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.

Late-onset mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and the role of serial imaging.

Mitochondria are essential for human metabolic function. Over 350 genetic mutations are associated with mitochondrial diseases, which are inherited in a matrilineal fashion. In mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), defective mitochondrial function and resultant impaired cellular energy production compromise vascular perfusion in affected tissues. Early diagnostic criteria suggested the diagnosis should be considered in those under 40. However, a broader range of phenotypes are now recognised, including those that present for the first time later in life. The primary presenting feature in MELAS is a stroke-like episode invariably resulting in patients undergoing neuroradiological imaging. We present a case of a woman with a first presentation of a stroke-like episode and seizures in her 40s who was eventually diagnosed with MELAS. We detail her clinical presentation, treatment and diagnosis, emphasising the role of serial imaging in her diagnosis.

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.

Clinical Reasoning: A 17-Year-Old Girl With Progressive Cognitive Impairment.

A 17-year-old girl presented with a long history of cognitive impairment, personality and behavioral changes, dysarthria, and paroxysmal lower-extremity weakness. She was initially suspected of having mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes because of stroke-like symptoms, such as episodic lower-extremity weakness, as well as abnormal brain MRI findings of generalized cerebral atrophy, extensive high-intensity lesions in the cortex and subcortical white matter on fluid-attenuated inversion recovery images, decreased N-acetyl aspartate/creatine ratio, and a lactate peak in the focal area on spectrum images. However, there were no relatives with similar presentations in the family of the patient. The whole mitochondrial genome and whole-exome sequencing did not suggest pathogenic mutations, and no abnormalities were found in the blood or CSF lactate levels. In this case, we detail the clinical manifestations, diagnostic workup, and imaging findings. This case highlights the importance of assessing cognitive function and the relevant differential diagnoses in an adolescent with cognitive impairment.

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.

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.

MELAS: Phenotype Classification into Classic-versus-Atypical Presentations.

BACKGROUND AND PURPOSE: An increased number of pathogenic variants have been described in mitochondrial encephalomyopathy lactic acidosis and strokelike episodes (MELAS). Different imaging presentations have emerged in parallel with a growing recognition of clinical and outcome variability, which pose a diagnostic challenge to neurologists and radiologists and may impact an individual patient's response to therapeutic interventions. By evaluating clinical, neuroimaging, laboratory, and genetic findings, we sought to improve our understanding of the sources of potential phenotype variability in patients with MELAS. MATERIALS AND METHODS: This retrospective single-center study included individuals who had confirmed mitochondrial DNA pathogenic variants and a diagnosis of MELAS and whose data were reviewed from January 2000 through November 2021. The approach included a review of clinical, neuroimaging, laboratory, and genetic data, followed by an unsupervised hierarchical cluster analysis looking for sources of phenotype variability in MELAS. Subsequently, experts identified "victory-variables" that best differentiated MELAS cohort clusters. RESULTS: Thirty-five patients with a diagnosis of mitochondrial DNA-based MELAS (median age, 12 years; interquartile range, 7-24 years; 24 female) were eligible for this study. Fifty-three discrete variables were evaluated by an unsupervised cluster analysis, which revealed that two distinct phenotypes exist among patients with MELAS. After experts reviewed the variables, they selected 8 victory-variables with the greatest impact in determining the MELAS subgroups: developmental delay, sensorineural hearing loss, vision loss in the first strokelike episode, Leigh syndrome overlap, age at the first strokelike episode, cortical lesion size, regional brain distribution of lesions, and genetic groups. Ultimately, 2-step differentiating criteria were defined to classify atypical MELAS. CONCLUSIONS: We identified 2 distinct patterns of MELAS: classic MELAS and atypical MELAS. Recognizing different patterns in MELAS presentations will enable clinical and research care teams to better understand the natural history and prognosis of MELAS and identify the best candidates for specific therapeutic interventions.

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.

Neuroimaging in mitochondrial disease.

The anatomic complexity of the brain in combination with its high energy demands makes this organ specifically vulnerable to defects of mitochondrial oxidative phosphorylation. Therefore, neurodegeneration is a hallmark of mitochondrial diseases. The nervous system of affected individuals typically shows selective regional vulnerability leading to distinct patterns of tissue damage. A classic example is Leigh syndrome, which causes symmetric alterations of basal ganglia and brain stem. Leigh syndrome can be caused by different genetic defects (>75 known disease genes) with variable disease onset ranging from infancy to adulthood. Other mitochondrial diseases are characterized by focal brain lesions, which is a core feature of MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). Apart from gray matter, also white matter can be affected by mitochondrial dysfunction. White matter lesions vary depending on the underlying genetic defect and may progress into cystic cavities. In view of the recognizable patterns of brain damage in mitochondrial diseases, neuroimaging techniques play a key role in diagnostic work-up. In the clinical setting, magnetic resonance imaging (MRI) and MR spectroscopy (MRS) are the mainstay of diagnostic work-up. Apart from visualization of brain anatomy, MRS allows the detection of metabolites such as lactate, which is of specific interest in the context of mitochondrial dysfunction. However, it is important to note that findings like symmetric basal ganglia lesions on MRI or a lactate peak on MRS are not specific, and that there is a broad range of disorders that can mimic mitochondrial diseases on neuroimaging. In this chapter, we will review the spectrum of neuroimaging findings in mitochondrial diseases and discuss important differential diagnoses. Moreover, we will give an outlook on novel biomedical imaging tools that may provide interesting insights into mitochondrial disease pathophysiology.

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

INTRODUCTION: 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. CASE REPORT: 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. CONCLUSION: 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.

Renal manifestations in adults with mitochondrial disease from the mtDNA m.3243A>G pathogenic variant.

Mitochondrial diseases are a phenotype and genotype heterogeneous group of disorders that typically have a multisystemic involvement. The m.3243A>G pathogenic variant is the most frequent mitochondrial DNA defect, and it causes several different clinical syndromes, such as mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS), and the maternally inherited diabetes and deafness (MIDD) syndromes. Not frequently reported, renal involvement in these diseases is probably underestimated, yet it increases morbidity. It generally manifests as subnephrotic proteinuria and progressive deterioration of kidney function. Adult presentation of mitochondrial diseases is hard to recognize, especially in oligosymptomatic patients or those with exclusive kidney involvement. However, suspicion should always arise when family history, particularly on the maternal side, and multisystemic symptoms, most often of the central nervous system and skeletal muscles, are present. In this review we discuss the clinical diagnosis and approach of patients with renal manifestations in the context of the mtDNA m.3243A>G pathogenic variant.

Impediments to Heart Transplantation in Adults With MELASMT-TL1:m.3243A>G Cardiomyopathy.

BACKGROUND: The heart is commonly involved in maternally inherited mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome caused by the MT-TL1 m.3243A>G mutation of the mitochondrial DNA. Heart transplantation (HTx) is controversial and has rarely been performed with conflicting results. OBJECTIVES: We analyzed factors preventing HTx in consecutive adult patients with MELASMT-TL1:m.3243A>G cardiomyopathy diagnosed and followed during the last 23 years in our HTx referral center. METHODS: The series consists of 14 unrelated adult probands who were referred for evaluation of cardiomyopathy from 1998 to 2021. None had a suspected diagnosis of MELAS before referral. All patients underwent clinical and genetic visit and counseling, mitochondrial DNA sequencing, cardiovascular investigation (including right heart catheterization and endomyocardial biopsy in 10), multidisciplinary assessment, and biochemical tests. Family screening identified 2 affected relatives. RESULTS: The cardiac phenotype was characterized by hypertrophic, concentric, nonobstructive cardiomyopathy that often evolved into a dilated cardiomyopathy-like phenotype. Of the 14 probands, 7 were potential candidates for HTx, 2 for heart and kidney Tx, and 1 was on the active HTx list for 3 years. None of the 10 probands underwent HTx. One is currently being evaluated for HTx. All had diabetes, hearing loss, and myopathy, and 10 had chronic kidney disease and progressive encephalomyopathy. During follow-up, 10 died from heart failure associated with multiorgan failure within 5 years of the genetic diagnosis. CONCLUSIONS: High risk of stroke-like episodes, chronic kidney disease, and wasting myopathy in MELASMT-TL1:m.3243A>G patients prevents activation of plans for HTx. As a result, the management of their cardiomyopathy in this syndromic context remains an unmet clinical need.

Delay in diagnosing a patient with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome who presented with status epilepticus and lactic acidosis: a case report.

BACKGROUND: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode syndrome is a rare mitochondrial genetic disorder that can present with a variety of clinical manifestations, including stroke, hearing loss, seizures, and lactic acidosis. The most common genetic mutation associated with this syndrome is M.3243A>G. The main underlying mechanism of the disease relates to protein synthesis, energy depletion, and nitric oxide deficiency. Controlling disease complications and improving patient quality of life are the primary aims of treatment options. CASE PRESENTATION: A 28-year-old Arabic female visited Al-Amiri Hospital in Kuwait. The patient was newly diagnosed with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode syndrome following her admission as a case of status epilepticus requiring further investigation. The patient's seizures were controlled, and she was evaluated to rule out the most serious complications by carrying out appropriate clinical, laboratory, and radiological imaging. The patient was discharged from the hospital after 2 weeks with a follow-up plan. CONCLUSION: This case report emphasizes the importance of considering mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episode syndrome as a potential cause of status epilepticus with lactic acidosis in a young female patient with a past history of stroke-like episodes. It also stresses the most important workup to rule out every possible life-threatening complication to improve patients' lives.