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MRA showed stenosis of right ICA. ICA = internal carotid artery, MRA = Magnetic Resonance Angiography.
Source publication
Rationale:
Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) are thought to be rarely accompanied by macroangiopathy. We reported a case of MELAS that presented right distal internal carotid arterial (ICA) stenosis and reviewed 12 similar previously reported cases involving intracranial large blood vessels.
Patient co...
Context in source publication
Context 1
... MRI (3.0 Tesla) at admission revealed a hyperintense lesion in the left occipital lobe in DWI and T2, and right occipital lobe atrophy (Fig. 2). MR angiography (MRA) revealed segmental stenosis at the C7 and M1 junctions, and sparse cortex blood vessels (Fig. 3). The same lesion was persistent and confirmed by digital subtraction angiography (DSA) (Fig. 4) after 20 days. It was a pity that he only received plain CT scanning 3 years ago, without CT angiography (CTA) or ...
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Introduction:
Microhemorrhages have not been described in mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome (MELAS) on magnetic resonance imaging (MRI). Main symptoms and/or important findings: A MELAS-patient had a rapid succession of 3 stroke-like episodes with dysphasia, visual field deficits and paresis of...
Objective
Mitochondrial myopathy without extraocular muscles involvement (MiMy) represents a distinct form of mitochondrial disorder predominantly affecting proximal/distal or axial muscles, with its phenotypic, genotypic features, and long-term prognosis poorly understood.
Methods
A cross-sectional study conducted at a national diagnostic center...
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like symptoms (MELAS) is a rare mitochondrial disorder that typically presents before the age of 40 with most patients diagnosed before the age of 20. Symptoms and signs typically include mitochondrial myopathy, encephalopathy with stroke-like episodes, seizures and/or dementia, and la...
Background
β-Ureidopropionase deficiency is a rare autosomal recessive disease affecting the last step of pyrimidine degradation. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a rare inherited disorder caused by genetic defects in mitochondrial DNA.
Case Presentation
One 8-year-old boy presented...
Mitochondrial encephalomyopathy, lactic acidosis, and recurrent stroke-like episodes syndrome (MELAS) is a rare degenerative disease. Recent studies have shown that resistant training (RT) can ameliorate muscular force in mitochondrial diseases. However, the effects of RT in MELAS are unknown. The aim of this case report was to investigate the effe...
Citations
... MRA has not been routinely performed in MELAS in the past, because major cerebral vessels were considered to be the target of mitochondrial metabolism defects in these patients. However, more and more studies have found major cerebral vessels dilation (39,44,45) or stenosis (46,47) on MRA in MELAS in the acute and chronic stages of the disease. Gramegna et al. (48) found that the proportion of cerebral major vessels dilation and stenosis was 40 and 19%, respectively, on MRA, and the middle cerebral artery was the most commonly involved. ...
Mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS) is an important cause of stroke-mimicking diseases that predominantly affect patients before 40 years of age. MELAS results from gene mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) responsible for the wide spectrum of clinical symptoms and imaging findings. Neurological manifestations can present with stroke-like episodes (the cardinal features of MELAS), epilepsy, cognitive and mental disorders, or recurrent headaches. Magnetic resonance imaging (MRI) is an important tool for detecting stroke-like lesions, accurate recognition of imaging findings is important in guiding clinical decision making in MELAS patients. With the development of neuroimaging technologies, MRI plays an increasingly important role in course monitoring and efficacy assessment of the disease. In this article, we provide an overview of the neuroimaging features and the application of novel MRI techniques in MELAS syndrome.
... Involvement of the arteries (Finsterer and Zarrouk-Mahjoub, 2016) may lead to arterial hypertension or ischemia due to dissection and consequent occlusion of an artery, or to aneurysm formation and consequent spontaneous rupture and bleeding (Kalashnikova et al., 2010;Sun et al., 2018). Rupture of intracerebral aneurysms may lead to subarachnoid bleeding. ...
Mitochondrial disorders (MIDs) are a heterogeneous group of genetic metabolic diseases due to mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA (nDNA) (Rahman and Rahman, 2018). Some affected genes encode proteins with various functions, or structural RNAs such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs). MIDs may also be caused by mutations in non-coding regions (e.g., D-loop of mtDNA) (Rahman and Rahman, 2018). Proteins involved in MIDs include enzymes, assembling factors, transport proteins, signaling proteins, pore proteins, and fusion/fission proteins (Gorman et al., 2016). The pathways most frequently affected by mutations in "mitochondrial genes" are the respiratory chain and the oxidative phosphorylation. Dysfunction of many other pathways (e.g., β-oxidation, pyruvate-dehydrogenase complex, and heme synthesis) may also manifest as MIDs (Hu et al., 2019). The estimated prevalence of MIDs is at least 1:5000 (Ng and Turnbull, 2016).
... Several patients with an MID have been reported in whom ASCL was one among other clinical manifestations. In a 38-year-old male with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome due to the variant m.3243A>G in tRNA(Leu), magnetic resonance angiography (MRA) and digital subtraction angiography revealed a distal stenosis of the right internal carotid artery (ICA) and sparse cortical vessels in the absence of any classical risk factor [2]. Additionally, this patient had migraine since age 18 years, hearing impairment, and recurrent stroke-like episodes (SLEs) [2]. ...
... Several patients with an MID have been reported in whom ASCL was one among other clinical manifestations. In a 38-year-old male with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome due to the variant m.3243A>G in tRNA(Leu), magnetic resonance angiography (MRA) and digital subtraction angiography revealed a distal stenosis of the right internal carotid artery (ICA) and sparse cortical vessels in the absence of any classical risk factor [2]. Additionally, this patient had migraine since age 18 years, hearing impairment, and recurrent stroke-like episodes (SLEs) [2]. The patient was initially put on aspirin and statins but did not improve. ...
... The patient was initially put on aspirin and statins but did not improve. On the contrary, he profited from coenzyme-Q (CoQ), L-arginine, vitamin-C, and valproic acid [2]. In another case report, a 58-year-old female with a sixyear history of cognitive decline was diagnosed with early-onset, subcortical, ischemic, vascular dementia in the absence of any classical risk factors for ASCL [3]. ...
One of the systems that are potentially affected in mitochondrial disorders, but hardly get systematically investigated, are the arteries. One of the phenotypic manifestations in arteries is atherosclerosis. This review focuses on the current knowledge and recent advances of mitochondrial atherosclerosis. We conducted a systematic literature review via PubMed using appropriate search terms.
Atherosclerosis in mitochondrial disorders may result from a primary pathomechanism or a secondary one due to mitochondrial diabetes, arterial hypertension, or hyperlipidemia. Anecdotal reports show that primary atherosclerosis can be a phenotypic feature of mitochondrial disorders. Predominantly, patients carrying mutations in mtDNA-located genes may develop primary mitochondrial atherosclerosis. Though not systematically investigated, it is conceivable that primary mitochondrial atherosclerosis results from increased oxidative stress, mitophagy, metabolic breakdown, or lactic acidosis. Mitochondrial disorder patients with primary mitochondrial atherosclerosis should receive not only antithrombotic medication but also antioxidants and cofactors.
Atherosclerosis in mitochondrial disorders may occur even in the absence of classical atherosclerosis risk factors, suggesting that atherosclerosis can be a primary manifestation of the metabolic defect. Though primary atherosclerosis in mitochondrial disorders has not been systematically investigated, anecdotal data indicate that mitochondrial dysfunction can be a mechanism for the development of primary, mitochondrial atherosclerosis. These patients require antioxidants and cofactors in addition to antithrombotic medication.
... Significant therapeutic benefit of L-arginine therapy was observed in these patients as well, which suggests that treatment with L-arginine is also favorable in patients with various genetic causes. Other clinical studies of L-arginine supplement therapy for MELAS have been done in different countries [15][16][17][18][19][20][21], and showed the improvement of the severity of the disease progression in MELAS. Additionally, several case studies showing the therapeutic efficacy of L-arginine on SLE have been reported. ...
Purpose of review:
We would like to inform clinicians that the systematic administration of oral and intravenous L-arginine is therapeutically beneficial and clinically useful for patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), when they maintain plasma arginine concentration at least 168 μmol/l.
Recent findings:
MELAS is associated with endothelial dysfunction by decreased plasma L-arginine, nitric oxide (NO), and cyclic guanosine monophosphate. Endothelial dysfunction is also evident using flow-mediated vasodilation measurement by high-resolution Doppler echocardiography in the forearm artery in patients with MELAS. L-arginine is known to be an important precursor of NO to normalize the endothelial function in MELAS. In our clinical trial followed by 7 years follow-up study, the systematic administration of L-arginine to patients with MELAS significantly improved the survival curve of patients compared with natural history. Maintaining plasma arginine concentration at least 168 μmol/l may prevent the ictuses through the putative pathophysiologic mechanism and optimal normalization of endothelial dysfunction.
Summary:
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. Therapeutic regimen of L-arginine on MELAS may be beneficial and clinically useful for patient care with MELAS.
Nearly 40 years have passed since the initial description of MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). The factors that mediate the pathogenesis and mechanism of MELAS syndrome remain elusive, as have effective therapies. In this review, we discuss the current basis of understanding and theories relating to the common phenotypic features of MELAS, in particular the pathognomonic “stroke-like episodes,” as well as implications towards future therapeutic developments.
Rationale:
Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is the most common subtype of mitochondrial encephalopathy. In the past, it was believed that most hereditary white matter lesions were lysosome storage disorders or peroxisome diseases. However, in recent years, white matter lesions have been increasingly regarded as a common feature of patients with mitochondrial diseases. In addition to stroke-like lesions, about half of the patients with MELAS reported white matter lesions in the brain.
Patient concerns:
Herein, we provide a case of A 48-year-old female who presented with episodic loss of consciousness with twitching of extremities. Previous medical history revealed 10 years of history of epilepsy, 10 years of history of diabetes, a history of hearing loss, and unknown etiology. Ancillary findings included brain magnetic fluid-attenuated inversion recovery showed symmetrical lesions in the bilateral parietal lobe with high signal intensity at the edge, and high signal intensity in the bilateral occipital lobe, paraventricular white matter, corona radiata, and the center of semiovale.
Diagnoses:
Mitochondrial deoxyribonucleic acid gene sequencing returned A3243G point mutation and it supports the diagnosis of intracranial hypertension.
Interventions:
Considered the diagnosis of symptomatic epilepsy, the patient was treated with mechanical ventilation, midazolam, and levetiracetam, and the limb twitching symptoms were controlled. The patient was comatose, chronically bedridden, with gastrointestinal dysfunction, and was treated prophylactically with antibiotics against infection, parenteral nutrition, and other supportive measures. B vitamins, vitamin C, vitamin E, coenzyme Q10, and idebenone were given, and mechanical ventilation and midazolam were stopped after 8 days. He was discharged from the hospital on 30 days and continued symptomatic treatment with B-vitamins, vitamin C, vitamin E, coenzyme Q10, and idebenone, and antiepileptic treatment with levetiracetam, with outpatient follow-up.
Outcomes:
No further seizures were recorded and the patient recovered well.
Lessons:
MELAS syndrome without stroke-like episodes of diffuse posterior cerebral white matter lesions is rare in clinical practice, and the possibility of MELAS syndrome should be considered in symmetric posterior cerebral white matter lesions.
Background: Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a rare multisystem mitochondrial cytopathy that is highly heterogeneous in severity and clinical presentation mostly caused by diverse mutations in the mitochondrial DNA. Clinical spectrum of MELAS is broadening as atypical presentations and more knowledge are gathering from this syndrome. There is no specific known treatment for the progressive disease however metabolic cocktail have been used to improve ATP production.
Case presentation: This report documents the case of a 37 year old Iranian woman diagnosed with MELAS. Her clinical manifestations include recurrent episodes of stroke-like events, focal seizures and elevated serum and CSF lactate. Mitochondrial DNA analysis (mtDNA) was positive for a very rare pathogen point mutation (mtDNA; m.3243A>G) in the MT-ND5 gene with a heteroplasmy level of 8.2%.
Conclusion: The clinical spectrum of MELAS is broadening as its atypical presentations make a diagnostic challenge that may lead to decades of delay in diagnosis. The number of molecular causes of MELAS and Leigh syndrome (LS) has increased steadily.
Objective
Stroke management in the context of primary mitochondrial disease is clinically challenging and the best treatment options for patients with stroke-like episodes remain uncertain. We sought to perform a systematic review on the safety and efficacy of L-arginine use in the acute and prophylactic management of stroke-like episodes in patients with mitochondrial disease.
Methods
The systematic review was registered in PROSPERO (CRD42020181230). We searched six databases from inception − 15/01/2021: MEDLINE, Embase, Scopus, Web of Science, CINAHL and ClinicalTrials.gov . Original articles and registered trials available, in English, reporting L-arginine use in the acute or prophylactic management of stroke-like episodes in patients with genetically confirmed mitochondrial disease were eligible for inclusion.
Data on safety and treatment response were extracted and summarized by multiple observers. Risk of bias was assessed by the methodological quality of case reports, case series and a risk-of-bias checklist for non-randomized studies. Quality of evidence was synthesized using the Oxford Centre for Evidence-Based Medicine Levels of Evidence and Grade of Recommendations. The predetermined main outcome measures were clinical response to L-arginine treatment, adverse events, withdrawals, and deaths (on treatment and/or during follow up), as defined by the author.
Results
Thirty-seven articles met inclusion [0=randomised controlled trials (RCTs); 3 open-label; 1 retrospective cohort; 33 case reports/case series] (N = 91 patients; 86% m.3243A>G). In the case reports, 54% of patients reported a positive clinical response to acute L-arginine, of which 40% were concomitantly treated with AEDs. Improved headache at 24-hours was the greatest reported benefit in response to IV L-arginine in the open-label trials (31/39, 79%). Of 15/48 patients (31%) who positively responded to prophylactic L-arginine, AEDs were either used (7/15) or unreported (8/15). Moderate adverse events were reported in the follow-up of both IV and oral L-arginine treatment and 11 patients (12%) died during follow up or while on prophylactic treatment.
Conclusion
The available evidence is of poor methodological quality and classified as Level 5. IV and/or oral L-arginine confers no demonstrable clinical benefit in either the acute or prophylactic treatment of MELAS, with more robust controlled trials required to assess its efficacy and safety profile.
A 45-year-old woman was admitted to our hospital because of speech difficulties. Initial magnetic resonance imaging (MRI) suggested subacute ischemic infarction in the left parietal to temporal area. Neurological examination on admission showed motor aphasia without any other deficits, and her symptoms gradually worsened with severe headaches. Nine days after admission, brain MRI revealed the development of an ischemic lesion, and magnetic resonance angiography (MRA) showed left internal carotid artery dissection. Emergency carotid stent placement was then performed on the stenotic lesion, which improved her severe headache. Based on her symptoms, she was diagnosed with Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) after revascularization therapy. This is the first case in which acute endovascular revascularization was performed for internal carotid artery dissection in MELAS.
Numerous factors make the initial diagnostic evaluation of children with suspected arterial ischemic stroke (AIS) a relatively unsettling challenge, even for the experienced stroke specialist. The low frequency of pediatric AIS, diversity of unique age-oriented stroke phenotypes, and unconventional approaches required for diagnosis and treatment all contribute difficulty to the process. This review aims to outline important features that differentiate pediatric AIS from adult AIS and provide practical strategies that will assist the stroke specialist with diagnostic decision making in the initial phase of care.
