Adult-onset mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): a diagnostic challenge.

Rare causes of stroke-like presentations can be difficult to diagnose. We report a case of a man in his 40s who first presented with stroke symptoms, but whose clinical course was not typical for a stroke. A detailed investigation of the patient's medical history revealed bilateral sensorineural hearing loss which prompted a wider diagnostic assessment.Furthermore, lack of vascular risk factors and a normal angiogram strengthened our suspicion of an unusual underlying condition. Raised lactic acid levels and genetic analysis confirmed a diagnosis of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome.

Bilateral cochlear implants in a MELAS patient.

BACKGROUND: Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disease that affects various systems in the body, particularly the brain, nervous system, and muscles. Among these systems, sensorineural hearing loss is a common additional symptom. METHODS: A 42-year-old female patient with MELAS who experienced bilateral profound deafness and underwent bilateral sequential cochlear implantation (CIs). Speech recognition and subjective outcomes were evaluated. RESULTS: Following the first CI follow-up, the patient exhibited improved speech recognition ability and decided to undergo the implantation of the second ear just two months after the initial CI surgery. The second CI also demonstrated enhanced speech recognition ability. Subjective outcomes were satisfactory for bilateral CIs. CONCLUSIONS: MELAS patients receiving bilateral CIs can attain satisfactory post-CI speech recognition, spatial hearing, and sound qualities.

A case of exacerbated encephalopathy with stroke-like episodes and lactic acidosis triggered by metformin in a patient with MELAS.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited multisystemic disorder caused by mutations in mitochondrial DNA that result in cellular energy deficiency. MELAS affects the most metabolically active organs, including the brain, skeletal muscles, cochlea, retina, heart, kidneys, and pancreas. As a result, about 85% of carriers of m.3243A > G, the most common mutation in MELAS, develop diabetes by the age of 70. Although metformin is the most widely prescribed drug for diabetes, its usefulness in mitochondrial dysfunction remains controversial. Here, we present the case of a 32-year-old Korean patient diagnosed with MELAS who presented with exacerbated stroke-like episodes and lactic acidosis triggered by metformin.

Heteroplasmic pathogenic m.12315G>A variant in MT-TL2 presenting with MELAS syndrome and depletion of nitric oxide donors.

The MT-TL2 m.12315G>A pathogenic variant has previously been reported in five individuals with mild clinical phenotypes. Herein we report the case of a 5-year-old child with heteroplasmy for this variant who developed neurological regression and stroke-like episodes similar to those observed in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Biochemical evaluation revealed depletion of arginine on plasma amino acid analysis and low z-scores for citrulline on untargeted plasma metabolomics analysis. These findings suggested that decreased availability of nitric oxide may have contributed to the stroke-like episodes. The use of intravenous arginine during stroke-like episodes and daily enteral L-citrulline supplementation normalized her biochemical values of arginine and citrulline. Untargeted plasma metabolomics showed the absence of nicotinamide and 1-methylnicotinamide, and plasma total glutathione levels were low; thus, nicotinamide riboside and N-acetylcysteine therapies were initiated. This report expands the phenotype associated with the rare mitochondrial variant MT-TL2 m.12315G>A to include neurological regression and a MELAS-like phenotype. Individuals with this variant should undergo in-depth biochemical analysis to include untargeted plasma metabolomics, plasma amino acids, and glutathione levels to help guide a targeted approach to treatment.

Prolonged misdiagnosis of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome: A case report.

RATIONALE: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a subset of rare mitochondrial diseases characterized by diverse clinical manifestations, which often complicates its diagnosis. PATIENT CONCERNS: This report chronicles the experiences of a 14-year-old female patient who underwent multiple misdiagnoses before the eventual identification of MELAS syndrome. Her journey began with symptoms that included growth retardation, hypertrophic cardiomyopathy, and epilepsy. DIAGNOSIS: The definitive diagnosis of MELAS syndrome was established through genetic confirmation, revealing a mutation in the MT-TL1 gene (m.3242A > G). INTERVENTIONS: Upon diagnosis, the patient received targeted symptomatic treatment, which led to pronounced improvements in her symptoms. OUTCOMES: The patient's condition stabilized with the administered treatments, and she exhibited significant symptom relief, emphasizing the importance of accurate diagnosis and timely intervention. LESSONS: This case underscores the imperative for heightened clinical vigilance and thorough differential diagnosis in the face of complex clinical presentations, such as those seen in MELAS syndrome, to ensure timely and appropriate interventions.

The mitochondrial tRNA MT-TW m.5537_5538insT variant presents with significant intra-familial clinical variability.

Mitochondrial disorders can present with a wide range of clinical and biochemical phenotypes. Mitochondrial DNA variants may be influenced by factors such as degree of heteroplasmy and tissue distribution. We present a four-generation family in which 10 individuals carry a pathogenic mitochondrial variant (m.5537_5538insT, MT-TW gene) with differing levels of heteroplasmy and clinical features. This genetic variant has been documented in two prior reports, both in individuals with Leigh syndrome. In the current family, three individuals have severe mitochondrial symptoms including Leigh syndrome (patient 1, 100% in blood), MELAS (patient 2, 97% heteroplasmy in muscle), and MELAS-like syndrome (patient 3, 50% heteroplasmy in blood and 100% in urine). Two individuals have mild mitochondrial symptoms (patient 4, 50% in blood and 67% in urine and patient 5, 50% heteroplasmy in blood and 30% in urine). We observe that this variant is associated with multiple mitochondrial presentations and phenotypes, including MELAS syndrome for which this variant has not previously been reported. We also demonstrate that the level of heteroplasmy of the mitochondrial DNA variant correlates with the severity of clinical presentation; however, not with the specific mitochondrial syndrome.

Neuropathological hallmarks in autopsied cases with mitochondrial diseases caused by the mitochondrial 3243A>G mutation.

The mitochondrial (m.) 3243A>G mutation is known to be associated with various mitochondrial diseases including mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Their clinical symptoms have been estimated to occur with an increased mitochondrial DNA (mtDNA) heteroplasmy and reduced activity of oxidative phosphorylation (OXPHOS) complexes, but their trends in the central nervous system remain unknown. Six autopsied mutant cases and three disease control cases without the mutation were enrolled in this study. The mutant cases had a disease duration of 1-27 years. Five of six mutant cases were compatible with MELAS. In the mutant cases, cortical lesions including a laminar necrosis were frequently observed in the parietal, lateral temporal, and occipital lobes; less frequently in the frontal lobe including precentral gyrus; and not at all in the medial temporal lobe. The mtDNA heteroplasmy in brain tissue samples of the mutant cases was strikingly high, ranging from 53.8% to 85.2%. The medial temporal lobe was preserved despite an inhospitable environment having high levels of mtDNA heteroplasmy and lactic acid. OXPHOS complex I was widely decreased in the mutant cases. The swelling of smooth muscle cells in the vessels on the leptomeninges, with immunoreactivity (IR) against mitochondria antibody, and a decreased nuclear/cytoplasmic ratio of choroidal epithelial cells were observed in all mutant cases but in none without the mutation. Common neuropathological findings such as cortical laminar necrosis and basal ganglia calcification were not always observed in the mutant cases. A high level of mtDNA heteroplasmy was observed throughout the brain in spite of heterogeneous cortical lesions. A lack of medial temporal lesion, mitochondrial vasculopathy in vessels on the leptomeninges, and an increased cytoplasmic size of epithelial cells in the choroid plexus could be neuropathological hallmarks helpful in the diagnosis of mitochondrial diseases.

Infraclavicular Catheter in MELAS Syndrome for Analgesic Purposes.

MELAS syndrome is defined as mitochondrial myopathy accompanied by encephalopathy, lactic acidosis, myoclonus, stroke-like episodes. It has a progressive course, multi-systemic effects and severe complications. Myoclonic contractions are unresponsive to many anti-epileptic drugs; these contractions and spasms may lead to severe pain. Systemic analgesic drugs are not sufficient to control pain. Therefore, continuous brachial plexus blockage may be preferred. Infraclavicular brachial plexus catheter is placed in our case. Local anesthetic injections through this catheter may be effective in pain management and results are to be discussed here.

Diffuse posterior leukoencephalopathy in MELAS without stroke-like episodes: A case report.

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.

[Therapeutics for Mitochondrial Encephalomyopathy].

In MELAS, taurine modification defect in the anticodon of mitochondrial leucine tRNA causes codon translation failure. An investigator-started clinical trials of high-dose taurine therapy, that showed its efficacy in preventing stroke-like episodes, and improving the taurine modification rate. The drug was found to be safe. Taurine has been approved as a drug covered by public insurance for prevention of stroke-like episodes since 2019. Recently, L-arginine hydrochloride has also been approved for off-label use as a treatment for both acute and intermittent stages of stroke-like episodes.

The Possible Role of COVID-19 in the Triggering of Underlying Mitochondrial Dysfunction in MELAS Syndrome, A Brief Report of three cases.

BACKGROUND: During corona virus pandemic, various neurological complications of COVID-19 have been reported. Recent studies demonstrated different pathophysiology for neurological manifestations of COVID-19 such as mitochondrial dysfunction and damage to cerebral vasculature. In addition, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder with a variety of neurological symptoms. In this study, we aim to assess a potential predisposition in mitochondrial dysfunction of COVID-19, leading to MELAS presentation. METHODS: We studied three previously healthy patients with the first presentation of acute stroke-like symptoms, following COVID-19 infection. We analyzed the patients' clinical data and brain magnetic resonance imaging (MRI) lesions that presented to the neurological center of a university-affiliated hospital in Tehran, Iran, from September 2020 to August 2021. RESULTS: All cases are characterized by a temporoparietal abnormality in imaging studies and electroencephalogram (EEG). Based on electrodiagnostic tests, three patients were diagnosed with myopathy. In two brothers with relatively the same symptoms, one performed muscle biopsy finding myopathic process, and genetic testing confirmed a 3243A>G point mutation in a heteroplasmic state in one of our patients. CONCLUSION: Although MELAS is not a prevalent condition, the recent increase in the number of these patients in our center might indicate the potential role of COVID-19 in triggering the silent pre- existing mitochondrial dysfunction in these patients.

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes diagnosed after metformin-triggered stroke-like episodes.

A 40-year-old man with sensorineural hearing loss and diabetes mellitus was hospitalized with acute-onset impaired consciousness and clumsiness in his left hand. He had been taking metformin for 4 months. A neurological examination revealed confusion and weakness in the left upper limb. Increased lactate levels were detected in the serum and cerebrospinal fluid. Magnetic resonance imaging revealed lesions in the right parietal and bilateral temporal lobes with a lactate peak in magnetic resonance spectroscopy. Finally, we made a genetic diagnosis of mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes based on the detection of m.3243A>G. It is well-known that metformin should not be administered in patients with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes because metformin inhibits mitochondrial function and triggers stroke-like episodes. However, our patient was diagnosed with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes after metformin administration. Thus, we encourage physicians to exercise caution in the prescription of metformin in patients with short stature, sensorineural hearing loss, or young-onset diabetes mellitus because these patients may have undiagnosed mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes.

Clinical score for early diagnosis and treatment of stroke-like episodes in MELAS syndrome.

BACKGROUND AND OBJECTIVES: Stroke-like episodes (SLEs) in patients with MELAS syndrome are often initially misdiagnosed as acute ischemic stroke (AIS), resulting in treatment delay. We aimed to determine clinical features that may distinguish SLEs from AISs and explore the benefit of early L-arginine treatment on patient outcomes. METHODS: We looked retrospectively for MELAS patients admitted between January 2005 and January 2022 and compared them to an AIS cohort with similar lesion topography. MELAS patients who received L-arginine within 40 days of their first SLE were defined as the early treatment group and the remaining as late or no treatment group. RESULTS: Twenty-three SLEs in 10 MELAS patients and 21 AISs were included. SLE patients had significantly different features: they were younger, more commonly reported hearing loss, lower body mass index, had more commonly a combination of headache and/or seizures at presentation, serum lactate was higher, and hemiparesis was less common. An SLE Early Clinical Score (SLEECS) was constructed by designating one point to each above features. SLEECS ≥ 4 had 80% sensitivity and 100% specificity for SLE diagnosis. Compared to late or no treatment, early treatment group patients (n = 5) had less recurrent SLEs (total 2 vs. 11), less seizures (14% vs. 25%, p = 0.048), lower degree of disability at first and last follow-up (modified ranking scale, mRS 2 ± 0.7 vs. 4.2 ± 1, p = 0.005; 2 ± 0.7 vs. 5.8 ± 0.5, p < 0.001, respectively), and a lower mortality (0% vs. 80% p = 0.048). CONCLUSIONS: The SLEECS model may aid in the early diagnosis and treatment of SLEs and lead to improved clinical outcomes.

Stroke-like episodes in adult mitochondrial disease.

Stroke-like episode is a paroxysmal neurological manifestation which affects a specific group of patients with mitochondrial disease. Focal-onset seizures, encephalopathy, and visual disturbances are prominent findings associated with stroke-like episodes, with a predilection for the posterior cerebral cortex. The most common cause of stroke-like episodes is the m.3243A>G variant in MT-TL1 gene followed by recessive POLG variants. This chapter aims to review the definition of stroke-like episode and delineate the clinical phenomenology, neuroimaging and EEG findings typically seen in patients. In addition, several lines of evidence supporting neuronal hyper-excitability as the key mechanism of stroke-like episodes are discussed. The management of stroke-like episodes should focus on aggressive seizure management and treatment for concomitant complications such as intestinal pseudo-obstruction. There is no robust evidence to prove the efficacy of l-arginine for both acute and prophylactic settings. Progressive brain atrophy and dementia are the sequalae of recurrent stroke-like episode, and the underlying genotype in part predicts prognosis.

Clinical features of epileptic seizures in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes.

BACKGROUND AND PURPOSE: This study aimed to characterize the clinical features of epilepsy in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and analyze the clinical determinants for drug-resistant epilepsy in MELAS. METHODS: A single-center, retrospective study was conducted to investigate the clinical features of epilepsy in patients with MELAS. Collected variables included seizure semiology, electroencephalography (EEG), muscle biopsy, genetic testing, neuroimaging findings, resting serum lactic value and modified Rankin scale (mRS) of patients with MELAS. We also investigated the differences between the adult-onset group and the child-onset group and analyzed the risk factors for drug-resistant epilepsy in MELAS. RESULTS: We studied 97 patients (56 males: 41 females) with confirmed MELAS. Epileptic seizure occurred in 100.0% of patients and the initial symptom of 69.1% patients was epileptic seizure. The average age of disease onset was 21.0 years, ranging from 2 to 60 years. The seizure types of these patients with MELAS were variable, with generalized onset (51.5%) to be the most common type. The EEG changes in the patients with MELAS were mainly slow wave (90.9%) and epileptiform discharge (68.2%). The child-onset group with earlier seizure onset presented significantly higher resting serum lactic value (p = 0.0048) and lower incidence of stroke-like lesion in the brain (p = 0.003), especially in the temporal lobe (p < 0.001), compared with the adult-onset group. Importantly, drug-resistant epilepsy in MELAS was demonstrated to be closely related to the earlier age of seizure onset (p = 0.013), as well as the higher mRS score (p < 0.001) and higher resting serum lactic value (p = 0.009). CONCLUSION: Early identification of MELAS should be considered among individuals with recurrent epilepsy through clinical screening. Age of seizure onset and resting serum lactic value may predict the development of drug-resistant epilepsy in MELAS. Close observation and appropriate anti-epileptic treatment are indispensable for individuals with MELAS to improve the prognosis. Further studies with larger sample size are required to further evaluate the risk factors of drug-resistant epilepsy in MELAS and provide guidance on treatment of MELAS.