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(a) Brain MRI T2‐weighted sequences showing progressive generalised atrophy and reciprocal dilatation of the ventricular system over 5 years: (i) 4 years after initial presentation; (ii) 9 years after initial presentation, following second emergency surgery. Multiple old signal abnormalities are present in bilateral basal ganglia, bilateral occipital lobes and right insula. (b) Histology slides of a muscle biopsy: (i) subsarcolemmal Gomori positivity forming the RRFs characteristic of mitochondrial cytopathy (×60 magnification); (ii) H&E staining showing muscle fibres, with a clear surrounding rim, that vary in size, as well as basophilic stippling (×40 magnification). (c) Electron microscopy at (i) ×15,000 magnification and (ii) ×40,000 magnification, both showing subsarcolemmal mitochondria with abnormal forms
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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 neurologi...
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Background
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a group of maternally inherited disorders caused by mutations or deletions in mitochondrial genes with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes as the main clinical manifestations.
Case presentation
We reported a 20...
Citations
... We ruled out pseudohypoparathyroidism due to resistance to the action of parathyroid hormone with hypocalcemia, hyperphosphatemia, and elevated PTH levels, [16] whereas our patient exhibited a low PTH level. Additionally, MELAS syndrome typically manifests in childhood, [17] which contrasts with our patient's presentation. While congenital disorders such as carbonic anhydrase deficiency due to tuberous sclerosis complex should be considered for differential diagnosis, the absence of skin hypopigmented macules and patches, or tumors associated with tuberous sclerosis [18] was not observed in our patient. ...
Rationale
Fahr syndrome is a rare, degenerative neurological condition characterized by bilateral idiopathic calcification of the periventricular region, especially the basal ganglia. This condition is often misdiagnosed as other neurological or psychiatric disorders due to its rarity and overlapping symptoms.
Patient concerns
A 34-year-old man had been experiencing seizures and cognitive dysfunction for few years, which were further compounded by slurred speech and motor difficulties as acute conditions.
Diagnosis
After investigations, severe hypocalcemia, and hypoparathyroidism were detected and his brain computed tomography showed extensive bilateral calcifications in basal ganglia, thalamus, dentate nuclei, and some parts of subcortical white matter, suggestive of Fahr syndrome. Although, the patient was initially misdiagnosed due to a lack of information and the rarity of this disease.
Intervention
The patient was treated with intravenous calcium gluconate, vitamin D3, l -ornithine l -aspartate syrup, and levetiracetam, replacing carbamazepine.
Outcome
His symptoms, including slurred speech, muscle pain, and stiffness improved, serum calcium normalized, and he was discharged with medications for memory deficit and depression.
Lessons
This case underscores the importance of raising awareness among physicians, especially in areas with limited medical resources, about the significance of prompt diagnosis and appropriate symptomatic treatment in enhancing patient prognosis and quality of life.
... However, degree of heteroplasmy alone falls short to explain the phenotypic diversity we observe. This has been shown in mtATP6-associated disorders [40,41] as well as in m.3243A>G (MT-TL)-associated phenotypes [42]. ...
Our understanding of rare disease genetics has been shaped by a monogenic disease model. While the traditional monogenic disease model has been successful in identifying numerous disease-associated genes and significantly enlarged our knowledge in the field of human genetics, it has limitations in explaining phenomena like phenotypic variability and reduced penetrance. Widening the perspective beyond Mendelian inheritance has the potential to enable a better understanding of disease complexity in rare disorders. Digenic inheritance is the simplest instance of a non-Mendelian disorder, characterized by the functional interplay of variants in two disease-contributing genes. Known digenic disease causes show a range of pathomechanisms underlying digenic interplay, including direct and indirect gene product interactions as well as epigenetic modifications. This review aims to systematically explore the background of digenic inheritance in rare disorders, the approaches and challenges when investigating digenic inheritance, and the current evidence for digenic inheritance in mitochondrial disorders.
... [4] Diagnosis is confirmed by finding a pathogenic mutation in one of the mitochondrial genes: MT-TL1 (the most common) and MT-ND5. [5] However, these genes are not included in most HCM or DCM panels. Treatment options include general considerations, such as GDMT, but also specific recommendations, namely, avoiding mitochondrion toxic drugs and situations which further aggravate the metabolic impairment to such an extent that they can become lethal. ...
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.
... Utilization of both nuclear and mitochondrial genomes to encode oxidative phosphorylation protein complexes leads to issues if mtDNA mutations are prevalent. The most common mtDNA mutations result in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), described as a point mutation A3243G in the tRNA-Leu gene [32]. Furthermore, mitochondrial tRNA gene mutations are responsible for a wide variety of human diseases [33]. ...
It is well known that muscular dystrophy disease severity is controlled by genetic modifiers. The expectation is that by identifying these modifiers, we can illuminate additional therapeutic targets with which to combat the disease. To this end we have been investigating the MRL mouse strain, which is highly resistant to muscular dystrophy-mediated fibrosis. The MRL mouse strain contains two mitochondrial-encoded, naturally occurring heteroplasmies: T3900C in tRNA-Met, and variable adenine insertions at 9821 in tRNA-Arg. Heteroplasmies are mitochondrial mutations that are variably present in a cell’s mitochondria. Therefore, MRL cells can contain 0 to 100% of each mitochondrial mutation. We have chosen the severely affected ϒ-sarcoglycan (Sgcg–/–) deficient mice on the DBA2/J background as our muscular dystrophy model to demonstrate the effects of these mitochondrial heteroplasmies on disease severity. Mice from the (Sgcg–/–) DBA2/J (D) and wildtype MRL (M) strains were crossed for more than 10 generations to establish two separate, pure breeding mouse lines: Sgcg+/–NucDMito%M and Sgcg+/–NucMMito%M. The Sgcg–/– mice from these separate lines were analyzed at 8 weeks old for membrane permeability, hydroxyproline content, pAMPK content, fibronectin content, and percentage of each heteroplasmy. We have identified that the MRL mitochondrial mutation T3900C confers a portion of the fibrosis resistance identified in the MRL mouse strain. These results have been extended to significantly correlate increased MRL mitochondria with increased pAMPK and decreased muscular dystrophy fibrosis. The beneficial mechanisms controlled by the MRL mitochondria will be discussed. We are establishing metabolic aspects of muscular dystrophy pathogenesis. These metabolic pathways will now be investigated for therapeutic targets.
... Relevant manifestations are: firstly, recurrent stroke-like episodes in the brain, leading to progressive and permanent neurological dysfunction and dementia, migraine-type headaches, vomiting, seizures, and lactic acidosis. Other symptoms may include PEO (progressive external ophthalmoplegia), muscle weakness, exercise intolerance, hearing loss, diabetes, and short stature [18,19]. ...
Mitochondrial myopathies represent a heterogeneous group of diseases caused mainly by genetic mutations to proteins that are related to mitochondrial oxidative metabolism. Meanwhile, a similar etiopathogenetic mechanism (i.e., a deranged oxidative phosphorylation and a dramatic reduction of ATP synthesis) reveals that the evolution of these myopathies show significant differences. However, some physiological and pathophysiological aspects of mitochondria often reveal other potential molecular mechanisms that could have a significant pathogenetic role in the clinical evolution of these disorders, such as: i. a deranged ROS production both in term of signaling and in terms of damaging molecules; ii. the severe modifications of nicotinamide adenine dinucleotide (NAD)+/NADH, pyruvate/lactate, and α-ketoglutarate (α-KG)/2- hydroxyglutarate (2-HG) ratios. A better definition of the molecular mechanisms at the basis of their pathogenesis could improve not only the clinical approach in terms of diagnosis, prognosis, and therapy of these myopathies but also deepen the knowledge of mitochondrial medicine in general.
(1) Background: Chronic progressive external ophthalmoplegia (CPEO) is a rare disorder that can be at the forefront of several mitochondrial diseases. This review overviews mitochondrial CPEO encephalomyopathies to enhance accurate recognition and diagnosis for proper management. (2) Methods: This study is conducted based on publications and guidelines obtained by selective review in PubMed. Randomized, double-blind, placebo-controlled trials, Cochrane reviews, and literature meta-analyses were particularly sought. (3) Discussion: CPEO is a common presentation of mitochondrial encephalomyopathies, which can result from alterations in mitochondrial or nuclear DNA. Genetic sequencing is the gold standard for diagnosing mitochondrial encephalomyopathies, preceded by non-invasive tests such as fibroblast growth factor-21 and growth differentiation factor-15. More invasive options include a muscle biopsy, which can be carried out after uncertain diagnostic testing. No definitive treatment option is available for mitochondrial diseases, and management is mainly focused on lifestyle risk modification and supplementation to reduce mitochondrial load and symptomatic relief, such as ptosis repair in the case of CPEO. Nevertheless, various clinical trials and endeavors are still at large for achieving beneficial therapeutic outcomes for mitochondrial encephalomyopathies. (4) Key Messages: Understanding the varying presentations and genetic aspects of mitochondrial CPEO is crucial for accurate diagnosis and management.
El síndrome de encefalomiopatía mitocondrial, acidosis láctica y episodio tipo ictus (stroke-like), también denominada MELAS por sus siglas en inglés, es una patología poco conocida; sin embargo, es la enfermedad mitocondrial más frecuente. Esta patología es hereditaria, multisistémica y progresiva. Presentamos el caso de una adolescente de 14 años, diagnosticada de MELAS en el HSVP (Hospital San Vicente de Paúl) en base de los criterios clínicos del Comité del Grupo de Estudio MELAS Japón – 2012. La paciente presentó desde los 10 años episodios de cefalea, vómitos y crisis tónico-clónicas generalizadas, a los 13 años presentó hipoacusia neurosensorial bilateral, a los 14 años presentó crisis focales clónicas, hiperlactatemia e imagen de infarto temporo- parietal izquierda en resonancia magnética cerebral. Desde nuestra perspectiva el síndrome MELAS todavía es poco conocido y el diagnostico llega a ser tardío. Este síndrome tiene un compromiso predominantemente neurológico, provoca discapacidad y elevada mortalidad. En este artículo se presenta un caso clínico que invita a conocer y profundizar sobre esta patología.
Mitochondrial dysfunction, especially perturbation of oxidative phosphorylation and adenosine triphosphate (ATP) generation, disrupts cellular homeostasis and is a surprisingly frequent cause of central and peripheral nervous system pathology. Mitochondrial disease is an umbrella term that encompasses a host of clinical syndromes and features caused by in excess of 300 different genetic defects affecting the mitochondrial and nuclear genomes. Patients with mitochondrial disease can present at any age, ranging from neonatal onset to late adult life, with variable organ involvement and neurological manifestations including neurodevelopmental delay, seizures, stroke-like episodes, movement disorders, optic neuropathy, myopathy, and neuropathy. Until relatively recently, analysis of skeletal muscle biopsy was the focus of diagnostic algorithms, but step-changes in the scope and availability of next-generation sequencing technology and multiomics analysis have revolutionized mitochondrial disease diagnosis. Currently, there is no specific therapy for most types of mitochondrial disease, although clinical trials research in the field is gathering momentum. In that context, active management of epilepsy, stroke-like episodes, dystonia, brainstem dysfunction, and Parkinsonism are all the more important in improving patient quality of life and reducing mortality.
While epigenetic modifications of DNA and histones play main roles in gene transcription regulation, recently discovered post-transcriptional RNA modifications, known as epitranscriptomic modifications, have been found to have a profound impact on gene expression by regulating RNA stability, localization and decoding efficiency. Importantly, genetic variations or environmental perturbations of epitranscriptome modifiers (that is, writers, erasers and readers) are associated with obesity and metabolic diseases, such as type 2 diabetes. The epitranscriptome is closely coupled to epigenetic signalling, adding complexity to our understanding of gene expression in both health and disease. Moreover, the epitranscriptome in the parental generation can affect organismal phenotypes in the next generation. In this Review, we discuss the relationship between epitranscriptomic modifications and metabolic diseases, their relationship with the epigenome and possible therapeutic strategies.
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.
