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Molecules (Basel, Switzerland) May 2022Mitochondrial diseases (MDs) may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins, or non-protein-coding mitochondrial... (Review)
Review
Mitochondrial diseases (MDs) may result from mutations affecting nuclear or mitochondrial genes, encoding mitochondrial proteins, or non-protein-coding mitochondrial RNA. Despite the great variability of affected genes, in the most severe cases, a neuromuscular and neurodegenerative phenotype is observed, and no specific therapy exists for a complete recovery from the disease. The most used treatments are symptomatic and based on the administration of antioxidant cocktails combined with antiepileptic/antipsychotic drugs and supportive therapy for multiorgan involvement. Nevertheless, the real utility of antioxidant cocktail treatments for patients affected by MDs still needs to be scientifically demonstrated. Unfortunately, clinical trials for antioxidant therapies using α-tocopherol, ascorbate, glutathione, riboflavin, niacin, acetyl-carnitine and coenzyme Q have met a limited success. Indeed, it would be expected that the employed antioxidants can only be effective if they are able to target the specific mechanism, i.e., involving the central and peripheral nervous system, responsible for the clinical manifestations of the disease. Noteworthily, very often the phenotypes characterizing MD patients are associated with mutations in proteins whose function does not depend on specific cofactors. Conversely, the administration of the antioxidant cocktails might determine the suppression of endogenous oxidants resulting in deleterious effects on cell viability and/or toxicity for patients. In order to avoid toxicity effects and before administering the antioxidant therapy, it might be useful to ascertain the blood serum levels of antioxidants and cofactors to be administered in MD patients. It would be also worthwhile to check the localization of mutations affecting proteins whose function should depend (less or more directly) on the cofactors to be administered, for estimating the real need and predicting the success of the proposed cofactor/antioxidant-based therapy.
Topics: Anticonvulsants; Antioxidants; DNA, Mitochondrial; Humans; Mitochondria; Mitochondrial Diseases; Mitochondrial Proteins; Precision Medicine
PubMed: 35684429
DOI: 10.3390/molecules27113494 -
Cureus May 2022Mitochondrial disorders are caused due to variants in genes located on the mitochondrial DNA or the nuclear DNA. Here, we report a case with mitochondrial...
Mitochondrial disorders are caused due to variants in genes located on the mitochondrial DNA or the nuclear DNA. Here, we report a case with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS)/Leigh overlap syndrome due to variant m.13513G>A in ND5. A 60-month-old female with a congenital, complex, multisystem phenotype was diagnosed with MELAS/Leigh overlap syndrome due to variant m.13513G>A in ND5 Brainstem involvement resulted in dysphagia, dysarthria, and respiratory failure with recurrent episodes of aspiration, respiratory insufficiency, desaturations, lack of respiratory drive, hypercapnia, and pneumonia. Treatment was symptomatic and included non-invasive ventilation, antibiotics, implantation of a percutaneous endoscopic gastrostomy, anti-seizure drugs, anti-dystonia medication, a cocktail of vitamins and antioxidants, and analgesics. Despite these measures, the outcome was poor as the patient died at the age of 62 months after being discharged to home palliative care. In summary, the m.13513G>A variant can manifest as MELAS/Leigh overlap syndrome with Leigh syndrome dominating. Because of brainstem involvement leading to respiratory dysfunction, dysarthria, and dysphagia, the outcome is poor, despite symptomatic measures.
PubMed: 35677009
DOI: 10.7759/cureus.24746 -
Molecular Genetics and Metabolism Jul 2022In patients with primary mitochondrial disease (MD), screening with electrocardiogram (ECG) and transthoracic echocardiography (TTE) is warranted according to current...
BACKGROUND
In patients with primary mitochondrial disease (MD), screening with electrocardiogram (ECG) and transthoracic echocardiography (TTE) is warranted according to current guidelines as structural cardiac abnormalities are frequent. This study aims to evaluate the cardiac phenotype of a large Dutch cohort of patients with MD and investigates whether ECG alone is sufficient for predicting structural cardiac abnormalities on TTE.
METHODS
In this retrospective cohort study, genetically confirmed MD patients >18 years old with an available ECG and TTE were included. Newcastle Mitochondrial Disease Scale for Adults (NMDAS) scores were assessed. ECG's were evaluated for rhythm and conduction disorders, voltage criteria for left ventricular hypertrophy (LVH) and repolarization disorders. Echocardiographic evaluation included left and right ventricular volumes and function, and presence of LVH or concentric remodeling.
RESULTS
In total, 200 MD patients were included with a median age of 45 years (IQR; 37-57) of whom 36% were male. Of all MD patients, 35% had abnormalities on ECG and 61% on TTE. Most frequent structural cardiac abnormalities on TTE were: global longitudinal strain > - 18% (54%), concentric remodeling (27%) and left ventricular (LV) ejection fraction <52% (14%). Patients with maternally inherited diabetes and deafness (MIDD) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) had the highest prevalence of ECG abnormalities (50% and 47%). TTE abnormalities were most prevalent in patients with MIDD (75%), followed by mitochondrial myopathy (MM) (55%), MELAS (47%) and Mitochondrial Epilepsy and Ragged Red Fibers (MERRF) (47%). MD patients with a high disease severity (NMDAS ≥21) had a higher prevalence of ECG abnormalities (44%, p = 0.039) and structural cardiac abnormalities (72%, p = 0.004) compared to patients with a NMDAS score of 11-20 and ≤ 10 (ECG: 34% and 19%; TTE: 63% and 39%). ECG abnormalities had a positive predictive value of 74% and a negative predictive value of 53% for structural cardiac abnormalities on TTE.
CONCLUSION
MD patients frequently have cardiac involvement especially patients with MIDD, MELAS or high NMDAS score. ECG as sole screening parameter is insufficient to detect structural cardiac abnormalities.
Topics: Deafness; Diabetes Mellitus, Type 2; Echocardiography; Electrocardiography; Female; Heart Defects, Congenital; Humans; Hypertrophy, Left Ventricular; MELAS Syndrome; Male; Mitochondrial Diseases; Prevalence; Retrospective Studies
PubMed: 35659503
DOI: 10.1016/j.ymgme.2022.05.004 -
JA Clinical Reports Jun 2022Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is characterized by cardiac depression, respiratory failure, myopathy,...
Remimazolam anesthesia for transcatheter mitral valve repair in a patient with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome: a case report.
BACKGROUND
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is characterized by cardiac depression, respiratory failure, myopathy, and anesthesia for affected patients is challenging. Although several anesthetics have been safely employed, there are no reports on remimazolam used in those patients.
CASE PRESENTATION
A 47-year-old male with MELAS syndrome was diagnosed with mitral regurgitation and scheduled for transcatheter mitral valve repair under general anesthesia. Anesthesia was induced with remimazolam and remifentanil (0.3 µg/kg/min). Remimazolam was administered at 12 mg/kg/h until loss of consciousness for approximately 1 min. Anesthesia was maintained with 1.1-1.2 mg/kg/h of remimazolam and 0.1 µg/kg/min of remifentanil without circulatory collapse or severe metabolic acidosis. The tracheal tube was removed in the operating room.
CONCLUSION
Remimazolam may be a new option for anesthesia for MELAS syndrome patients with depressed heart function.
PubMed: 35648295
DOI: 10.1186/s40981-022-00528-1 -
Medicina (Kaunas, Lithuania) May 2022a stroke-like lesion, the morphological equivalent of a stroke-like episode and the hallmark of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes...
OBJECTIVES
a stroke-like lesion, the morphological equivalent of a stroke-like episode and the hallmark of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome, have not been reported as manifestations of thiamine deficiency.
CASE REPORT
a 62-year-old man with a history of chronic alcoholism was admitted after a series of epileptic seizures. Upon waking up from the coma, he presented with disorientation, confusion, confabulation, psychomotor agitation, aggressiveness, right hemianopsia, aphasia, and right hemineglect over weeks. Electroencephalography showed a questionable focal status epilepticus over the left hemisphere, responsive to lorazepam and oxcarbazepine. Follow-up electroencephalographies no longer recorded epileptiform discharges. Cerebral magnetic resonance imaging (MRI) revealed T2-/diffusion weighted imaging (DWI) hyperintensity in the left occipito-temporal region that was not congruent to a vascular territory which persisted for at least nine weeks. Since a lactate-peak could be seen in this lesion by magnetic resonance-spectroscopy, this was interpreted as a stroke-like lesion. Since thiamine was reduced, the stroke-like lesion was attributed to thiamine deficiency after the exclusion of differential diseases, including MELAS and status epilepticus. The patient's behavioural and cognitive dysfunctions largely resolved upon vitamin-B1 substitution.
CONCLUSIONS
the case suggests that thiamine deficiency presumably causes mitochondrial dysfunction with cerebrospinal fluid lactic acidosis and a stroke-like lesion mimicking MELAS syndrome. It should be further studied whether nutritional deficits, such as thiamine deficiency, could give rise to secondary stroke-like lesions.
Topics: Acidosis, Lactic; Humans; MELAS Syndrome; Male; Middle Aged; Mitochondrial Encephalomyopathies; Status Epilepticus; Stroke; Thiamine Deficiency; Wernicke Encephalopathy
PubMed: 35630076
DOI: 10.3390/medicina58050660 -
The Journal of International Advanced... May 2022
Topics: Hearing; Hearing Tests; Humans; MELAS Syndrome
PubMed: 35608499
DOI: 10.5152/iao.2022.22750 -
Radiology Case Reports Jul 2022Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome presents with the features of herpes simplex encephalitis (HSE), which...
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome presents with the features of herpes simplex encephalitis (HSE), which is rare and has been described in only a few case reports. Our case describes a 17-year-old female with no significant previous medical history presenting with an acute onset of fever, headache, and epilepsy, similar to HSE. Computed tomography of the brain showed bilateral basal ganglia calcification. Magnetic resonance imaging demonstrated gyriform restricted diffusion with T2-weighted images prolongation. Further investigation showed elevated blood lactate concentration at rest. Hence, MELAS was suspected and the diagnosis was confirmed by the presence of a nucleotide 3243 A→G mutation in the mitochondrial DNA. The clinical presentation and imaging studies of MELAS are variable and may mimic those of HSE. Infection may have also precipitated MELAS manifestation in this patient. Laboratory features, such as elevated lactate, basal ganglia calcification, and gyriform restricted diffusion may be helpful in identifying patients with MELAS.
PubMed: 35601382
DOI: 10.1016/j.radcr.2022.04.019 -
Annals of Clinical and Translational... Jun 2022To examine the correlation between verbal and visual memory function and correlation with brain metabolites (lactate and N-Acetylaspartate, NAA) in individuals with...
OBJECTIVE
To examine the correlation between verbal and visual memory function and correlation with brain metabolites (lactate and N-Acetylaspartate, NAA) in individuals with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
METHODS
Memory performance and brain metabolites (ventricular lactate, occipital lactate, and occipital NAA) were examined in 18 MELAS, 58 m.3243A > G carriers, and 20 familial controls. Measures included the Selective Reminding Test (verbal memory), Benton Visuospatial Retention Test (visual memory), and MR Spectroscopy (NAA, Lactate). ANOVA, chi-squared/Fisher's exact tests, paired t-tests, Pearson correlations, and Spearman correlations were used.
RESULTS
When compared to carriers and controls, MELAS patients had the: (1) most impaired memory functions (Visual: p = 0.0003; Verbal: p = 0.02), (2) greatest visual than verbal memory impairment, (3) highest brain lactate levels (p < 0.0001), and (4) lowest brain NAA levels (p = 0.0003). Occipital and ventricular lactate to NAA ratios correlated significantly with visual memory performance (p ≤ 0.001). Higher lactate levels (p ≤ 0.01) and lower NAA levels (p = 0.0009) correlated specifically with greater visual memory dysfunction in MELAS. There was little or no correlation with verbal memory.
INTERPRETATION
Individuals with MELAS are at increased risk for impaired memory. Although verbal and visual memory are both affected, visual memory is preferentially affected and more clearly associated with brain metabolite levels. Preferential involvement of posterior brain regions is a distinctive clinical signature of MELAS. We now report a distinctive cognitive phenotype that targets visual memory more prominently and earlier than verbal memory. We speculate that this finding in carriers presages a conversion to the MELAS phenotype.
Topics: Brain; Humans; Lactic Acid; MELAS Syndrome; Phenotype; Stroke
PubMed: 35522125
DOI: 10.1002/acn3.51564 -
Molecular Genetics & Genomic Medicine Jul 2022Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the most well-known mitochondrial diseases, with most cases... (Review)
Review
BACKGROUND
Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome is one of the most well-known mitochondrial diseases, with most cases attributed to m.3243A>G. MELAS syndrome patients typically present in the first two decades of life with a broad, multi-systemic phenotype that predominantly features neurological manifestations--stroke-like episodes. However, marked phenotypic variability has been observed among paediatric patients, creating a clinical challenge and delaying diagnoses.
METHODS
A literature review of paediatric MELAS syndrome patients and a retrospective analysis in a UK tertiary paediatric neurology centre were performed.
RESULTS
Three children were included in this case series. All patients presented with seizures and had MRI changes not confined to a single vascular territory. Blood heteroplasmy varied considerably, and one patient required a muscle biopsy. Based on a literature review of 114 patients, the mean age of presentation is 8.1 years and seizures are the most prevalent manifestation of stroke-like episodes. Heteroplasmy is higher in a tissue other than blood in most cases.
CONCLUSION
The threshold for investigating MELAS syndrome in children with suspicious neurological symptoms should be low. If blood m.3243A>G analysis is negative, yet clinical suspicion remains high, invasive testing or further interrogation of the mitochondrial genome should be considered.
Topics: Acidosis, Lactic; Child; Humans; MELAS Syndrome; Retrospective Studies; Seizures; Stroke
PubMed: 35474314
DOI: 10.1002/mgg3.1955 -
Frontiers in Neurology 2022Verbal auditory agnosia is rarely caused by mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Lactate acidosis, which is the...
INTRODUCTION
Verbal auditory agnosia is rarely caused by mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome. Lactate acidosis, which is the adverse effect of metformin, has proposed links to mitochondrial dysfunction and may trigger clinical features of mitochondrial diseases.
CASE PRESENTATION
A 43-year-old right-handed man presented to our emergency department with acute onset fever and headache accompanied by impaired hearing comprehension. He could communicate well through handwritten notes but could not understand what others were saying. He had been diagnosed as having diabetes mellitus 2 months prior to this event. Vildagliptin 100 mg/day and metformin 1,700 mg/day were prescribed for glucose control. Laboratory tests revealed elevated lactate levels in serum and cerebrospinal fluid of the patient. Brain MRI disclosed bilateral temporal lesions. Acute encephalitis with temporal involved was initially diagnosed and acyclovir was given empirically. However, follow-up MRI after acyclovir treatment revealed a progression of prior lesions. Further mitochondrial genome analysis revealed a mitochondrial DNA point mutation at position 3,243 (m.3243A > G) with 25% heteroplasmy, which is compatible with MELAS. His clinical symptoms and serum lactate levels were improved after discontinuing the metformin use.
CONCLUSIONS
To our knowledge, this is the first report of a patient having late-onset MELAS syndrome that manifested as acute verbal auditory agnosia, which was identified after the patient began using metformin. Metformin is known to inhibit mitochondrial function and could trigger clinical features of MELAS syndrome. We encourage clinicians to maintain a high level of awareness that diabetes mellitus can be caused by mitochondrial disease and to exercise caution in the prescription of metformin.
PubMed: 35401420
DOI: 10.3389/fneur.2022.863047