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Background Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a common mitochondrial syndrome. The aim of this study was to conduct a survival analysis based on the clinical features of a Chinese MELAS patient cohort. Methods This is a retrospective single-center study. The MELAS patients were followed up for 1–8 years (median 4 years). The disease severity was evaluated by the modified Rankin Scale (mRS). The survival analysis was performed using Kaplan-Meier analysis and Cox proportional hazards model. Results A total of 138 subjects were enrolled, and the median disease duration was 7 years [interquartile range (IQR) 4–11 years]. The stroke-like episodes were the most common initial symptoms (70.3%). Seventeen (17.3%) subjects lost to follow-up. Of the 121 subjects who successfully completed the follow-up, 28 subjects died (mortality rate 23.1%). An acute stroke-like episode and/or status epilepticus were the predominant causes of death (42.9%). Among the surviving patients (n = 93), 39.8% (37/93) required assistance in daily life (mRS scores 3–5). The mRS scores were inversely correlated with the age of onset ( r = − 0.28, P = 0.0022) but not with the disease duration ( r = 0.10, P = 0.2709). The survival rate declined mainly within 12 years after the disease onset. The stroke-like episode as the initial symptom was an independent risk factor for death (hazard ratio = 2.86, 95% CI 1.03–7.94, P = 0.043). Conclusions MELAS had high mortality and morbidity in this cohort of Chinese patients. The early onset of stroke-like episodes might indicate the more severe form of the disease, highlighting the importance of management of stroke-like episodes to improve the prognosis. [ABSTRACT FROM AUTHOR]

The pathophysiology of stroke-like episode (SLE) in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) was uncertain, though mitochondrial metabolic crisis of cortical neurons and mitochondrial proliferation in small vessels of brain have been considered. However, the involvement of major cerebral vessels was debated. We aimed to investigate whether major cerebral vessels participate in SLE. We retrospectively collected the clinical and neuroimaging data of MELAS patients diagnosed in our center. Through follow-up, the cases harboring reversible cerebral artery constriction on brain magnetic resonance angiography (MRA) examination were included in this study. There were 20 patients with intact brain MRA data at acute and non-acute phases. Only 3 cases with m.3243A > G mutation were enrolled. They suffered once or twice SLEs manifesting headache, blurred vision, seizures or mental and behavior disorder. New lesions were present in temporo-parietal and/or temporo-occipital regions. Segmental stenosis at middle cerebral artery and/or posterior cerebral artery, proximal portions in particular, was ipsilateral to the lesions at acute phase in all the 3 patients, which was resolved during the subacute or chronic stages. Moreover, the SLEs lesions were located within the stenotic arteries territory. In addition, dilation at distal portions of the stenotic arteries was observed at acute phase as well in 2 patients. Reversible constriction of cerebral arteries may contribute to SLE of MELAS. MELAS should be a differential diagnosis when stenosis of major cerebral vessels is present at acute phase of SLE. • Segmental stenosis of major cerebral arteries was found at acute phase of MELAS. • SLE lesions were located within the stenotic arteries territory. • Dilation at distal portions of the stenotic arteries was also observed. • Stenosis was resolved after the acute stage of SLE. • Reversible constriction of cerebral arteries may participate in SLE of MELAS. [ABSTRACT FROM AUTHOR]

Abstract: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial syndrome characterized by seizures, migrainous headaches, lactic acidosis, vomiting, and recurrent stroke-like episodes. Patients often suffer from cognitive dysfunction of unclear pathogenesis. In this study, we explored a possible link between cognitive dysfunction and hippocampal expression of calbindin D28KD (CB), a high affinity calcium-binding protein, in four MELAS patients, using post mortem hippocampal tissues. We found significantly reduced CB levels in all patients by immunohistochemistry, Western blot, and quantitative real-time PCR. Reduction in CB expression has been associated with aging and with neurodegenerative disorders, including Alzheimer''s disease. We postulate that the reduced CB expression may play a role in the cognitive abnormalities associated with MELAS. [Copyright &y& Elsevier]

Abstract: In recent years, a considerable number of new sporadic or hereditary small artery diseases of the brain have been detected which preferably occur in younger age, below 45years. Cerebral microangiopathies constitute an appreciable portion of all strokes. In middle aged patients, hereditary cerebral small vessel diseases have to be separated from sporadic degenerative cerebral microangiopathy which is mainly due to a high vascular risk load. Features of the following disorders and details how to differentiate them, are reviewed here, namely CADASIL, MELAS, AD-RVLC, HEMID, CARASIL, PADMAL, FABRY, COL4A1-related cerebral small vessel diseases and a Portuguese type of autosomal dominant cerebral small vessel disease (SVDB). The symptomatic overlap of the cerebral microangiopathies include also other distinctive non-hereditary diseases like posterior (reversible) encephalopathy and Susac''s syndrome which are also described. Some of the microangiopathies described here are not only seen in the young but also in the elderly. The precise diagnosis has direct therapeutic implications in several of these entities. Cerebral microangiopathies cause recurring strokes and diffuse white matter lesions leading to a broad spectrum of gait disturbances and in most of these disorders cognitive impairment or even vascular dementia in the long term. Often, they also involve the eye, the inner ear or the kidney. Several typical imaging findings from illustrative cases are presented. The order in which these diseases are presented here is not dictated by an inner logic principle, because a genetically or pathophysiologically based classification system of all these entities does not exist yet. Some entities are well established and not unusual, whereas others have only been described in a few cases in total. [Copyright &y& Elsevier]

Abstract: Point mutations in the mitochondrial genome are associated with a variety of metabolic disorders. The myopathy, encephalopathy, lactic acidosis, stroke-like episodes syndrome (MELAS), is most frequently associated with an A to G transition at position 3243 of the mitochondrial tRNALeu(UUR) gene, and is characterized by biochemical and structural alterations of mitochondria. In the present study, we analyzed proteomic changes in an immortalized B-cell line harbouring the MELAS A3243G mutation by two-dimensional difference gel electrophoresis and immunoblot analysis. Although the cell line contained only 10% mutated mitochondrial genomes, we detected significant alterations in numerous proteins associated with the actin cytoskeleton and in nuclear-encoded subunits of mitochondrial respiratory chain complexes. Notably, mitochondrial Lon protease and Hsp60 were deregulated in MELAS cells, indicating an effect on the mitochondrial protein quality control system. By immunofluorescence microscopy, we detected mitochondrial Lon protease accumulation and changes in actin-binding proteins preferentially in MELAS cells containing numerous mitochondria with mutated genomes. Enzymatic assays revealed that Lon protease activity is increased in MELAS cell lysates. Although Lon protease has been shown to degrade misfolded proteins and to stabilize respiratory chain complexes within mitochondria, our MELAS cell line exhibited a higher sensitivity to mitochondrial stress. These findings provide novel insights into the cellular response to dysfunctional mitochondria containing mutated genomes. [Copyright &y& Elsevier]

Abstract: m.3243A>G mutation in mitochondrial DNA is the most common pathogenic point mutation, causing a variety of phenotypes. To further elucidate its clinical characteristics, we recruited 47 Chinese families carrying m.3243A>G mutation and analyzed their symptoms, disease history, inheritance, and mitochondria-related complications. In the probands, lactic acidosis, myopathy, seizures, short stature, weight loss and hirsutism were the most common clinical features. In their mothers, lactic acidosis, exercise intolerance, short stature and weight loss were the frequent manifestations, and normal phenotype was found in 59.6% mothers. m.3243A>G mutation was detected in 47 probands and 42 mothers. In the probands, the mutation ratio in blood was threefold higher and the ratio in urine was twofold higher than those of their mothers. m.3243A>G mutation ratio in mothers'' urine and in their probands'' blood were weakly correlated. In conclusion, (a) stroke-like episode induced by m.3243A>G mutation may be the symptom predominantly found in older patients; (b) m.3243A>G mutation ratio correlates with the severity of the disease; (c) m.3243A>G mutation ratio in mothers'' urine may correlate to the ratio in blood in their offspring. [Copyright &y& Elsevier]

Abstract: Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is the most common mitochondrial disease due to mitochondrial DNA (mtDNA) mutations. At least 15 distinct mtDNA mutations have been associated with MELAS, and about 80% of the cases are caused by the A3243G tRNALeu(UUR) gene mutation. We report here a novel tRNAVal mutation in a 37-year-old woman with manifestations of MELAS, and compare her clinicopathological phenotype with other rare cases associated tRNAVal mutations. [Copyright &y& Elsevier]

Abstract: Background: Ischemic vascular hypothesis as a causative role in the pathogenesis of stroke-like episodes in MELAS remains to be debated. Methods: This study consisted of two parts. Part 1 is a clinicoradiological study during acute stage of 18 consecutive stroke-like episodes in six patients with MELAS. Part 2 is a SPECT study to assess the regional cerebrovascular reactivity (rCVR) to acetazolamide during chronic stage in five patients with MELAS. Results: Headache and epileptic seizure were the most common presenting symptoms. Unique features of acute stroke-like lesions included progressive spread of cortical lesions with vasogenic edema, focal periodic epileptiform discharges, focal hyperperfusion, and cortical laminar necrosis during subacute stage. During chronic stage, SPECT showed hypoperfusion in non-affected occipital cortex in three patients as well as in previously affected regions in four. The rCVR was preserved in three patients, focally impaired in one, and extensively impaired in one, but relatively preserved in the occipital cortex in all patients. Conclusions: Stroke-like episodes could be non-ischemic neurovascular events initiated by neuronal hyperexcitability. Once neuronal hyperexcitability develops in a focal brain region, epileptic activities depolarize adjacent neurons, leading to a propagation of epileptic activities into the surrounding cortex, and resulting in energy imbalance. The mechanisms for neuronal hyperexcitability remain to be elucidated. [Copyright &y& Elsevier]

Abstract: We describe a 13-year-old boy with mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) who experienced a stroke-like episode resulting in severe mental regression and quadriplegia. We tested 14-3-3 protein in the cerebrospinal fluid (CSF) of the patient four times around a stroke-like episode in a magnetic resonance imaging (MRI) study. Detection of the protein in the CSF was well correlated with the clinical course and range of damage of the brain lesion on MRI. Interestingly, 14-3-3 CSF protein was detected at the beginning of mitochondrial encephalopathy without new MRI abnormalities, suggesting that it is a sensitive brain marker. We conclude that 14-3-3 CSF protein is a useful biological marker of brain disruption in MELAS as well as other neurological disorders. [Copyright &y& Elsevier]

Abstract: Localized magnetic resonance spectroscopy (MRS) yields sensitive metabolic markers to provide insight into the pathophysiology of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) in vivo. Findings in full MELAS syndrome at 1H MRS of the brain typically include severely elevated lactate and reduced N-acetylaspartate, glutamate, myo-inositol, and total creatine concentrations in stroke-like lesions. Similar but less extreme alterations are also common in gray matter (GM) regions that appear normal at magnetic resonance imaging. Phosphorus spectroscopy of peripheral muscle permits investigation of the bioenergetic status. A decline of the phosphorylation potential indicates a low energy reserve at rest. Phosphocreatine resynthesis during post-exercise recovery is delayed pointing to reduced mitochondrial capacity. As MRS is inherently non-invasive, follow-up studies can be performed to assess treatment response quantitatively. [Copyright &y& Elsevier]

We report two patients with migraine, acute visual field defects and other neurological symptoms who were found to have high T2 signal and FLAIR abnormalities on brain MRI in temporal and parieto-occipital regions. In these patients, the apparent diffusion coefficient (ADC) of their lesions was increased, distinguishing these lesions from those of ischemic stroke. Both were ultimately diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). We conclude that conventional MRI when used with diffusion-weighted MR imaging may be invaluable in detecting mitochondrial-related CNS dysfunction. [Copyright &y& Elsevier]

Objectives: One of the most frequent cerebral lesions in mitochondrial disorders(MIDs) on imaging is the stroke-like lesion(SLL) clinically manifesting as stroke-like episode (SLE, metabolic stroke). This review aims at discussing recent advances concerning the presentation, diagnosis, and treatment of SLLs., Methods: Systematic literature review using appropriate search terms., Results: SLLs are the hallmark of MELAS but occasionally occur in other MIDs. SLLs are best identified on multimodal, cerebral MRI. SLLs may present as uni-/multilocular, symmetric/asymmetric, cortical/subcortical, supra-/infratentorial condition, initially resembling a cytotoxic edema and later a vasogenic edema, or a variable mix between them. SLLs run through an acute and a chronic stage. The acute stage is characterised by a progressively expanding lesion over days, weeks, or months, showing up as increasing hyperintensity on T2/FLAIR, DWI, and PWI and by hyperperfusion, that does not conform to a vascular territory. ADC maps are initially hypointens to become hyperintens during the course. More rarely, a variable mixture of hyper- and hypointensities may be found. The chronic stage is characterised by hypoperfusion, gadolinium enhancement, and regression of hyperintensities to various endpoints. SLLs originate from an initial cortical lesion due to focal metabolic breakdown, which either remains stable or expands within the cortex or to subcortical areas. Some SLLs show spontaneous reversibility (fleeing cortical lesions) suggesting that neuronal/glial damage does not reach the threshold of irreversible cell death., Conclusions: SLLs are a unique feature of various MIDs in particular MELAS. SLLs are dynamic and change their appearance over time. SLLs are accessible to treatment., (Copyright © 2020 Elsevier B.V. All rights reserved.)

• MELAS is a mitochondrial cytopathy caused by mtDNA point mutations with variable clinical features. • Here we report a case of MELAS who carries a novel mtDNA mutation (m.13376T>C, p.I347T) with progressive right medial temporal lobe atrophy. • The present case suggests the unique pathological mechanism of mtDNA mutations in MELAS. [ABSTRACT FROM AUTHOR]

Muscle pathology usually contributes to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode (MELAS), even in patients without prominent muscle symptoms. We report a series of patients with MELAS without significant myopathic changes. Twelve patients without ragged-red fibers (RRFs) on muscle pathology (RRF-negative group) and 99 patients with MELAS and RRFs and/or cytochrome c oxidase (COX)-deficient fibers (control RRF-positive group) were recruited. We analyzed clinical features, neuroimaging and pathological findings, gene mutation data, immunofluorescence assay of key respiratory chain subunits of complexes I and IV and mitochondrial DNA (mtDNA) mutation load in biopsied muscle samples. None of the RRF-negative patients had RRF or COX-negative fibers, but four patients had strongly succinate dehydrogenase-stained vessels (SSVs). There was a lower proportion of m.3243A>G and higher proportion of mitochondria-encoded ND gene mutations in RRF-negative than RRF-positive patients. The proportion of aphasia was relatively higher, while complex I and IV subunit abundance in muscle and mutation load were lower in RRF-negative than in RRF-positive patients. RRF-negative patients had a similar disease course, clinical symptoms, and neuroimaging results to RRF-positive patients with MELAS. SSV is a valuable diagnostic indicator for MELAS. For highly suspected MELAS yet without positive myopathological findings, combined immunofluorescence and genetic studies should be used to achieve final diagnosis. • RRF-negative patients with MELAS showed a higher rate of aphasia compared with the RRF-positive group; • Mutations in the MT-ND genes could be hotspot targets for RRF-negative patients with MELAS; • Immunofluorescence and genetic analysis are powerful tools for the diagnosis of MELAS with negative myopathology. [ABSTRACT FROM AUTHOR]