Mitochondrial Encephalopathy, Lactic Acidosis, And Stroke-like Episodes Syndrome Research Articles

MELAS syndrome and risk of infection

Abstract This perspective explores the relationship between mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome and an increased risk of infections. Mitochondrial dysfunction impairs immune cell function, impacting the body’s defense against pathogens. Additional effects on the immune system may manifest through altered B-cell function and disruptions in the gut microbiota balance. The complex connection between infections, MELAS symptoms, and treatment complicates patient management. We propose greater focus on genetic abnormalities and their immunologic impacts, indicating a possible path for targeted pharmaceutical therapies to improve overall illness management.

Neurological manifestations in adult patients with the m.3243A>G variant in mitochondrial DNA

BackgroundThe m.3243A>G variant in mitochondrial DNA (mtDNA) is the most common cause of the MELAS (Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome usually commencing in childhood or adolescence. In...

A Case of MELAS Syndrome Involving Diabetes Mellitus, Cerebellar Ataxia and Progressive Sensorineural Hearing Loss

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a maternally inherited mitochondrial disorder. MELAS syndrome manifests different clinical symptoms due to mitochondrial heteroplasmy and individual susceptibility and tends to be aggravated by metabolic events. It presents various clinical manifestations including hearing impairment, diabetes mellitus, and stroke like episodes. However, to date, only a few cases of MELAS syndrome accompanied with cerebellar ataxia have been reported in Korea. We hereby present an unusual case of a patient diagnosed with MELAS syndrome involving diabetes mellitus, cerebellar ataxia and sensorineural hearing loss, which were aggravated by metabolic stresses such as pregnancy and hypoglycemic shock.

Comprehensive Diagnostic Criteria for MELAS Syndrome; a Case Study Involving an Elderly Patient With MT-TWm.5541C>T Mutation.

The mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a matrilineal hereditary multisystem disease caused by mutations in the mitochondrial DNA. Although the initial diagnostic criteria correlate with a range of clinical phenotypes, including clinical onset after the age of 40, there is still lack of a unified single diagnostic standard for MELAS. A 71-year-old female patient with recurrent stroke was reported. Magnetic resonance imaging showed a cerebral gyrus-like diffusion weighted imaging high signal lesion in the parietal-occipital lobe and the area of this lesion expanded with disease progression. The MRS result showed significantly inverted Lac/Lip peaks. The nucleic acid sequencing result displayed a MT-TWm.5541C>T mutation, and a 12.86% mutation rate in the blood sample. The patient had a 6-year history of type 2 diabetes. Patients with the MELAS syndrome may present with a variety of clinical manifestations. Our data demonstrated that, for patients with atypical cerebral infarction and suspected MELAS syndrome, gene sequencing and muscle biopsy should be performed in time. This case provides a reference for the diagnostic criteria of MELAS syndrome.

Psihijatrijski aspekti sindroma MELAS

MELAS (Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like episodes) syndrome is a condition characterized by mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. It is a rare, inherited, neurodegenerative disorder caused by mitochondrial dysfunction that leads to energy production disturbances. The disease most commonly begins at a younger age, before the age of 40, with episodes resembling strokes, and psychiatric symptoms can also occur in the early stages of the disease. Later on, encephalopathy may develop, which is accompanied by epileptic seizures and/ or dementia. Psychiatric disorders in MELAS syndrome are present but insufficiently studied, which should be considered during diagnosis to prevent th disease from going unrecognized. Early diagnosis of any disease, including MELAS, is crucial as timely initiation of treatment significantly contributes to a more favorable course and better prognosis of the disease. When diagnosing MELAS, attention should be paid to the potential presence of psychiatric disorders.

Renal involvement by mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome – a case report

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a clinical syndrome caused by mutations in mitochondrial DNA, which is maternally inherited. This disruption to mitochondrial function manifests primarily as neurological signs and symptoms that result in progressive functional decline, although multiorgan system involvement has also been described. We report a case of a 70-year-old man recently diagnosed with MELAS syndrome who was referred for nephrology review due to acute on chronic renal impairment, with a background history of Type 2 Diabetes Mellitus and hypertension. A renal biopsy was performed to delineate the cause of the acute decline in renal function. The kidney biopsy showed marked chronic damage consistent with diabetic and hypertensive nephropathy, which was corroborated by electron microscopy findings. In addition, occasional tubular cells showed mitochondria with large vacuoles and abnormal cristae. This case highlights the ultrastructural changes within the kidney that are indicative of MELAS syndrome. These changes can be focal, and should not be overlooked in the presence of other causes of chronic kidney damage.

A novel nonsense variant in MT-CO3 causes MELAS syndrome

Both mitochondrial and nuclear gene mutations can cause cytochrome c oxidase (COX, complex Ⅳ) dysfunction, leading to mitochondrial diseases. Although numerous diseases caused by defects of the COX subunits or COX assembly factors have been documented, clinical cases directly related to mitochondrial cytochrome c oxidase subunit 3 gene (MT-CO3) mutations are relatively rare. Here, we report a 47-year-old female patient presented with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Muscle pathology revealed ragged-red fibres and remarkable COX-deficient muscle fibres. Muscle mitochondrial DNA sequencing analysis identified a novel MT-CO3 variant (m.9553G>A) that changed a highly conserved amino acid to a stop codon (p.Trp116*). This variant was heteroplasmic in multiple tissues, where the mutation load was 13% in oral epithelial cells, 89% in muscle samples, and not detectable in the peripheral blood lymphocytes. Single muscle fiber PCR analysis showed clear segregation of the mutation load with COX deficient fibres. Western blot analysis of the muscle samples revealed a significant decrease in the levels of COX1, COX2, COX3, COX4 and UQCRC2. COX respiration activity was remarkably reduced (58.84%) relative to the controls according to spectrophotometric assays. Taken together, our results indicated that this m.9553G>A variant may be responsible for the MELAS symdrome in the proband by affecting the stability and function of COX. The study expands the clinical and molecular spectrum of COX3-specific mitochondrial diseases.

Contribution of nuclear and mitochondrial gene mutations in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome

BackgroundMitochondrial disorders are clinically complex and have highly variable phenotypes among all inherited disorders. Mutations in mitochondrial 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.

Audiological and Vestibular Findings in Subjects with MELAS Syndrome.

The mitochondrial DNA (mtDNA) point mutation m.3243A>G is known to express the following two syndromes among others: maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Sensorineural hearing loss (SNHL) is the most frequent symptom in individuals harboring the m.3243A>G mutation. However, dysfunction of the vestibular organs has been scarcely examined. Therefore, the present study aimed to study the impact of the m.3243A>G mutation on the inner ear. A total of 8 subjects harboring the blood-verified m.3243A>G mutation underwent thorough audiological and vestibular examinations, including tone and speech audiometry, video head impulse test (vHIT), ocular and cervical vestibular-evoked myogenic potential (oVEMP and cVEMP), and full otoneurological examination. The subjects also answered a Dizziness Handicap Inventory (DHI) questionnaire. SNHL was identified in all the 8 subjects, with a mean pure-tone average-4 (PTA-4) of 59 dB. Speech discrimination score (n=7) ranged from 24% to 100% (mean 74%), and vHIT (n=42) detected pathology in nine lateral semicircular canals (SCCs), five posterior SCCs, and one anterior SCC, whereas three measurements were inconclusive. All oVEMPs (n=14 ears) were absent, nine cVEMPs were absent, and two were inconclusive. Based on the DHI scores, 6 subjects reported none to mild dizziness, 1 reported moderate, and 1 reported severe dizziness. Our study population had pathological findings from every audiological and vestibular end organs. The results indicated that the pathological findings originated from within the end organs themselves and not within the superior and inferior vestibular or cochlear nerve.

Detection of a new case harboring mitochondrial A3243G mutation of MELAS syndrome

Mitochondrial genome A3243G mutation in the tRNALeu(UUR) encodinggene (MTTL)is the main cause of mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS). This mutation exists in heteroplasmic form and severity of the disease is affected by many factors including heteroplasmy level.
 In this study, a pediatric proband (female, 8 years old) was found to carry A3243G mutation at 77.6% of heteroplasmy by using PCR-RFLP in combination with real-time PCR. The results of the A3243G mutation analysis of the proband’s family showed that her mother without any symptoms of encephalopathyalso carried the mutation at 7.9% of heteroplasmy whereas the mutation was not found in the proband’s healthy father and healthy sister, indicating that the proband received the A3243G mutation from her mother and the expression of MELAS syndromes depended on the level of heteroplasmy.

Serum lactic acid and pyruvic acid levels in patients with migraine and tension type headache

Serum lactic acid and pyruvic acid levels in patients with migraine and tension type headache Objective: MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome is frequently associated with migraine like headaches. The relationship between migraine and mitochondrial diseases is interesting. Also mitochondrial disorders in tension like headache still remain to be investigated. The aim of this report is to evaluate the serum lactic acid and pyruvic acid levels in patients with migraine and tension type headache and compare them with healthy control group. Methods: We evaluated 30 patients with migraine, 30 patients with tension like headache and 30 healthy control. Lactic and pyruvic acid levels in serum samples were measured by biochemical methods. Kruskal Wallis and Mann-Whitney tests were used for statistical analysis using SPSS 11.5 for Windows program. Results: Serum lactic and pyruvic acid levels in patients with migraine and tension type headache were significantly higher than control group. Conclusion: Multi-disciplinary researches are needed to determine mitochondrial diseases in patients with

A whole mitochondrial genome screening in a MELAS patient: A novel mitochondrial tRNAVal mutation

Mitochondrial encephalopathy, lactic acidosis and strokelike episodes (MELAS) syndrome is a mitochondrial disorder characterized by a wide variety of clinical presentations and a multisystemic organ involvement. In this study, we report a Tunisian girl with clinical features of MELAS syndrome who was negative for the common m.3243A>G mutation, but also for the reported mitochondrial DNA (mtDNA) mutations and deletions. Screening of the entire mtDNA genome showed several known mitochondrial variants besides to a novel transition m.1640A>G affecting a wobble adenine in the anticodon stem region of the tRNAVal. This nucleotide was conserved and it was absent in 150 controls suggesting its pathogenicity. In addition, no mutations were found in the nuclear polymerase gamma-1 gene (POLG1). These results suggest further investigation nuclear genes encoding proteins responsible for stability and structural components of the mtDNA or to the oxidative phosphorylation machinery to explain the phenotypic variability in the studied family.

Wolff-Parkinson-White Syndrome in a Patient With Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-Like Episodes Syndrome

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is a multisystem disorder, which is clinically characterized by encephalopathy, dementia, seizures and stroke-like episodes. Multiple organs can be affected and cardiac involvement often dominates the clinical picture because of its high energy requirement. We report a case of a 21-year-old woman with MELAS syndrome who had pre-excitation ECG and one episode of tachycardia attack.

Regression of stroke‐like lesions in MELAS‐syndrome after seizure control

There are some indications that seizure activity promotes the development of stroke-like episodes, or vice versa, in patients with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome or other syndromic mitochondrial disorders. A41-year-old Caucasian female with MELAS syndrome, presenting with short stature, microcytic anaemia, increased blood-sedimentation rate, myopathy, hyper-gammaglobulinaemia, an iron-metabolism defect, migraine-like headaches, and stroke-like episodes, developed complex partial and generalised seizures at age 32years. Valproic acid was ineffective but after switching to lamotrigine and lorazepam, she became seizure-free for five years and stroke-like episodes did not recur. Cerebral MRI initially showed enhanced gyral thickening and a non-enhanced T2-hyperintensity over the left parieto-temporo-occipital white matter and cortex and enhanced caudate heads. After two years without seizures, the non-enhanced hyperintense parieto-temporo-occipital lesion had disappeared, being attributed to consequent seizure control. The caudate heads, however, remained hyperintense throughout the observational period. This case indicates that adequate seizure control in a patient with MELAS syndrome may prevent the recurrence of stroke-like episodes and may result in the disappearance of stroke-like lesions on MRI.

The study of mitochondrial A3243G mutation in different samples

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS) is the most frequent syndromic manifestation of A3243G mutation in mitochondrial DNA. Detection of A3243G mutation in blood is less helpful for the diagnosis of MELAS and the carriers, and the mutation ratio in blood correlates only in a limited extent with the severity of the disease. Here we compared the ratio of A3243G mutation in four easily available samples (blood, urine, hair follicle and saliva) in patients with MELAS carrying A3243G mutation as well as their maternal relatives from 32 families, to find out the samples appropriate for the detection of the patients and carriers and useful for the evaluation of clinical severity from their mutation ratio. In MELAS patients and the carriers with minor symptoms or normal phenotype, A3243G mutation ratio was significantly higher in urine than in blood. A close correlation between A3243G mutation ratio in blood and that in urine, hair follicles and saliva was found in the probands and their relatives. Clinical features closely correlated with the mutation ratio in urine. Measurement of A3243G mutation ratio in urine is a non-invasive, convenient and rapid method with its diagnostic meaning superior to blood testing.

A Case of MELAS Syndrome Manifested by Insulin-deficient Diabetes Mellitus

MELAS (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes) syndrome is characterized by stroke-like episodes before the age of 40, encephalopathy, seizures, dementia and lactic acidosis, and is caused by mutations in mitochondrial DNA. Diabetes mellitus and cardiac involvement are also frequently seen in MELAS syndrome. It is a classic mitochondrial disorder that shows a slow, chronic, progressive course, and presents with multiple organ involvement including the central nervous system, skeletal muscle, eye, cardiac muscle and gastrointestinal system. Here, we report a case of 33 year-old woman with insulin-deficient diabetes mellitus and sensorineural hearing loss experiencing repeated stroke-like episodes. MELAS syndrome with an A3243G point mutation was confirmed by mitochondrial DNA sequencing analysis. (J Korean Endocr Soc 23:444~449, 2008) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ

Wolff-Parkinson-White Syndrome in Patients With MELAS

Tissues with high energy demands, such as the heart, are susceptible to the effects of mitochondrial DNA point mutations. To investigate the frequency of Wolff-Parkinson-White (WPW) syndrome among a phenotypically and genotypically homogeneous cohort of patients with MELAS (mitochondrial encephalopathy, lactic acidosis, and strokelike episodes) and the A3243G mutation most commonly associated with MELAS syndrome. Survey. The Pediatric Neuromuscular Disease Center at Columbia University. Patients Thirty patients with the A3243G mutation and MELAS syndrome enrolled in a clinical trial to assess the effect of dichloroacetate on neurologic symptoms. Medical histories and electrocardiograms were reviewed and DNA samples from fibroblasts, urine and cheek epithelial cells, leukocytes, and hair were analyzed to determine mitochondrial mutation abundance and estimate total mutation burden. Four of 30 patients (13%) had a clinical history of, or electrocardiographic findings consistent with, WPW syndrome. In 2 patients, WPW syndrome preceded MELAS syndrome by 15 and 21 years. The tissue burden of mutant mitochondria was similar in patients with (49.4%) and without (39.1%) WPW syndrome. The prevalence of WPW syndrome among patients with MELAS syndrome and the A3243G mutation appears much higher than in the normal population and may become manifest earlier than neurologic symptoms. Patients with WPW syndrome and neurologic abnormalities consistent with MELAS syndrome, such as seizures, deafness, short stature, and stroke, should be screened for the A3243G mutation. Moreover, patients with MELAS syndrome should be monitored for cardiac anomalies including cardiomyopathy and WPW syndrome.

The MELAS mutations 3946 and 3949 perturb the critical structure in a conserved loop of the ND1 subunit of mitochondrial complex I

The ND1 subunit gene of the mitochondrial NADH-ubiquinone oxidoreductase (complex I) is a hot spot for mutations causing Leber hereditary optic neuropathy and several mutations causing the mitochondrial encephalopathy, lactic acidosis and stroke-like episodes syndrome (MELAS). We have used Escherichia coli and Paracoccus denitrificans as model systems to study the effect of mutations 3946 and 3949, which change conserved residues in ND1 and cause MELAS. The vicinity of these mutations was also explored with a series of mutations in charged residues. The 3946 mutation results in E214K substitution in human ND1. Replacement of the equivalent residue in E. coli with lysine or glutamine detracted from enzyme assembly and the assembled enzyme was inactive. However, the equivalent E234Q mutant enzyme in P. denitrificans failed to assemble completely (or was rapidly degraded). Also the corresponding substitution with aspartate decreased the enzyme activity in P. denitrificans and E. coli. The 3949-equivalent substitution, Y229H in E. coli, lowered the catalytic activity by 30%. In addition, an activation of the enzyme during catalytic turnover was seen in this bacterial NDH-1, something that was even more pronounced in another mutant in the same loop, D213E. Several other mutations in this region decreased the enzyme activity. The studied MELAS mutations are situated in a matrix-side loop, which appears to be highly sensitive to structural perturbations. The results provide new information on the function of the region affected by the MELAS mutations 3946 and 3949 that is not obtainable from patient samples or current eukaryote models.

Heart Transplantation for Progressive Cardiomyopathy as a Manifestation of MELAS Syndrome

Mitochondrial diseases represent a heterogeneous group of disorders associated with a wide array of clinical manifestations. The presentation of patients with mitochondrial pathology largely depends upon the dysfunction of organ systems with large metabolic/energy requirements, including cardiac, neurologic, and musculoskeletal. In particular, mitochondrial myocardial disease can be progressive resulting in congestive heart failure and end-stage heart disease. This article reviews the role of heart transplantation for a particular variant of mitochondrial disorder, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, and discusses perioperative management issues related to transplantation for mitochondrial cardiomyopathies.

Renal cell carcinoma in a pediatric patient with an inherited mitochondrial mutation

Renal cell carcinoma (RCC) is a rare pediatric renal cancer. Recent molecular genetic studies discovered a tumor-specific mutation involving translocation of a transcription factor TFE3 in a subset of pediatric RCC with distinct histopathology. We reported a case of a 2-year-old boy with RCC associated with TFE3 translocation resulting in a PRCC-TFE3 fusion gene. Interestingly, the case carried a maternally inherited mitochondrial DNA (mtDNA) alteration at the position which is usually found in MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes) syndrome (A3243G). Although evidence of somatic alterations in mtDNA existed in various cancers, association between inherited mtDNA mutation and pediatric renal cancer has not been reported. Our case provided the first evidence of a co-occurrence between a germ line mutation in mtDNA and the somatic mutation of pediatric RCC. With this information, we speculated a role of mitochondria mutation in the pathogenesis of this cancer.