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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 -
Ideggyogyaszati Szemle Jan 2023
Objective – Stroke-like lesions (SLLs) are pathognomonic for mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes... (Review)
Review
Objective – Stroke-like lesions (SLLs) are pathognomonic for mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome but occur in other mitochondrial and non-mitochondrial disorders as well. This mini-review aims at summarising and discussing recent findings to open up future perspectives how to manage this fleeting phenomenon.
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Results – Typically, SLLs are dynamic lesions, which increase in size and intensity to regress after a nadir. SLLs are incongruent with a vascular territory, originate frequently from the cortex to spread subcortically, can be monofocal or multifocal, run through an acute (attack) and chronic (remission) stage, and may either completely disappear or end up as laminar cortical necrosis, white matter lesion, subcortical atrophy, cyst, or the toenail sign. On cerebral CT, SLLs are hypodense. SLLs can be best visualized on multimodal MRI showing up as hyperintensity on T2, FLAIR, DWI, and PWI, and as hypointensity on OEF-MRI. On MR-spectroscopy, SLLs typically present with a decreased N-acetyl-aspartate peak and an increased lactate peak. DTI in acute SLLs reveals reduced connectivity, increased global efficiency, and reduced focal efficiency. Tc-HMPAO SPECT of SLLs indicates hyperperfusion and L-iomazenil SPECT reduced tracer uptake. FDG-PET typically shows hypometabolism within a SLL.
Conclusion – SLLs present with typical findings on various imaging modalities but the combination of cerebral CT, multimodal MRI, MRS, and PET clearly delineate a SLL from other acute or chronic cerebral lesions.Topics: Humans; Stroke; MELAS Syndrome; Magnetic Resonance Imaging; Tomography, Emission-Computed, Single-Photon; Positron-Emission Tomography; Brain
PubMed: 36892301
DOI: 10.18071/isz.76.0005 -
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 -
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 -
Pharmacological Research Jun 2022A mitochondrial stroke-like event is an evolving subacute neurological syndrome linked to seizure activity and focal metabolic brain derangement in a genetically...
A mitochondrial stroke-like event is an evolving subacute neurological syndrome linked to seizure activity and focal metabolic brain derangement in a genetically determined mitochondrial disorder. The acronym "MELAS" (mitochondrial encephalopathy associated with lactic acidosis and stroke-like lesions) identifies subjects with molecular, biochemical and/or histological evidence of mitochondrial disorder who experience stroke-like lesions. MELAS is a rare inherited mitochondrial disease linked to severe multiorgan involvement and stress-induced episodes of metabolic decompensation and lactic acidosis. Unfortunately, there are no etiopathogenetic therapies for stroke-like episodes to date, and the treatment is mainly based on anti-epileptic drugs and supportive therapies. This perspective opinion article discusses the current care standards for MELAS patients and revises current and innovative emerging therapies for mitochondrial stroke-like episodes.
Topics: Acidosis, Lactic; DNA, Mitochondrial; Humans; MELAS Syndrome; Mitochondrial Diseases; Mutation; Stroke
PubMed: 35462010
DOI: 10.1016/j.phrs.2022.106228 -
Journal of Neurology Jun 2022Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA)... (Observational Study)
Observational Study
BACKGROUND
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a genetically heterogeneous disorder caused by mitochondrial DNA (mtDNA) mutations in the MT-TL1 gene. The pathophysiology of neurological manifestations is still unclear, but neuronal hyperexcitability and neuron-astrocyte uncoupling have been suggested. Glutamatergic neurotransmission is linked to glucose oxidation and mitochondrial metabolism in astrocytes and neurons. Given the relevance of neuron-astrocyte metabolic coupling and astrocyte function regulating energetic metabolism, we aimed to assess glutamate and glutamine CSF levels in MELAS patients.
METHODS
This prospective observational case-control study determined glutamate and glutamine CSF levels in patients with MELAS syndrome and compared them with controls. The plasma and CSF levels of the remaining amino acids and lactate were also determined.
RESULTS
Nine adult patients with MELAS syndrome (66.7% females mean age 35.8 ± 3.2 years) and 19 controls (63.2% females mean age 42.7 ± 3.8 years) were included. The CSF glutamate levels were significantly higher in patients with MELAS than in controls (18.48 ± 1.34 vs. 5.31 ± 1.09 μmol/L, p < 0.001). Significantly lower glutamine concentrations in patients with MELAS than controls were shown in CSF (336.31 ± 12.92 vs. 407.06 ± 15.74 μmol/L, p = 0.017). Moreover, the CSF levels of alanine, the branched-chain amino acids (BCAAs) and lactate were significantly higher in patients with MELAS.
CONCLUSIONS
Our results suggest the glutamate-glutamine cycle is altered probably due to metabolic imbalance, and as a result, the lactate-alanine and BCAA-glutamate cycles are upregulated. These findings might have therapeutic implications in MELAS syndrome.
Topics: Adult; Alanine; Case-Control Studies; DNA, Mitochondrial; Female; Glutamic Acid; Glutamine; Humans; Lactic Acid; MELAS Syndrome; Male; Middle Aged; Stroke
PubMed: 35088140
DOI: 10.1007/s00415-021-10942-7 -
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 -
Practical Neurology Aug 2019
Topics: Diagnosis, Differential; Epilepsies, Myoclonic; Genetic Diseases, Inborn; Humans; Leukoencephalitis, Acute Hemorrhagic; MELAS Syndrome; Optic Atrophy, Hereditary, Leber; Recurrence
PubMed: 30948557
DOI: 10.1136/practneurol-2018-002181 -
Pediatric Neurology Jan 2019
Topics: Atrophy; Brain; Child; Humans; MELAS Syndrome; Magnetic Resonance Imaging; Male
PubMed: 30396830
DOI: 10.1016/j.pediatrneurol.2018.07.011 -
Nefrologia Dec 2023Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is... (Review)
Review
Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is the most frequent mitochondrial DNA defect, and it causes several different clinical syndromes, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and the maternally inherited diabetes and deafness (MIDD) syndromes. Not frequently reported, renal involvement in these diseases is probably underestimated, yet it increases morbidity. It generally manifests as subnephrotic proteinuria and progressive deterioration of kidney function. Adult presentation of mitochondrial diseases is hard to recognize, especially in oligosymptomatic patients or those with exclusive kidney involvement. However, suspicion should always arise when family history, particularly on the maternal side, and multisystemic symptoms, most often of the central nervous system and skeletal muscles, are present. In this review we discuss the clinical diagnosis and approach of patients with renal manifestations in the context of the mtDNA m.3243A>G pathogenic variant.
Topics: Adult; Humans; DNA, Mitochondrial; MELAS Syndrome; Mitochondrial Diseases; Diabetes Mellitus, Type 2; Kidney; Hearing Loss, Sensorineural; Deafness
PubMed: 38355238
DOI: 10.1016/j.nefroe.2024.01.017