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Epileptic Disorders : International... Sep 2016Mitochondrial disorders is a group of clinical entities associated with abnormalities of the mitochondrial respiratory chain (MRC), which carries out the oxidative... (Review)
Review
Mitochondrial disorders is a group of clinical entities associated with abnormalities of the mitochondrial respiratory chain (MRC), which carries out the oxidative phosphorylation (OXPHOS) of ADP into ATP. As the MRC is the result of genetic complementation between two separate genomes, nuclear and mitochondrial, OXPHOS failure can derive from mutations in either nuclear-encoded, or mitochondrial-encoded, genes. Epilepsy is a relatively common feature of mitochondrial disease, especially in early-onset encephalopathies of infants and children. However, the two most common entities associated with epilepsy include MERRF, for Myoclonic Epilepsy with Ragged Red Fibers, and AHS, or Alpers-Huttenlocher syndrome, also known as hepatopathic poliodystrophy. Whilst MERRF is a maternally inherited condition caused by mtDNA mutations, particularly the 8344A>G substitution in the gene encoding mt-tRNA, AHS is typically caused by recessive mutations in POLG, encoding the catalytic subunit of polymerase gamma, the only mtDNA polymerase in humans. AHS is the most severe, early-onset, invariably fatal syndrome within a disease spectrum, which also include other epileptogenic entities, all due to POLG mutations and including Spino-cerebellar Ataxia and Epilepsy (SCAE). This review reports the main clinical, neuroimaging, biochemical, and molecular features of epilepsy-related mitochondrial syndrome, particularly MERRF and AHS.
Topics: Diffuse Cerebral Sclerosis of Schilder; Humans; MERRF Syndrome
PubMed: 27618766
DOI: 10.1684/epd.2016.0846 -
Polish Journal of Pathology : Official... 2020The interesting case about a patients with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome due to the variant m.8344A>G with a heteroplasmy rate of 95%...
The interesting case about a patients with myoclonic epilepsy with ragged-red fibers (MERRF) syndrome due to the variant m.8344A>G with a heteroplasmy rate of 95% reported by Felczak et al. expands the phenotypic spectrum of MERRF syndrome. The authors reported a pituitary adenoma, calcium deposits in arterial walls, and an intra-cerebral lipoma in the corpus callosum in their patient. Shortcomings of the study are that the diagnostic criteria for MERRF were not accomplished, that the patient should be rather diagnosed as a mitochondrial, multiorgan disorder syndrome (MIMODS), that no pedigree and heteroplasmy rates in first degree relative were provided, that hormone levels were not provided despite obvious endocrinological involvement, and that no serum or cerebrospinal fluid (CSF) lactate levels were reported.
Topics: DNA, Mitochondrial; Humans; MERRF Syndrome; Mutation; Pedigree
PubMed: 33112121
DOI: 10.5114/pjp.2020.99797 -
Nucleic Acids Research Aug 2023Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes...
Mutations in mitochondrial (mt-)tRNAs frequently cause mitochondrial dysfunction. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and myoclonus epilepsy associated with ragged red fibers (MERRF) are major clinical subgroups of mitochondrial diseases caused by pathogenic point mutations in tRNA genes encoded in mtDNA. We previously reported a severe reduction in the frequency of 5-taurinomethyluridine (τm5U) and its 2-thiouridine derivative (τm5s2U) in the anticodons of mutant mt-tRNAs isolated from the cells of patients with MELAS and MERRF, respectively. The hypomodified tRNAs fail to decode cognate codons efficiently, resulting in defective translation of respiratory chain proteins in mitochondria. To restore the mitochondrial activity of MELAS patient cells, we overexpressed MTO1, a τm5U-modifying enzyme, in patient-derived myoblasts. We used a newly developed primer extension method and showed that MTO1 overexpression almost completely restored the τm5U modification of the MELAS mutant mt-tRNALeu(UUR). An increase in mitochondrial protein synthesis and oxygen consumption rate suggested that the mitochondrial function of MELAS patient cells can be activated by restoring the τm5U of the mutant tRNA. In addition, we confirmed that MTO1 expression restored the τm5s2U of the mutant mt-tRNALys in MERRF patient cells. These findings pave the way for epitranscriptomic therapies for mitochondrial diseases.
Topics: Humans; DNA, Mitochondrial; MELAS Syndrome; MERRF Syndrome; Mitochondria; Mutation; RNA, Transfer
PubMed: 36928678
DOI: 10.1093/nar/gkad139 -
Journal of Biomedical Science Aug 2023Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNA...
BACKGROUND
Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare inherited mitochondrial disease mainly caused by the m.8344A > G mutation in mitochondrial tRNA gene, and usually manifested as complex neurological disorders and muscle weakness. Currently, the pathogenic mechanism of this disease has not yet been resolved, and there is no effective therapy for MERRF syndrome. In this study, MERRF patients-derived iPSCs were used to model patient-specific neurons for investigation of the pathogenic mechanism of neurological disorders in mitochondrial disease.
METHODS
MERRF patient-derived iPSCs were differentiated into excitatory glutamatergic neurons to unravel the effects of the m.8344A > G mutation on mitochondrial bioenergetic function, neural-lineage differentiation and neuronal function. By the well-established differentiation protocol and electrophysiological activity assay platform, we examined the pathophysiological behaviors in cortical neurons of MERRF patients.
RESULTS
We have successfully established the iPSCs-derived neural progenitor cells and cortical-like neurons of patients with MERRF syndrome that retained the heteroplasmy of the m.8344A > G mutation from the patients' skin fibroblasts and exhibited the phenotype of the mitochondrial disease. MERRF neural cells harboring the m.8344A > G mutation exhibited impaired mitochondrial bioenergetic function, elevated ROS levels and imbalanced expression of antioxidant enzymes. Our findings indicate that neural immaturity and synaptic protein loss led to the impairment of neuronal activity and plasticity in MERRF neurons harboring the m.8344A > G mutation. By electrophysiological recordings, we monitored the in vivo neuronal behaviors of MERRF neurons and found that neurons harboring a high level of the m.8344A > G mutation exhibited impairment of the spontaneous and evoked potential-stimulated neuronal activities.
CONCLUSIONS
We demonstrated for the first time the link of mitochondrial impairment and synaptic dysfunction to neurological defects through impeding synaptic plasticity in excitatory neurons derived from iPSCs of MERRF patients harboring the m.8344A > G mutation. This study has provided new insight into the pathogenic mechanism of the tRNA gene mutation of mtDNA, which is useful for the development of a patient-specific iPSCs platform for disease modeling and screening of new drugs to treat patients with MERRF syndrome.
Topics: Humans; MERRF Syndrome; RNA, Transfer, Lys; Neurons; Mitochondria; Neural Stem Cells
PubMed: 37605213
DOI: 10.1186/s12929-023-00966-8 -
Developmental Period Medicine 2015Mitochondrial disorders (MD) represent a clinically, biochemically and genetically heterogeneous group of diseases associated with dysfunction of the oxidative... (Review)
Review
Mitochondrial disorders (MD) represent a clinically, biochemically and genetically heterogeneous group of diseases associated with dysfunction of the oxidative phosphorylation system and pyruvate dehydrogenase complex. Our aim was to illustrate the most common clinical presentation of MD on the example of selected diseases and syndromes. The minimal prevalence of MD is estimated as 1 to 5,000. MD may manifest at any age since birth until late-adulthood with acute manifestation or as a chronic progressive disease. Virtually any organ may be impaired, but the organs with the highest energetic demands are most frequently involved, including brain, muscle, heart and liver. Some MD may manifest as a characteristic cluster of clinical features (e.g. MELAS syndrome, Kearns-Sayre syndrome). Diagnostics includes detailed history, the comprehensive clinical examination, results of specialized examinations (especially cardiology, visual fundus examination, brain imaging, EMG), laboratory testing of body fluids (lactate, aminoacids, organic acids), and analysis of bioptic samples of muscle, skin, and liver, eventually. Normal lactate level in blood does not exclude the possibility of MD. Although the aimed molecular genetic analyses may be indicated in some of mitochondrial diseases, the methods of next generation sequencing come into focus. Examples of treatment are arginine supplementation in MELAS syndrome, ketogenic diet in pyruvate oxidation disorders or quinone analogs in patients with LHON. Conclusion: The clinical suspicion of a mitochondrial disorder is often delayed, or the disease remains undiagnosed. The correct diagnosis and adequate treatment can improve prognosis of the patient. Access to genetic counseling is also of great importance.
Topics: Brain; DNA, Mitochondrial; Electroencephalography; Humans; Kearns-Sayre Syndrome; MELAS Syndrome; MERRF Syndrome; Mitochondrial Diseases; Mitochondrial Encephalomyopathies; Mitochondrial Myopathies
PubMed: 26982751
DOI: No ID Found -
Case Reports in Neurological Medicine 2020Although endocrinologic involvement and epilepsy are frequent features of myoclonic epilepsy with ragged-red fibers (MERRF), polycystic ovary syndrome (PCOS) and...
OBJECTIVES
Although endocrinologic involvement and epilepsy are frequent features of myoclonic epilepsy with ragged-red fibers (MERRF), polycystic ovary syndrome (PCOS) and photosensitive epilepsy have not been reported. . A 32-year-old female was diagnosed with MERRF at age 19 y upon presence of the four canonical features and the variant m.8344A > G in () (blood heteroplasmy rate: 50%). She experienced recurrent photosensitive focal and generalised seizures since age 19 y, which could be triggered by flickering light or by looking at small stones, leaves, or dirty snow on the ground. Since the last 42 months, she was seizure-free upon levetiracetam (4000 mg/d), clonazepam (1.5 mg/d), and topiramate (25 mg/d). Additionally, she suffered from secondary amenorrhoea since adolescence. She was married between ages 19 y and 25 y but did not get pregnant. PCOS was diagnosed and treated with desogestrel plus estradiol. Nonetheless, the course was progressive, particularly with regard to ataxia, myocloni, and myopathy.
CONCLUSIONS
The phenotypic spectrum of MERRF is broader than anticipated and may additionally include PCOS and photosensitive epilepsy. PCOS in MERRF may respond to hormone substitution and photosensitive epilepsy to levetiracetam, clonazepam, and topiramate.
PubMed: 33062354
DOI: 10.1155/2020/8876272 -
Journal of Neuromuscular Diseases 2020Neuropathies in Myoclonic Epilepsy with Ragged Red Fibers (MERRF) syndrome are frequent but ganglionopathies have never been reported. We retrospectively identified 24...
Neuropathies in Myoclonic Epilepsy with Ragged Red Fibers (MERRF) syndrome are frequent but ganglionopathies have never been reported. We retrospectively identified 24 patients with MERRF mutations in the neuromuscular center Nord/Est/Ile de France (Pitié-Salpêtrière, Paris, France). Seventeen nerve conduction studies (NCS) were available. Five patients had MERRF syndrome and ganglionopathy, a pure sensory neuropathy. All of them displayed ataxia and mild clinical sensory abnormalities. Ganglionopathies have been reported in mitochondrial diseases but never in MERRF syndrome. We suggest that patients presenting with ganglionopathy, especially if associated with myopathy, lipomatosis or epilepsy, should be screened for MERRF mutations.
Topics: Adult; Ataxia; Ganglia, Spinal; Humans; MERRF Syndrome; Neural Conduction; Peripheral Nervous System Diseases; Retrospective Studies; Sensation Disorders
PubMed: 32538863
DOI: 10.3233/JND-200513 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2023Patients with epilepsy who have also hearing loss represent a distinct group of patients, often with aggravated medical history, comorbidities and high potential for...
Patients with epilepsy who have also hearing loss represent a distinct group of patients, often with aggravated medical history, comorbidities and high potential for disability. The etiopathogenetic factors of epilepsy and hearing loss may be common to these conditions (neuroinfections, craniocerebral injuries, cerebral circulatory disorders, perinatal pathology, etc.). In addition, these two syndromes may occur as part of hereditary diseases, so their timely recognition and genetic diagnosis are important for determining further medical and genetic prognosis. This article provides an overview of orphan genetic diseases associated with epilepsy and hearing loss - MERRF syndrome, MELAS syndrome, EAST syndrome, Ayme-Grippsyndrome, epilepsy, hearing loss and mental retardation syndromes, associated with mutations in SPATA5 gene, DOOR syndrome, Gustavson syndrome.
Topics: Humans; Deafness; Epilepsy; Epileptic Syndromes; Hearing Loss; Hearing Loss, Sensorineural; Mutation
PubMed: 36719116
DOI: 10.17116/jnevro202312301128 -
Arquivos de Neuro-psiquiatria Oct 2014Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disorder. Diagnostic criteria for MERRF include typical manifestations of the... (Review)
Review
Myoclonic epilepsy associated with ragged red fibers (MERRF) is a rare mitochondrial disorder. Diagnostic criteria for MERRF include typical manifestations of the disease: myoclonus, generalized epilepsy, cerebellar ataxia and ragged red fibers (RRF) on muscle biopsy. Clinical features of MERRF are not necessarily uniform in the early stages of the disease, and correlations between clinical manifestations and physiopathology have not been fully elucidated. It is estimated that point mutations in the tRNALys gene of the DNAmt, mainly A8344G, are responsible for almost 90% of MERRF cases. Morphological changes seen upon muscle biopsy in MERRF include a substantive proportion of RRF, muscle fibers showing a deficient activity of cytochrome c oxidase (COX) and the presence of vessels with a strong reaction for succinate dehydrogenase and COX deficiency. In this review, we discuss mainly clinical and laboratory manifestations, brain images, electrophysiological patterns, histology and molecular findings as well as some differential diagnoses and treatments.
Topics: Diagnosis, Differential; Humans; MERRF Syndrome
PubMed: 25337734
DOI: 10.1590/0004-282x20140124 -
Orphanet Journal of Rare Diseases Oct 2023Mitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic...
BACKGROUND
Mitochondrial Diseases (MDs) are a diverse group of neurometabolic disorders characterized by impaired mitochondrial oxidative phosphorylation and caused by pathogenic variants in more than 400 genes. The implementation of next-generation sequencing (NGS) technologies helps to increase the understanding of molecular basis and diagnostic yield of these conditions. The purpose of the study was to investigate diagnostic and genotypic spectrum in patients with suspected MD. The comprehensive analysis of mtDNA variants using Sanger sequencing was performed in the group of 83 unrelated individuals with clinically suspected mitochondrial disease. Additionally, targeted next generation sequencing or whole exome sequencing (WES) was performed for 30 patients of the study group.
RESULTS
The overall diagnostic rate was 21.7% for the patients with suspected MD, increasing to 36.7% in the group of patients where NGS methods were applied. Mitochondrial disease was confirmed in 11 patients (13.3%), including few classical mitochondrial syndromes (MELAS, MERRF, Leigh and Kearns-Sayre syndrome) caused by pathogenic mtDNA variants (8.4%) and MDs caused by pathogenic variants in five nDNA genes. Other neuromuscular diseases caused by pathogenic variants in seven nDNA genes, were confirmed in seven patients (23.3%).
CONCLUSION
The wide spectrum of identified rare mitochondrial or neurodevelopmental diseases proves that MD suspected patients would mostly benefit from an extensive genetic profiling allowing rapid diagnostics and improving the care of these patients.
Topics: Humans; Mutation; Mitochondrial Diseases; DNA, Mitochondrial; Mitochondria; Genotype
PubMed: 37784170
DOI: 10.1186/s13023-023-02921-0