.3243A>G mutation could be caused by multiple nuclear DNA defect.
PubMed: 36742238
DOI: 10.18502/ijph.v51i12.11473 -
European Heart Journal. Case Reports Jan 2023Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a multi-organ disorder resulting from mitochondrial DNA (mtDNA)...
BACKGROUND
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a multi-organ disorder resulting from mitochondrial DNA (mtDNA) mutations. We report a case of suspected MELAS syndrome that progressed to left ventricular dysfunction 24 years after an initial diagnosis of atrioventricular block (AVB).
CASE SUMMARY
A 51-year-old woman was referred to heart failure clinic because of dyspnoea on exertion and progressive cardiomegaly. She had a dual-chamber pacemaker implanted for 24 years because of a high-degree AVB. She was treated for diabetes mellitus for 23 years and used hearing aids for 12 years because of sensorineural hearing loss. Transthoracic echocardiography revealed reduced left ventricular ejection fraction (26%), with increased thickness and unusual texture of the myocardium. The absence of abnormal findings on serum and urine protein electrophoresis suggested that light-chain amyloidosis was unlikely. In addition, Tc-3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy revealed no definite uptake in the myocardium. Endomyocardial biopsy revealed a hypertrophy of myocytes in haematoxylin-eosin staining, and electron microscopy revealed a disarrangement of mitochondrial cristae, which were suggestive of mitochondrial cardiomyopathy. A mtDNA test detected the m.3243A > G mutation in the gene. According to these findings, MELAS syndrome was the most probable diagnosis despite the absence of common symptoms such as stroke-like episodes or lactic acidosis.
DISCUSSION
The patient had progressed to heart failure with reduced ejection fraction 24 years after the first cardiac manifestation. An identification of the mutation in the gene, indicative of MELAS syndrome, enabled the diagnosis of MELAS syndrome without typical manifestations.
PubMed: 36733687
DOI: 10.1093/ehjcr/ytad028 -
Cureus Dec 2022Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disease that lacks a definitive treatment. Lately, there has... (Review)
Review
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disease that lacks a definitive treatment. Lately, there has been an increased interest in the scientific community about the role of arginine in the short and long-term settings of the disease. We aim to conduct a systematic review of the clinical use of arginine in the management of MELAS and explore the role of arginine in the pathophysiology of the disease. We used PubMed advanced-strategy searches and only included full-text clinical trials on humans written in the English language. After applying the inclusion/exclusion criteria, four clinical trials were reviewed. We used the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol for this systematic review. We used the Cochrane Collaboration risk-of-bias tool to assess the bias encountered in each study. Overall, IV arginine seems to be effective in improving symptoms during acute attacks of MELAS, while oral arginine supplementation increases endothelial function, preventing further stroke-like episodes.
PubMed: 36686069
DOI: 10.7759/cureus.32709 -
Metabolites Dec 2022Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited genetic mitochondrial disease with a typical onset...
Traumatic Brain Injury Triggers Neurodegeneration in a Mildly Symptomatic MELAS Patient: Implications on the Detrimental Role of Damaged Mitochondria in Determining Head Trauma Sequalae in the General Population.
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited genetic mitochondrial disease with a typical onset in the first two decades of life and a major involvement of central nervous system (CNS). We present the case of a man affected with an oligosymptomatic, genetically determined MELAS syndrome, whose clinical picture dramatically and irreversibly worsened following a mild head injury. We hypothesize that the CNS metabolic stress induced by the brain injury activated an irreversible cascade of events leading to progressive neurodegeneration because damaged mitochondria were unable to restore the balance between energy requirements and availability.
PubMed: 36676971
DOI: 10.3390/metabo13010046 -
Seizure Jan 2023
Topics: Humans; MELAS Syndrome; Epilepsy; Brain; Stroke
PubMed: 36642493
DOI: 10.1016/j.seizure.2022.09.012 -
Cells Dec 2022The MELAS syndrome primarily affecting the CNS is mainly caused by the m.A3243G mutation. The heteroplasmy in different tissues affects the phenotypic spectrum, yet the...
The MELAS syndrome primarily affecting the CNS is mainly caused by the m.A3243G mutation. The heteroplasmy in different tissues affects the phenotypic spectrum, yet the impact of various levels of m.A3243G heteroplasmy on CNS remains elusive due to the lack of a proper neuronal model harboring m.A3243G mutation. We generated induced neurons (iNs) through the direct reprogramming of MELAS patients, with derived fibroblasts harboring high (>95%), intermediate (68%), and low (20%) m.A3243G mutation. iNs demonstrated neuronal morphology with neurite outgrowth, branching, and dendritic spines. The heteroplasmy and deficiency of respiratory chain complexes were retained in MELAS iNs. High heteroplasmy elicited the elevation in ROS levels and the disruption of mitochondrial membrane potential. Furthermore, high and intermediate heteroplasmy led to the impairment of mitochondrial bioenergetics and a change in mitochondrial dynamics toward the fission and fragmentation of mitochondria, with a reduction in mitochondrial networks. Moreover, iNs derived from aged individuals manifested with mitochondrial fission. These results help us in understanding the impact of various heteroplasmic levels on mitochondrial bioenergetics and mitochondrial dynamics in neurons as the underlying pathomechanism of neurological manifestations of MELAS syndrome. Furthermore, these findings provide targets for further pharmacological approaches of mitochondrial diseases and validate iNs as a reliable platform for studies in neuronal aspects of aging, neurodegenerative disorders, and mitochondrial diseases.
Topics: Humans; Aged; MELAS Syndrome; Heteroplasmy; DNA, Mitochondrial; Mitochondria; Energy Metabolism; Neurons
PubMed: 36611807
DOI: 10.3390/cells12010015 -
Frontiers in Neurology 2022Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes, and other features (short stature, headaches, seizures, and sensorineural hearing loss)...
Mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes, and other features (short stature, headaches, seizures, and sensorineural hearing loss) constitute characteristics of MELAS syndrome. MELAS is a rare condition due to mutations in maternally inherited mitochondrial DNA with levels of heteroplasmy possibly related to late adulthood presentation. A previously reported MELAS case coexisted with presumed Antiphospholipid Antibody Syndrome (APLAS), but the connection between MELAS and a potential APLAS is unclear. A 29-year-old woman presented with mild right-sided sensorimotor symptoms and mixed aphasia in November 2021. She presented again in May 2022 for unrelenting headaches and was found to have a new right hemisphere syndrome with mild left-sided sensorimotor symptoms, hemineglect, and anosognosia. Characteristic lab and imaging studies were obtained. During the first presentation (October 2021), the discovery of anticardiolipin IgM antibodies (aCL) (and their replication 3 months later) led to a diagnosis of APLAS, and Warfarin was initiated. During the second admission (May 2022), a new stroke-like lesion on the right hemisphere with characteristic features not suggestive of ischemia was detected, which led to a diagnosis of MELAS (m3243A > G mutation). Although MELAS and APLAS could co-exist, alternatively, it is possible that antiphospholipid antibodies might be generated when the strongly anionic Cardiolipin-Hydroperoxide from the inner mitochondrial membrane is exposed to immune component cells upon cell lysis. Thus, the presence of aCL in patients with stroke-like lesions might masquerade as an APLAS, but should probably be questioned if only aCL are repeatedly found and imaging findings are not characteristic for ischemic lesions.
PubMed: 36588908
DOI: 10.3389/fneur.2022.1043695 -
Journal of Neuromuscular Diseases 2023Mitochondrial tRNA (MTT) genes are hotspot for mitochondrial DNA mutation and are responsible of half mitochondrial disease. MTT mutations are associated with a broad...
BACKGROUND
Mitochondrial tRNA (MTT) genes are hotspot for mitochondrial DNA mutation and are responsible of half mitochondrial disease. MTT mutations are associated with a broad spectrum of phenotype often with complex multisystem involvement and complex genotype-phenotype correlations. MT-TL1 mutations, among which the m.3243A>G mutation is the most frequent, are associated with myopathy, maternal inherited diabetes and deafness, MELAS, cardiomyopathy, and focal segmental glomerulosclerosis.
CASE STUDY
Here we report the case of an Italian 49-years old female presenting with encephalomyopathy, chronic proteinuric kidney disease and a new heteroplasmic m.3274_3275delAC MT-TL1 gene mutation.
CONCLUSIONS
Our case demonstrates a systemic mitochondrial disease caused by the heteroplasmic m.3274_3275delAC MT-TL1 gene mutation, not yet described in the literature. A mitochondrial disease should be suspected in case of complex multisystem phenotypes, including steroid-resistant nephrotic syndrome with multisystemic involvement.
Topics: Female; Humans; DNA, Mitochondrial; Mitochondria; Mitochondrial Diseases; Mutation; MELAS Syndrome
PubMed: 36404555
DOI: 10.3233/JND-221526 -
International Journal of Molecular... Oct 2022Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect... (Review)
Review
Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects >1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options.
Topics: Humans; Neurologists; Mitochondrial Diseases; DNA, Mitochondrial; Epilepsy; Mitochondria; Mutation
PubMed: 36362003
DOI: 10.3390/ijms232113216 -
Frontiers in Neurology 2022Krabbe disease (KD), also known as globoid cell leukodystrophy, is a rare autosomal recessive condition caused by mutations in the galactocerebrosidase (GALC) gene. KD...
Krabbe disease (KD), also known as globoid cell leukodystrophy, is a rare autosomal recessive condition caused by mutations in the galactocerebrosidase (GALC) gene. KD is more common in infants and young children than in adults. We reported the case of an adult-onset KD presenting with progressive myoclonic epilepsy (PME) and cortical lesions mimicking mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. The whole-exome sequencing (WES) identified a pathogenic homozygous missense mutation of the gene. Parents of the patient were heterozygous for the mutation. The clinical, electrophysiological, and radiological data of the patient were retrospectively analyzed. The patient was a 24-year-old woman presenting with generalized seizures, progressive cognitive decline, psychiatric symptoms, gait ataxia, and action-induced myoclonus. The brain magnetic resonance imaging (MRI) revealed a right occipital cortical ribbon sign without any other damage. This single case expands the clinical phenotypes of adult-onset KD.
PubMed: 36341094
DOI: 10.3389/fneur.2022.1010150