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Life (Basel, Switzerland) Oct 2021Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, a maternally inherited mitochondrial disorder, is characterized by its... (Review)
Review
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, a maternally inherited mitochondrial disorder, is characterized by its genetic, biochemical and clinical complexity. The most common mutation associated with MELAS syndrome is the mtDNA A3243G mutation in the MT-TL1 gene encoding the mitochondrial tRNA-leu(UUR), which results in impaired mitochondrial translation and protein synthesis involving the mitochondrial electron transport chain complex subunits, leading to impaired mitochondrial energy production. Angiopathy, either alone or in combination with nitric oxide (NO) deficiency, further contributes to multi-organ involvement in MELAS syndrome. Management for MELAS syndrome is amostly symptomatic multidisciplinary approach. In this article, we review the clinical presentations, pathogenic mechanisms and options for management of MELAS syndrome.
PubMed: 34832987
DOI: 10.3390/life11111111 -
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 -
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 -
Frontiers in Neurology 2021Mitochondrial diseases are characterized by considerable clinical and genetic heterogeneity. Mitochondrial encephalomyopathy with lactate acidosis and stroke-like...
Mitochondrial diseases are characterized by considerable clinical and genetic heterogeneity. Mitochondrial encephalomyopathy with lactate acidosis and stroke-like episodes (MELAS) and Leigh syndrome (LS) are both established mitochondrial syndromes; sometimes they can overlap. A retrospective observational cohort study was done to analyze the clinical manifestations, biochemical findings, neuroimaging and genetic data, and disease outcomes of 14 patients with identified MELAS/LS overlap syndrome. A total of 14 patients, 9 males and 5 females, were enrolled. The median age at onset was 14 years, while the average age was 12.6 years. As for clinical features in concordance with MELAS, the top three most common symptoms were seizures, cognitive impairment, and stroke-like episodes (SLE). Brain atrophy was present in seven patients. As for the clinical hallmarks of LS, the top three most common symptoms were ataxia, spastic paraplegia, and bulbar palsy. Patients presented with individual syndrome or overlap syndromes with similar frequency, and the prognosis did not seem to be related to the initial presentation. Thirteen patients were identified with mutations, among which m.13513G>A mutation in the gene was the most common. Only one patient with m.8344A>G mutation of gene was found. Our study demonstrated that genes are important mutation hot spots in MELAS/LS overlap syndrome. The follow-up is very important for the final diagnosis of overlap syndrome.
PubMed: 34025555
DOI: 10.3389/fneur.2021.648740 -
Nucleic Acids Research Aug 2023Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes...
Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged red fibers (MERRF) are major clinical subgroups of mitochondrial diseases caused by pathogenic point mutations in tRNA genes encoded in mtDNA. We previously reported a severe reduction in the frequency of 5-taurinomethyluridine (τm5U) and its 2-thiouridine derivative (τm5s2U) in the anticodons of mutant mt-tRNAs isolated from the cells of patients with MELAS and MERRF, respectively. The hypomodified tRNAs fail to decode cognate codons efficiently, resulting in defective translation of respiratory chain proteins in mitochondria. To restore the mitochondrial activity of MELAS patient cells, we overexpressed MTO1, a τm5U-modifying enzyme, in patient-derived myoblasts. We used a newly developed primer extension method and showed that MTO1 overexpression almost completely restored the τm5U modification of the MELAS mutant mt-tRNALeu(UUR). An increase in mitochondrial protein synthesis and oxygen consumption rate suggested that the mitochondrial function of MELAS patient cells can be activated by restoring the τm5U of the mutant tRNA. In addition, we confirmed that MTO1 expression restored the τm5s2U of the mutant mt-tRNALys in MERRF patient cells. These findings pave the way for epitranscriptomic therapies for mitochondrial diseases.
Topics: Humans; DNA, Mitochondrial; MELAS Syndrome; MERRF Syndrome; Mitochondria; Mutation; RNA, Transfer
PubMed: 36928678
DOI: 10.1093/nar/gkad139 -
JCI Insight Sep 2023Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic...
Pathogenic mutations in mitochondrial (mt) tRNA genes that compromise oxidative phosphorylation (OXPHOS) exhibit heteroplasmy and cause a range of multisyndromic conditions. Although mitochondrial disease patients are known to suffer from abnormal immune responses, how heteroplasmic mtDNA mutations affect the immune system at the molecular level is largely unknown. Here, in mice carrying pathogenic C5024T in mt-tRNAAla and in patients with mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS) syndrome carrying A3243G in mt-tRNALeu, we found memory T and B cells to have lower pathogenic mtDNA mutation burdens than their antigen-inexperienced naive counterparts, including after vaccination. Pathogenic burden reduction was less pronounced in myeloid compared with lymphoid lineages, despite C5024T compromising macrophage OXPHOS capacity. Rapid dilution of the C5024T mutation in T and B cell cultures could be induced by antigen receptor-triggered proliferation and was accelerated by metabolic stress conditions. Furthermore, we found C5024T to dysregulate CD8+ T cell metabolic remodeling and IFN-γ production after activation. Together, our data illustrate that the generation of memory lymphocytes shapes the mtDNA landscape, wherein pathogenic variants dysregulate the immune response.
Topics: Animals; Mice; Mutation; Receptors, Antigen; DNA, Mitochondrial; Acidosis, Lactic; RNA, Transfer
PubMed: 37681412
DOI: 10.1172/jci.insight.167656 -
The Journal of International Advanced... Aug 2019The mitochondrial DNA (mtDNA) point mutation m.3243A>G is known to express the following two syndromes among others: maternally inherited diabetes and deafness (MIDD)...
OBJECTIVES
The mitochondrial DNA (mtDNA) point mutation m.3243A>G is known to express the following two syndromes among others: maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Sensorineural hearing loss (SNHL) is the most frequent symptom in individuals harboring the m.3243A>G mutation. However, dysfunction of the vestibular organs has been scarcely examined. Therefore, the present study aimed to study the impact of the m.3243A>G mutation on the inner ear.
MATERIALS AND METHODS
A total of 8 subjects harboring the blood-verified m.3243A>G mutation underwent thorough audiological and vestibular examinations, including tone and speech audiometry, video head impulse test (vHIT), ocular and cervical vestibular-evoked myogenic potential (oVEMP and cVEMP), and full otoneurological examination. The subjects also answered a Dizziness Handicap Inventory (DHI) questionnaire.
RESULTS
SNHL was identified in all the 8 subjects, with a mean pure-tone average-4 (PTA-4) of 59 dB. Speech discrimination score (n=7) ranged from 24% to 100% (mean 74%), and vHIT (n=42) detected pathology in nine lateral semicircular canals (SCCs), five posterior SCCs, and one anterior SCC, whereas three measurements were inconclusive. All oVEMPs (n=14 ears) were absent, nine cVEMPs were absent, and two were inconclusive. Based on the DHI scores, 6 subjects reported none to mild dizziness, 1 reported moderate, and 1 reported severe dizziness.
CONCLUSION
Our study population had pathological findings from every audiological and vestibular end organs. The results indicated that the pathological findings originated from within the end organs themselves and not within the superior and inferior vestibular or cochlear nerve.
Topics: Aged; Audiometry, Pure-Tone; Audiometry, Speech; Dizziness; Female; Head Impulse Test; Hearing Loss, Sensorineural; Humans; Labyrinth Diseases; MELAS Syndrome; Male; Middle Aged; Point Mutation; Saccades; Speech Perception; Vestibular Evoked Myogenic Potentials; Vestibule, Labyrinth
PubMed: 31347509
DOI: 10.5152/iao.2019.5913 -
Annals of Clinical and Translational... Jun 2022To examine the correlation between verbal and visual memory function and correlation with brain metabolites (lactate and N-Acetylaspartate, NAA) in individuals with...
OBJECTIVE
To examine the correlation between verbal and visual memory function and correlation with brain metabolites (lactate and N-Acetylaspartate, NAA) in individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
METHODS
Memory performance and brain metabolites (ventricular lactate, occipital lactate, and occipital NAA) were examined in 18 MELAS, 58 m.3243A > G carriers, and 20 familial controls. Measures included the Selective Reminding Test (verbal memory), Benton Visuospatial Retention Test (visual memory), and MR Spectroscopy (NAA, Lactate). ANOVA, chi-squared/Fisher's exact tests, paired t-tests, Pearson correlations, and Spearman correlations were used.
RESULTS
When compared to carriers and controls, MELAS patients had the: (1) most impaired memory functions (Visual: p = 0.0003; Verbal: p = 0.02), (2) greatest visual than verbal memory impairment, (3) highest brain lactate levels (p < 0.0001), and (4) lowest brain NAA levels (p = 0.0003). Occipital and ventricular lactate to NAA ratios correlated significantly with visual memory performance (p ≤ 0.001). Higher lactate levels (p ≤ 0.01) and lower NAA levels (p = 0.0009) correlated specifically with greater visual memory dysfunction in MELAS. There was little or no correlation with verbal memory.
INTERPRETATION
Individuals with MELAS are at increased risk for impaired memory. Although verbal and visual memory are both affected, visual memory is preferentially affected and more clearly associated with brain metabolite levels. Preferential involvement of posterior brain regions is a distinctive clinical signature of MELAS. We now report a distinctive cognitive phenotype that targets visual memory more prominently and earlier than verbal memory. We speculate that this finding in carriers presages a conversion to the MELAS phenotype.
Topics: Brain; Humans; Lactic Acid; MELAS Syndrome; Phenotype; Stroke
PubMed: 35522125
DOI: 10.1002/acn3.51564 -
American Journal of Ophthalmology Case... Jun 2024To describe examination and findings in a case of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with particular focus on the ocular...
PURPOSE
To describe examination and findings in a case of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) with particular focus on the ocular sequelae from diabetes.
OBSERVATIONS
Neovascular glaucoma is not a common manifestation of MELAS.
CONCLUSIONS AND IMPORTANCE
We present a rare case of neovascular glaucoma in a patient with MELAS with a history of diabetes, hearing loss, and macular dystrophy. MELAS should be suspected in patients with this constellation of symptoms.
PubMed: 38707951
DOI: 10.1016/j.ajoc.2024.102064 -
Neurology. Genetics Aug 2023Stroke-like episodes (SLEs) in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome are often misdiagnosed as acute...
BACKGROUND AND OBJECTIVES
Stroke-like episodes (SLEs) in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome are often misdiagnosed as acute ischemic stroke (AIS). We aimed to determine unique clinical and neuroimaging features for SLEs and formulate diagnostic criteria.
METHODS
We retrospectively identified patients with MELAS admitted for SLEs between January 2012 and December 2021. Clinical features and imaging findings were compared with a cohort of patients who presented with AIS and similar lesion topography. A set of criteria was formulated and then tested by a blinded rater to evaluate diagnostic performance.
RESULTS
Eleven MELAS patients with 17 SLE and 21 AISs were included. Patients with SLEs were younger (median 45 [37-60] vs 77 [68-82] years, < 0.01) and had a lower body mass index (18 ± 2.6 vs 29 ± 4, < 0.01), more commonly reported hearing loss (91% vs 5%, < 0.01), and more commonly presented with headache and/or seizures (41% vs 0%, < 0.01). The earliest neuroimaging test performed at presentation was uniformly a noncontrast CT. Two main patterns of lesion topography with a stereotypical spatiotemporal evolution were identified-an anterior pattern (7/21, 41%) starting at the temporal operculum and spreading to the peripheral frontal cortex and a posterior pattern (10/21, 59%) starting at the cuneus/precuneus and spreading to the lateral occipital and parietal cortex. Other distinguishing features for SLEs vs AIS were cerebellar atrophy (91% vs 19%, < 0.01), previous cortical lesions with typical SLE distribution (46% vs 9%, = 0.03), acute lesion tissue hyperemia and venous engorgement on CT angiography (CTA) (45% vs 0%, < 0.01), and no large vessel occlusion on CTA (0% vs 100%, < 0.01). Based on these clinicoradiologic features, a set of diagnostic criteria were constructed for possible SLE (sensitivity 100%, specificity 81%, AUC 0.905) and probable SLE (sensitivity 88%, specificity 95%, AUC 0.917).
DISCUSSION
Clinicoradiologic criteria based on simple anamnesis and a CT scan at presentation can accurately diagnose SLE and lead to early administration of appropriate therapy.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence that an algorithm using clinical and imaging features can differentiate stroke-like episodes due to MELAS from acute ischemic strokes.
PubMed: 37426458
DOI: 10.1212/NXG.0000000000200082