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Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a rare mitochondrial genetic disorder primarily caused by the m.3243A>G mutation in the MT-TL1 gene. It is marked by defects in mitochondrial translation, nitric oxide deficiency, and reduced energy production, resulting in multiorgan dysfunction. Standard clinical features include recurrent stroke-like episodes, hearing loss, seizures, and various neurological impairments. The primary goals of treatment are to manage disease complications and enhance the patient's quality of life. A 56-year-old man with a history of bilateral hearing loss since his 20s and mild hypertension presented with left visual field defects. MRI revealed a right occipital infarct, prompting initiation of dual antiplatelet therapy, later switched to anticoagulation due to a heterozygous prothrombin gene mutation. Over the subsequent two months, he experienced a recurrent, stepwise neurological decline, including worsening left-sided weakness, subjective cognitive impairment, and functional deterioration. Repeat brain MRIs demonstrated progressive cortical hyperintensities on DWI and FLAIR sequences in the right posterior brain regions. Further evaluation revealed persistently elevated serum and CSF lactate, elevated pyruvate, and increased serum alanine. Based on the clinical progression and biochemical abnormalities, MELAS was suspected, with genetic testing pending confirmation. Mitochondrial-targeted supplements, including riboflavin, CoQ10, and B vitamins, were initiated, and atorvastatin was discontinued due to potential mitochondrial toxicity. Hematology consultation recommended stopping anticoagulation therapy. The patient exhibited a progressive neurological decline with recurrent stroke-like episodes over two months despite appropriate anticoagulation and antiplatelet therapy and cognitive decline. MRI showed a right occipital infarct, and lab results revealed increased serum and CSF lactate and pyruvate levels. Given the biochemical abnormalities and radiological findings, MELAS syndrome was suspected, and appropriate management was initiated. This case highlights the importance of considering mitochondrial disorders in patients with recurrent strokes, mainly when imaging and clinical progression are atypical for a vascular etiology. Timely recognition and metabolic testing are essential for effective management. This report emphasizes the significance of early intervention in improving outcomes for patients with MELAS.

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a disease that should be considered as a differential diagnosis to acute ischemic stroke taking into account its onset pattern and neurological symptoms, which are similar to those of an ischemic stroke. Technological advancements in neuroimaging modalities have greatly facilitated differential diagnosis between stroke and MELAS on diagnostic imaging. Stroke-like episodes in MELAS have the following features: (1) symptoms are neurolocalized according to lesion site; (2) epileptic seizures are often present; (3) lesion distribution is inconsistent with vascular territory; (4) lesions are common in the posterior brain regions; (5) lesions continuously develop in adjacent sites over several weeks or months; (6) neurological symptoms and stroke-like lesions tend to be reversible, as presented on magnetic resonance imaging; (7) the rate of recurrence is high; and; (8) brain dysfunction and atrophy are slowly progressive. The m.3243ANG mutation in the MT-TL1 gene encoding the mitochondrial tRNALeu(UUR) is most commonly associated with MELAS. Although the precise pathophysiology is still unclear, one possible hypothesis for these episodes is a neuronal hyperexcitability theory, including neuron–astrocyte uncoupling. Supplementation, such as with L-arginine or taurine, has been proposed as preventive treatments for stroke-like episodes. As this disease is still untreatable and devastating, numerous drugs are being tested, and new gene therapies hold great promise for the future. This article contributes to the understanding of MELAS and its implications for clinical practice, by deepening their insight into the latest pathophysiological hypotheses and therapeutic developments.

Objective The aim was to summarise the clinical characteristics of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), evaluate patient survival status, and identify prognostic factors. Methods This retrospective study enrolled 150 children with MELAS from 07/2004 to 07/2023. The patients were followed up for a median of 3.37 years (IQR: 2.07–6.16 years). Disease burden was assessed using the Newcastle Pediatric Mitochondrial Disease Scale (NPMDS), and Spearman’s correlation coefficient was used to analyse factors affecting disease severity. The Kaplan–Meier and Cox proportional methods were used for survival analysis. Results Overall, 150 patients (73 male) were enrolled, of whom 118 were followed up and 22 died. The mean age at onset was 8.2 years (0.4–15.3), and stroke-like episodes were the most common initial symptoms (54%). Among the surviving patients, 78 completed the NPMDS (mean score: 23.6 ± 6.7 points), and 71.8% (56/78) had moderate-to-severe disease (NPMDS score ≥ 15 points). The NPMDS score was positively correlated with disease duration (r = 0.41, P  < 0.001) and negatively correlated with age at onset (r =  −0.26, P  < 0.01). Among 48 patients who received long-term oral L-arginine and anti-seizure medications (ASMs), 56.3% (27/48) experienced reductions in seizures and stroke-like episodes. The 10- and 15-year survival rates were 65.3% and 34.5%, respectively. Muscle weakness was an independent risk factor for death (HR = 4.83, 95% CI 1.32–17.68; P  = 0.017). Conclusions This study had the largest cohort and longest follow-up of pediatric MELAS. Early onset was associated with severe disease, while muscle weakness was associated with a worse prognosis. Early identification and effective management of stroke-like episodes and seizures are crucial to reduce the disease burden.

Backround Cardiac involvement has been reported in different mitochondrial geno- and phenotypes, including mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like (MELAS) syndrome. However, cardiac manifestations are diverse and not well described. Methods We prospectively examined cardiac manifestations in 11 adult patients with MELAS syndrome harboring the MTTL1 m.3243A < G-mutation using patient records, cardiac MRI (1.5 Tesla), echocardiography, electrocardiogram (ECG), laboratory tests of cardiac markers (CK, CK-MB, Trop I, BNP), and clinical severity (NMDAS = Newcastle Mitochondrial Disease Scale). Results Among 11 consecutive patients with MELAS syndrome (73% male, mean age 37.5 ± 10.6 years) cardiac manifestations were found in nine (82%). Pathology was mainly detected using MRI (9 of 11, 82%). Six patients showed diffuse late enhancement in the left ventricle, one a left ventricular ejection fraction (LVEF) below 30%, two with a LVEF in the range of 40–50% in the cardiac MRI, and another five patients presenting diastolic dysfunction as defined by echocardiography. Only one patient with late enhancement on MRI also showed a conduction block in the ECG. There was no correlation between the cardiac manifestations and the NMDAS score or heteroplasmy grade. Conclusions Cardiac involvement in MELAS syndrome harboring the MTTL1 m.3243A > G mutation mostly entails cardiomyopathy, which was particularly evident in the cardiac MRI. Only one patient (1/11, 9.1%) had conduction defects. Thus, cardiac testing including cardiac MRI, echocardiography and ECG seems to be important for prognosis of MELAS patients.

ObjectiveTo examine the efficacy and safety of the therapeutic regimen using oral and intravenous l-arginine for pediatric and adult patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS).MethodsIn the presence and absence of an ictus of stroke-like episodes within 6 h prior to efficacy assessment, we correspondingly conducted the systematic administration of oral and intravenous l-arginine to 15 and 10 patients with MELAS in two, 2-year, prospective, multicenter clinical trials at 10 medical institutions in Japan. Subsequently, patients were followed up for 7 years. The primary endpoint in the clinical trial of oral l-arginine was the MELAS scale, while that for intravenous l-arginine was the improvement rates of headache and nausea/vomiting at 2 h after completion of the initial intravenous administration. The relationships between the ictuses of stroke-like episodes and plasma arginine concentrations were examined.ResultsOral l-arginine extended the interictal phase (p = 0.0625) and decreased the incidence and severity of ictuses. Intravenous l-arginine improved the rates of four major symptoms—headache, nausea/vomiting, impaired consciousness, and visual disturbance. The maximal plasma arginine concentration was 167 μmol/L when an ictus developed. Neither death nor bedriddenness occurred during the 2-year clinical trials, and the latter did not develop during the 7-year follow-up despite the progressively neurodegenerative and eventually life-threatening nature of MELAS. No treatment-related adverse events occurred, and the formulations of l-arginine were well tolerated.ConclusionsThe systematic administration of oral and intravenous l-arginine may be therapeutically beneficial and clinically useful for patients with MELAS.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most common mitochondrial disorders, typically presenting with symptoms before the age of 40. Epileptic seizures are a common manifestation, with both focal and generalized seizures being observed. EEG findings can be variable, with the most common patterns being slow background activity followed by epileptiform discharges.Here, we present monozygotic twin sisters with late-onset MELAS and specific EEG features, including lateralized periodic discharges and sensitivity to photic stimulation, which have been rarely reported in the literature. These cases emphasize the importance of considering MELAS in the differential diagnosis of late-onset symptoms. Furthermore, EEG findings such as sensitivity to photic stimulation may contribute to understanding MELAS pathophysiology, even during asymptomatic periods. •Adult onset MELAS is rare syndrome.•Lateralized periodic discharges and photic sensitivity may associated with MELAS rarely.•Adult onset MELAS can be challenging to diagnose due to frequent misdiagnosis as recurrent stroke or autoimmune encephalitis.

Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is the commonest inherited mitochondrial disorder. Dilation of the major cerebral arteries is seldom mentioned in MELAS because magnetic resonance angiography (MRA) usually shows normal findings. Here, we described a 24-year-old male patient with MELAS who had migratory vasodilatation of cerebral arteries on MRA and positive antibodies against contactin-associated protein-like-2 in serum during stroke-like episodes (SLEs). Moreover, a total of 18 MELAS cases were included in this literature review. MELAS with cerebrovascular dilatation was mainly seen in young adults and the commonest clinical manifestations were visual symptoms, headache, and seizures. Vasodilatation predominantly occurred in the acute phase of SLEs. Dilation of the major cerebral artery mainly happened in the posterior cerebral artery and the middle cerebral artery. The region of increased cerebral blood flow (CBF) always corresponded to the range of vascular supply of the dilated cerebral artery. Multimodal neuroimaging evaluation is very important for the diagnosis of mitochondrial diseases. Migratory vasodilation of cerebral arteries may be a specific imaging sign of MELAS. Dilation of cerebral artery together with increased CBF not only indicates the clinical onset, but also implies an upcoming stroke-like attack.

ObjectivesTo investigate a diversity of stroke-like episodes (SLEs) in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and report a disseminated form of SLEs (D-SLEs) attributed to a cluster of disseminated small cortical lesions.MethodsWe retrospectively reviewed the clinical information of 27 MELAS patients seen at Kitasato University Hospital between January 1990 and April 2018. Among those, we selected 13 patients with m.3243A>G mutation [median age at onset, 35 years (11–68 years), two pediatric onset < 17 years] who had at least one SLE. SLEs were classified into classic or non-classic based on characteristic features of stroke-like lesions.Results44 SLEs were identified during a median observational period of 119 months (3–240 months). Among those, 29 (65.9%) were classic SLEs (C-SLEs) mainly attributed to a single continuous lobular lesion incongruent to vascular territory and occasionally accompanied by a gradual spread associated with hyperperfusion and persistent seizure activity. The remaining 15 were non-classic attributed to sparsely distributed (n = 10), disseminated (n = 4) or cerebellar lesions (n = 1). C-SLEs developed in all patients but non-classic SLEs in 5; D-SLEs developed in 4 patients accounting for 4 of 44 SLEs (9.1%). Non-classic SLEs developed more frequently in pediatric-onset than in adult-onset patients (12/15 vs. 3/29, p < 0.0001). SLEs began with acute onset of symptoms in 42 SLEs (95.5%), but D-SLEs of 2 adult-onset patients began with ill-defined subacute-onset fluctuating encephalopathy.ConclusionsThis study showed a diversity of SLEs in patients with m.3243A>G mutation. Further studies are required to elucidate the pathophysiological mechanisms of non-classic SLEs including D-SLEs.

BackgroundMitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders. Mutations in mitochon drial DNA (mtDNA) and nuclear genome or both have been reported in mitochondrial diseases suggesting common pathophysiological pathways. Considering the clinical heterogeneity of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) phenotype including focal neurological deficits, it is important to look beyond mitochondrial gene mutation.MethodsThe clinical, histopathological, biochemical analysis for OXPHOS enzyme activity, and electron microscopic, and neuroimaging analysis was performed to diagnose 11 patients with MELAS syndrome with a multisystem presentation. In addition, whole exome sequencing (WES) and whole mitochondrial genome sequencing were performed to identify nuclear and mitochondrial mutations.ResultsAnalysis of whole mtDNA sequence identified classical pathogenic mutation m.3243A > G in seven out of 11 patients. Exome sequencing identified pathogenic mutation in several nuclear genes associated with mitochondrial encephalopathy, sensorineural hearing loss, diabetes, epilepsy, seizure and cardiomyopathy (POLG, DGUOK, SUCLG2, TRNT1, LOXHD1, KCNQ1, KCNQ2, NEUROD1, MYH7) that may contribute to classical mitochondrial disease phenotype alone or in combination with m.3243A > G mutation.ConclusionIndividuals with MELAS exhibit clinical phenotypes with varying degree of severity affecting multiple systems including auditory, visual, cardiovascular, endocrine, and nervous system. This is the first report to show that nuclear genetic factors influence the clinical outcomes/manifestations of MELAS subjects alone or in combination with m.3243A > G mutation.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a complex mitochondrial disorder characterized by a wide range of systemic manifestations. Key clinical features include recurrent stroke-like episodes, seizures, lactic acidosis, muscle weakness, exercise intolerance, sensorineural hearing loss, diabetes, and progressive neurological decline. MELAS is most commonly associated with mutations in mitochondrial DNA, particularly the m.3243A>G mutation in the MT-TL1 gene, which encodes tRNALeu (CUR). These mutations impair mitochondrial protein synthesis, leading to defective oxidative phosphorylation and energy failure at the cellular level. The clinical presentation and severity vary widely among patients, but the syndrome often results in significant morbidity and reduced life expectancy because of progressive neurological deterioration. Current management is largely focused on conservative care, including anti-seizure medications, arginine or citrulline supplementation, high-dose taurine, and dietary therapies. However, these therapies do not address the underlying genetic mutations, leaving many patients with substantial disease burden. Emerging experimental treatments, such as gene therapy and mitochondrial replacement techniques, aim to correct the underlying genetic defects and offer potential curative strategies. Further research is essential to understand the pathophysiology of MELAS, optimize current therapies, and develop novel treatments that may significantly improve patient outcomes and extend survival.