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Imaging findings in MELAS differential diagnoses. Exemplary FLAIR, DWI and ADC images of diseases that can mimic MELAS lesions on MRI including herpes simplex encephalitis, posterior reversible encephalopathy syndrome (PRES), subacute territorial ischemic stroke and recanalized territorial ischemic stroke are displayed. Herpes simplex encephalitis may mimic many MELAS MRI findings including cortical restricted diffusion (arrow), subcortical vasogenic oedema and local mass effect on FLAIR images. Nevertheless, herpes simplex encephalitis lesions usually affect mesiotemporal areas and spread continuously. PRES lesions are typically located in the occipital and temporal lobes showing subcortical vasogenic oedema (circle). Subacute ischemic stroke is hyperintense on FLAIR and diffusion is restricted, but the lesion is confined within a vascular territory. In case of early recanalization, restriction of diffusion may be limited to cortical areas but is usually more pronounced than in MELAS
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Background
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is a mitochondrial cytopathy caused by mutations in mitochondrial DNA. Clinical manifestation is typically before the age of 40.
Case presentation
We present the case of a 63-year-old female in whom the symptoms of MELAS were initially misdiagnosed as epis...
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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...
Fifteen-month-old male child, known to have a congenital bone marrow failure syndrome, presented in a state of shock with severe lactic acidosis following a brief episode of vomiting. Hospital stay was complicated by recurrent bouts of metabolic acidosis and progressive hepatic failure. Blood mitochondrial DNA sequencing revealed a large heteroplas...
Citations
... Intermediates in this pathway that inhibit ATP generation include tryptophan and nicotinamide adenine dinucleotide [14]. Mutations in mitochondrial DNA may also cause MELAS (Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) in adult patients [76]. ...
... In another study involving patients with eGFR of <30mL/min, a comparison was made between GLP-1RA medications and dipeptidyl peptidase 4 (DPP-4) inhibitors. The results demonstrated significantly lower rates of loss of kidney function or requirement for dialysis for the GLP-1RA study subgroup [33,34,[76][77][78][79]. Although additional studies will be required to assess their direct physiologic roles in preventing lipid toxicity, they are currently used in the treatment of persons with type 2 diabetes and chronic kidney disease [80,81]. ...
Recent studies of Cardiovascular-Kidney-Metabolic Syndrome (CKMS) indicate that elevated concentrations of derivatives of phospholipids (ceramide, sphingosine), oxidized LDL, and lipoproteins (a, b) are toxic to kidney and heart function. Energy production for renal proximal tubule resorption of critical fuels and electrolytes is required for homeostasis. Cardiac energy for ventricular contraction/relaxation is preferentially supplied by long chain fatty acids. Metabolism of long chain fatty acids is accomplished within the cardiomyocyte cytoplasm and mitochondria by means of the glycolytic, tricarboxylic acid, and electron transport cycles. Toxic lipids and excessive lipid concentrations may inhibit cardiac function. Cardiac contraction requires calcium movement from the sarcoplasmic reticulum from a high to a low concentration at relatively low energy cost. Cardiac relaxation involves calcium return to the sarcoplasmic reticulum from a lower to a higher concentration and requires more energy consumption. Diastolic cardiac dysfunction occurs when cardiomyocyte energy conversion is inadequate. Diastolic dysfunction from diminished ATP availability occurs in the presence of inadequate blood pressure, glycemia, or lipid control and may lead to heart failure. Similar disruption of renal proximal tubular resorption of fuels/electrolytes has been found to be associated with phospholipid (sphingolipid) accumulation. Elevated concentrations of tissue oxidized low-density lipoprotein cholesterols are associated with loss of filtration efficiency at the level of the renal glomerular podocyte. Macroscopically excessive deposits of epicardial and intra-nephric adipose are associated with vascular pathology, fibrosis, and inhibition of essential functions in both heart and kidney. Chronic triglyceride accumulation is associated with fibrosis of the liver, cardiac and renal structures. Successful liver, kidney, or cardiac allograft of these vital organs does not eliminate the risk of lipid toxicity. Lipid lowering therapy may assist in protecting vital organ function before and after allograft transplantation.
... The original diagnostic criteria of MELAS included the first stroke-like episode (SLE) presenting before age 40. As more has been learned about MELAS there has been greater appreciation for cases presenting much later in life with cases reported of patients with their first SLE presenting in their 40s to 60s (2)(3)(4)13). A population-based study in Japan observed a bimodal distribution in the initial SLE presentation and saw that patients with juvenile MELAS (first SLE <18 years) had higher incidence of short stature in the juvenile form, whereas hearing loss, cortical blindness, and diabetes were more commonly seen in the adult-onset group (first SLE ≥18). ...
Objective
Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a severe multisystemic disease, although some have a milder phenotype. We aimed to evaluate the clinical spectrum of this disease from MELAS patients to asymptomatic carriers and identify predictors of severity.
Methods
We reviewed 81 patients, who had MELAS or had positive genetics without meeting clinical criteria. Patients who met criteria including lactic acidosis, encephalomyopathy, and stroke-like episodes (SLE) were categorized as MELAS, symptomatic non-MELAS, and asymptomatic. MELAS was further categorized as “standard-onset” if the first stroke-like episode (SLE) occurred before age 40 or “late-onset.”
Results
Eighty-one patients were included: 42 MELAS (13 late-onset), 30 symptomatic non-MELAS, and 9 asymptomatic. MELAS patients had lower BMI at onset (mean 18.6 vs. 25.1 asymptomatic and 22.0 symptomatic non-MELAS, p < 0.05). There was a trend toward higher serum heteroplasmy in MELAS compared to symptomatic non-MELAS and asymptomatic (means 39.3, 29.3, and 21.8% p = 0.09). Symptomatic non-MELAS had more sensorineural hearing loss as first presenting symptom (51.6% vs. 24.4%, p < 0.05). MELAS had higher prevalence of seizures (88.1% vs. 16.7%, p < 0.05) and shorter survival from onset to death (50% mortality at 25 years vs. 10%, p < 0.05). Late-onset MELAS had longer disease duration from first symptom to first SLE (mean 16.6 vs. 9.3 yrs) and also lived longer (mean age at death 62 vs. 30). Standard-onset MELAS had more neurologic involvement at onset than late-onset (51.7% vs. 15.4%). Late-onset patients had more prevalent diabetes (69.2% vs. 13.8%) and nephropathy (53.8% vs. 10.3%). Patients with late-onset MELAS also had more organ systems involved (mean 4.1 vs. 2.7, p < 0.05). There was a trend toward higher heteroplasmy levels in standard-onset (mean 44.8% vs. 25.3%, p = 0.18).
Discussion
Our study highlights the spectrum of MELAS. The lower BMI in MELAS at presentation as well as higher rates of sensorineural hearing loss as initial symptom in symptomatic non-MELAS may be useful clinical markers. While many patients present before age 40 with SLE, some can present with SLE later in life. Standard onset MELAS is more likely to present with neurologic symptoms. Late-onset is more likely to suffer diabetes or nephropathy and have more organ systems involved.
... According to which body parts are damaged at a given period, patients are treated. There is no known treatment for MELAS which is progressive and fatal [119]. ...
DNA is a remarkably precise medium for copying and storing biological information. It serves as a design for cellular machinery that permits cells, organs, and even whole organisms to work. The fidelity of DNA replication results from the action of hundreds of genes involved in proofreading and damage repair. All human cells can acquire genetic changes in their DNA all over life. Genetic mutations are changes to the DNA sequence that happen during cell division when the cells make copies of themselves. Mutations in the DNA can cause genetic illnesses such as cancer, or they could help humans better adapt to their environment over time. The endogenous reactive metabolites, therapeutic medicines, and an excess of environmental mutagens, such as UV rays all continuously damage DNA, compromising its integrity. One or more chromosomal alterations and point mutations at a single site (monogenic mutation) including deletions, duplications, and inversions illustrate such DNA mutations. Genetic conditions can occur when an altered gene is inherited from parents, which increases the risk of developing that particular condition, or some gene alterations can happen randomly. Moreover, symptoms of genetic conditions depend on which gene has a mutation. There are many different diseases and conditions caused by mutations. Some of the most common genetic conditions are Alzheimer’s disease, some cancers, cystic fibrosis, Down syndrome, and sickle cell disease. Interestingly, scientists find that DNA mutations are more common than formerly thought. This review outlines the main DNA mutations that occur along the human genome and their influence on human health.
... Syndromic disorders caused by mitochondrial mutations are a spectrum of rare diseases which usually become clinically manifest before the age of 40, with later onsets being described. [1,2] MELAS is a rare and life-threatening mitochondrial disorder due to the severe metabolic impairment, predominantly affecting organs with the highest metabolic activity: heart, muscles, and brain. The metabolic impairment translates into lactic acidosis, severe hypoglycemia and hyperglycemia, which can lead to diabetes mellitus. ...
Introduction
MELAS is a systemic hereditary condition that can present as hypertrophic or mixed hypertrophic and dilated phenotype cardiomyopathy in young individuals, although a late-onset form is also described in the literature. Genetic testing is essential for correct diagnosis and appropriate management.
Case presentation
We present the case of a 22-year-old male who was referred to our center after being diagnosed with NYHA class III heart failure with a mixed hypertrophic and dilated cardiomyopathy. His medical history included stroke episodes, seizures, progressive hypoacusis, neurocognitive impairment, and muscle atrophy. Lactic acidosis and elevated CK levels were also noted. The ECG revealed short PR interval and delta wave in lateral leads. TTE showed mildly dilated and hypertrophied LV and RV with severe biventricular systolic impairment. The CMR study was relevant for ring-like subepicardial fibrosis, predominantly in the medium and apical segments. Brain MRI showed multifocal supratentorial subcortical stroke-like lesions in both cerebral hemispheres, involving multiple vascular territories and following a migratory pattern. Genetic testing confirmed a pathogenic MT-TL1 mutation (m.324A>G) and the patient was diagnosed with MELAS. Further management included specific lifestyle recommendations and cascade genetic screening, as well as starting GDMT for HFrEF. Three months after discharge, his clinical status improved. However, the LVEF remained reduced. After careful consideration, an ICD was implanted for primary prevention.
Conclusion
A red-flag approach in this young patient, which took into consideration the stroke-like episodes, lactic acidosis, seizures, hypoacusis, myopathy, as well as the short PR interval, led to the correct diagnosis, further confirmed by using the appropriate genetic test. Failure to diagnose affects the patient’s prognosis, as their prognosis and clinical status are influenced by enforcing specific recommendations.
... The most frequently identified mutations are A-G 11,778 in the ND4 gene and G-A 3460 in the ND1 gene [117,118]. Another disease associated with point mutations is Myoclonic Epilepsy and Ragged Red Fibers Syndrome (MERRF), produced by an A-G 8344 mutation and a reduced number of T-C 8356 [119]. Mitochondrial encephalomyopathies, lactic acidosis, and encephalic stroke-like episodes syndrome, or MELAS, are related to the A-G 3243 mutation [120]. ...
Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview of the intricate relationship between mitochondria and brain disease, focusing on the underlying pathological mechanisms and exploring potential therapeutic opportunities. The review covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, mitochondrial dynamics, calcium dysregulation, and reactive oxygen species generation in the context of brain disease. Additionally, it discusses emerging strategies targeting mitochondrial dysfunction, including mitochondrial protective agents, metabolic modulators, and gene therapy approaches. By critically analysing the existing literature and recent advancements, this review aims to enhance our understanding of the multifaceted role of mitochondria in brain disease and shed light on novel therapeutic interventions.
... Clinical traits usually demonstrate as symptoms in high energyconsuming organs such as the brain, skeletal muscles, myocardium, and endocrine systems. 1 Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes (MELAS) is presumably the most common mitochondrial disorder, which is inherited maternally, 2 and usually becomes symptomatic before the age of 40 years. 3 MELAS was first introduced in 1984, 4 which typically presents with stroke-like episodes, seizures, short stature, encephalopathy, muscle weakness, nausea, vomiting, headaches, diabetes mellitus, exercise intolerance, sensorineural hearing loss, myopathy, lactic acidosis, and RRFs on muscle biopsy. [4][5][6][7][8] Magnetic Resonance Imaging (MRI), in a company with muscle biopsy and genetic studies, is now the foundation of diagnosis in MELAS cases. ...
Key Clinical Message
The stroke‐like episodes and brain MRI lesions in MELAS usually have a nonischemic pattern, are resolved over time, and have a migrating pattern that helps us distinguish them from ischemic cerebral infarcts. Nevertheless, conditions such as intracardiac thromboses, PFO, and hypercoagulable state may be present concomitantly, leading to mismanagement. Therefore, further investigation and echocardiography are suggested in MELAS patients.
Abstract
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke‐like episodes (MELAS) is the most common maternally‐inherited mitochondrial disorder presenting by stroke‐like episodes, seizures, encephalopathy and muscle weakness. We report the clinical, imaging, echocardiography and muscle biopsy findings of a patient presenting by unique characteristics which have not been reported in previous cases of MELAS. The reported case is a 34 year old man with the history of three times hospitalization due to muscle weakness, encephalopathy, progressive cognitive decline, and gradual visual loss. Muscle biopsy revealed Ragged Red Fibers concomitant with mitochondrial disorders. PFO was found in echocardiography leading to mismanagement of this patient and MR imaging showed ischemic lesions with a progressive pattern. This is the first reported case of MELAS accompanying with PFO. All previous reported cases of MELAS have mentioned a fluctuating characteristic for the ischemic lesions; hence this is the first case of MELAS with the progressive pattern of ischemic lesions.
... In clinical practice, many patients with a first SLE are misdiagnosed as acute ischemic stroke (AIS) or, less often, as viral or autoimmune encephalitis or CNS vasculitis. [7][8][9][10][11] This translates to significant delays in diagnosis and administration of appropriate therapy. ...
... Previous reports on SLE neuroimaging features focused mainly on MRI and MRS. [12][13][14][15] However, many patients with a first SLE are initially misdiagnosed as AIS, [7][8][9][10][11] and MRI is seldom performed in the acute setting. 16 Our set of criteria does not rely on MRI but rather on a single NCCT scan performed at presentation with the optional use of additional criteria based on CTA or MRI. ...
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, p < 0.01) and had a lower body mass index (18 ± 2.6 vs 29 ± 4, p < 0.01), more commonly reported hearing loss (91% vs 5%, p < 0.01), and more commonly presented with headache and/or seizures (41% vs 0%, p < 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%, p < 0.01), previous cortical lesions with typical SLE distribution (46% vs 9%, p = 0.03), acute lesion tissue hyperemia and venous engorgement on CT angiography (CTA) (45% vs 0%, p < 0.01), and no large vessel occlusion on CTA (0% vs 100%, p < 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.
... [2]. MELAS has a high overall morbidity and mortality rates and may affect people at any age, with the vast majority of patients experiencing their rst symptom before the age of 20 years and over 90% before age 40 [3]. Despite normal early development, later in life mitochondrial dysfunction leads to multi-organ damage including neurological (partially reversible stroke-like episodes, epilepsy, dementia, migrainous headaches, psychiatric illnesses, sensorineural hearing loss, peripheral neuropathy, ophthalmologic involvement) and non-neurological systems (cardiac, GI, endocrine, renal and muscle systems) with myopathy, exercise intolerance, cardiomyopathy, Wolff-Parkinson-White, DM, short stature, hypothyroidism, cyclic vomiting and etc. ...
... MELAS is an important differential diagnosis for juvenile strokes and must be considered in cases of recurrent events with atypical imaging ndings particularly when multiple areas are involved without respecting arterial territories, even among middle aged patients with vascular risk factors or concurrent macroangiopathic lesions [3],[6]. ...
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.
... Brain MRI in the patient indicated a corresponding abnormal linear signals in the cerebral hemisphere cortex on the opposite side of the hemiplegic limb. MELAS patients show gyri-like patchy signals that are randomly distributed and not assigned according to vascular territory (Kraya et al., 2019;Renard & Ion, 2020;Sinnecker et al., 2019). The lesions in this patient and MELAS patients are mainly located in the temporoparietal lobe and mainly invaded the cortex (Ikawa et al., 2013). ...
... MELAS patients' lesions also invaded a small amount of subcortical white matter (Huang et al., 1995;Niehues et al., 2008). In addition, the lesions of MELAS patients emerge in an endless stream (Sinnecker et al., 2019), and focal hyperperfusion was identified as an imaging hallmark in acute encephalopathy of MELAS (Li & Lin, 2017). The distribution of lesions in this patient and MELAS patients are migratory and recurrent (Sinnecker et al., 2019). ...
... In addition, the lesions of MELAS patients emerge in an endless stream (Sinnecker et al., 2019), and focal hyperperfusion was identified as an imaging hallmark in acute encephalopathy of MELAS (Li & Lin, 2017). The distribution of lesions in this patient and MELAS patients are migratory and recurrent (Sinnecker et al., 2019). The brain MRI changes disappeared when the patient's condition improved. ...
Background:
Pathogenic variants of ATP1A2 (OMIM ID: 182340) are usually associated with familial hemiplegic migraine type 2 (FHM-2), alternating hemiplegia of childhood (AHC), early infantile epileptic encephalopathy (EIEE), transient cytotoxic edema, and so on. Here, we present a novel heterozygous ATP1A2 variant in a girl with alternating hemiplegia, febrile seizures, developmental delay (which subsequently subsided), and MELAS-like syndrome (as indicated by brain MRI). The patient did not experience migraine with aura.
Methods:
The patient was an 8-year-old girl with normal growth and development. Beginning from the age of 3 years and 8 months, the patient experienced several episodes of alternating limb paralysis. The episodes were accompanied by the appearance of MELAS-like findings on brain MRI, which corresponded to the hemiplegia. There were abnormal linear signals in the cerebral cortex on the opposite side of the hemiplegic limb. Each time the patient recovered from hemiplegia, and each time MRI showed no lesions remained after recovery. No obvious abnormality was found in other examinations. Finally, the patient underwent whole-exome sequencing (WES).
Results:
WES revealed a novel and de novo heterozygous variant in the ATP1A2 (NM_000702.3) c.335C>A:p.Ala112Asp (not previously reported). We examined the variant position in the 3D protein structure and found that a missense mutation at this site is a nonconservative substitution. The variation is nonpolymorphic. It occurs at a very low frequency in the population, and its ACMG classification is likely pathogenic.
Conclusion:
At present, there are limited reports of mutations in the ATP1A2 gene causing AHC. This is the first case of brain MRI showing MELAS-like imaging in an AHC patient, and more cases are needed for verification. Early genetic testing and family screening can aid in the diagnosis and treatment of genetic diseases. The relationship between ATP1A2 gene mutation genotype and clinical phenotype needs to be further studied.
... Only 1-6% of patients develop the disease after 40 years of age (4). It is even rare in patients after 60 years of age, and there have been only a few cases reported in female patients (5)(6)(7). In this report, we described the case of a 61-year-old male patient with MELAS. ...
Background
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is one of the most common maternally inherited mitochondrial diseases which rarely affects elderly people.
Case presentation
We reported the case of a 61-year-old male patient with MELAS. He was experiencing acute migraine-like headaches as the first symptoms. Laboratory data showed elevated lactate and creatine kinase levels. Brain magnetic resonance imaging (MRI) found a high signal intensity lesion in the left occipital-temporal-parietal lobe on diffusion-weighted imaging (DWI). Magnetic resonance angiography (MRA) revealed reversible vasoconstriction of the middle cerebral arteries and superficial temporal arteries. A muscle biopsy suggested minor muscle damage. A genetic study revealed a mitochondrial DNA A3243G mutation.
Conclusion
Elderly onset of MELAS is rare and easily misdiagnosed as an ischemic stroke. MELAS with the onset of stroke-like episodes should be considered in adult or elderly patients with imaging findings that are atypical for cerebral infarction. The use of multimodal MRI in the clinical diagnosis of MELAS could be extremely beneficial.
