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Expert Opinion on Pharmacotherapy Jul 2019Epilepsy is a prominent feature of myoclonic epilepsy with ragged-red fibers (MERRF)-syndrome. The most frequent seizure type is myoclonic seizures, of which the... (Review)
Review
INTRODUCTION
Epilepsy is a prominent feature of myoclonic epilepsy with ragged-red fibers (MERRF)-syndrome. The most frequent seizure type is myoclonic seizures, of which the treatment is challenging and empiric.
AREAS COVERED
Herein, the author summarises and discusses previous and recent findings of antiepileptic drug (AED) treatment in MERRF-syndrome.
EXPERT OPINION
MERRF-syndrome is a predominantly maternally inherited, multisystem mitochondrial disorder caused by pathogenic variants predominantly of the mitochondrial DNA (mtDNA). Canonical clinical features of MERRF include myoclonus, epilepsy, ataxia, and myopathy. Additionally, other manifestations in the CNS, peripheral nerves, eyes, ears, heart, gastrointestinal tract, and endocrine organs may occur (MERRF-plus). Today, MERRF is considered rather as myoclonic ataxia than as myoclonic epilepsy. Genotypically, MERRF is due to mutations in 13 mtDNA-located genes and 1 nDNA-located gene. According to the modified Smith-score, the strongest gene-disease relationship exists for , and . Epilepsy is the second most frequent phenotypic feature of MERRF. Seizure-types associated with MERRF include focal myoclonic, focal clonic, and focal atonic seizures, generalized myoclonic, tonic-clonic, atonic, and myoclonic-atonic seizures, or typical absences. Treatment of myoclonic epilepsy relies on expert judgments recommending levetiracetam, together with clonazepam, or topiramate, zonisamide, or piracetam in monotherapy as the first line AEDs.
Topics: Anticonvulsants; Epilepsy; Humans; MERRF Syndrome; Mutation; Seizures
PubMed: 31063406
DOI: 10.1080/14656566.2019.1609941 -
Seizure Aug 2017Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare syndromic mitochondrial disorder (MID) with a broad phenotypic but narrow genotypic heterogeneity.... (Review)
Review
Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is a rare syndromic mitochondrial disorder (MID) with a broad phenotypic but narrow genotypic heterogeneity. One of the predominant phenotypic features in addition to myopathy is epilepsy. The most frequent seizure type in MERRF is generalised myoclonic seizure but also focal myoclonic, focal atonic, generalised tonic-clonic, generalised atonic, generalised myoclonic-atonic, typical absences, or tonic-clonic seizures of unknown onset have been reported. There are no guidelines available for the management of epilepsy in MERRF syndrome but several expert opinions and general recommendations for the treatment of mitochondrial epilepsy have been published. According to these recommendations the antiepileptic drugs (AEDs) of choice are levetiracetam, topiramate, zonisamide, piracetam, and benzodiazepines. Perampanel has not been applied in MERRF patients but is promising in non-mitochondrial myoclonic epilepsy. Mitochondrion-toxic agents, including mitochondrion-toxic AEDs, such as valproate, carbamazepine, phenytoin, and barbiturates, should be avoided as well as AEDs potentially enhancing the frequency of myoclonus, such as phenytoin, carbamazepine, lamotrigine, vigabatrin, tiagabine, gabapentin, pregabalin, and oxcarbazepine.
Topics: Anticonvulsants; Epilepsy; Humans; MERRF Syndrome
PubMed: 28686997
DOI: 10.1016/j.seizure.2017.06.010 -
Hearing Research Oct 2023Mitochondrial encephalomyopathy is a multi-system disorder mostly caused by inborn errors of the oxidative phosphorylation (OXPHOS) system and usually manifested as... (Review)
Review
Identification of new variants in MTRNR1 and MTRNR2 genes using whole mitochondrial genome sequencing in a Taiwanese family with MERRF (myoclonic epilepsy with ragged-red fibers) syndrome.
Mitochondrial encephalomyopathy is a multi-system disorder mostly caused by inborn errors of the oxidative phosphorylation (OXPHOS) system and usually manifested as complex neurological disorder and muscle weakness. Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome is one of the major subtypes of mitochondrial disease associated with the m.8344A>G mutation in mitochondrial tRNA gene. In addition to the symptoms in central nervous and muscle systems, a portion of the patients may develop hearing loss, which has been linked to the genetic mutations of mitochondrial DNA (mtDNA) especially in the mitochondrial ribosome RNA (rRNA) gene. Despite a great number of studies focusing on the consequences of mtDNA mutations, the mechanism of pathogenesis of these overt diseases has remained unclear, and there is no specific and effective treatment for MERRF syndromes. In this study, we developed a high-quality mtDNA sequencing method by next generation sequencing technology to search for the additional pathogenic variations of mtDNA from skin fibroblasts of four members in a Taiwanese family with MERRF syndrome. Through uncovering the signatures of all mtDNA variants in the MERRF family, we identified novel mtDNA variants in the genes encoding mitochondrial 12S and 16S rRNAs. The finding from this study will give us further insight into the molecular mechanisms driving the phenotypic variability and timing of onset of the MERRF syndrome.
Topics: Humans; MERRF Syndrome; Genome, Mitochondrial; Mitochondria; DNA, Mitochondrial; Mutation
PubMed: 37683310
DOI: 10.1016/j.heares.2023.108876 -
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 -
International Journal of Molecular... Oct 2022Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect... (Review)
Review
Primary mitochondrial diseases are relatively common inborn errors of energy metabolism, with a combined prevalence of 1 in 4300. These disorders typically affect tissues with high energy requirements, including the brain. Epilepsy affects >1% of the worldwide population, making it one of the most common neurological illnesses; it may be the presenting feature of a mitochondrial disease, but is often part of a multisystem clinical presentation. The major genetic causes of mitochondrial epilepsy are mutations in mitochondrial DNA and in the nuclear-encoded gene POLG. Treatment of mitochondrial epilepsy may be challenging, often representing a poor prognostic feature. This narrative review will cover the most recent advances in the field of mitochondrial epilepsy, from pathophysiology and genetic etiologies to phenotype and treatment options.
Topics: Humans; Neurologists; Mitochondrial Diseases; DNA, Mitochondrial; Epilepsy; Mitochondria; Mutation
PubMed: 36362003
DOI: 10.3390/ijms232113216 -
European Annals of Otorhinolaryngology,... Apr 2019Patients with MERRF syndrome (Myoclonic Epilepsy with Ragged Red Fibres) usually present with encephalomyopathy. However, progressive, recurrent cervicothoracic...
INTRODUCTION
Patients with MERRF syndrome (Myoclonic Epilepsy with Ragged Red Fibres) usually present with encephalomyopathy. However, progressive, recurrent cervicothoracic lipomatosis may be rarely observed.
CASE REPORT
The authors report 4 cases of MERRF syndrome associated with lipomatosis. In 3 patients, the diagnosis of MERRF syndrome was established on the basis of the clinical features of the lipomas and clinical interview revealing a personal or family history of lipomas and myopathy.
DISCUSSION
In the presence of extensive spinal lipomatosis, the presence of other clinical signs of MERRF syndrome in the patient or the patient's family must be investigated. A diagnosis of MERRF syndrome can guide appropriate genetic counselling.
Topics: Adult; Female; Humans; Lipomatosis; MERRF Syndrome; Male; Middle Aged; Neck; Siblings; Spinal Neoplasms; Thorax
PubMed: 30409749
DOI: 10.1016/j.anorl.2018.10.015 -
Molecular Neurobiology Jun 2010Myoclonic epilepsy and ragged-red fibers (MERRF) syndrome is a rare disorder characterized by myoclonus, muscle weakness, cerebellar ataxia, heart conduction block, and... (Review)
Review
Myoclonic epilepsy and ragged-red fibers (MERRF) syndrome is a rare disorder characterized by myoclonus, muscle weakness, cerebellar ataxia, heart conduction block, and dementia. It has been documented that 80-90% of the patients with MERRF syndrome are caused by the A8344G mutation in the tRNA(Lys) gene of mitochondrial DNA (mtDNA). We and other investigators have reported that the mtDNA mutation results in not only inefficient generation of adenosine triphosphate but also increased production of reactive oxygen species (ROS) in cultured cells harboring A8344G mutation of mtDNA. In addition, we found an imbalance in the gene expression of antioxidant enzymes in the skin fibroblasts of MERRF patients. The mRNA, protein, and enzyme activity levels of manganese-superoxide dismutase were increased, but those of Cu,Zn-SOD, catalase, and glutathione peroxidase did not show significant changes. Recently, we showed that the excess ROS could damage voltage-dependent anion channel, prohibitin, Lon protease, and aconitase in the MERRF cells. Moreover, there was a dramatic increase in the gene expression and activity of matrix metalloproteinase 1, which may contribute to the cytoskeleton remodeling involved in the weakness and atrophy of muscle commonly seen in MERRF patients. Taken together, we suggest that mtDNA mutation-elicited oxidative stress, oxidative damage, and altered gene expression are involved in the pathogenesis and progression of MERRF syndrome.
Topics: Antioxidants; Cell Respiration; Cells, Cultured; Cytoskeleton; DNA Damage; DNA, Mitochondrial; Fibroblasts; Gene Expression; Humans; MERRF Syndrome; Matrix Metalloproteinase 1; Mitochondrial Diseases; Mitochondrial Proteins; Mutation; Oxidative Phosphorylation; Oxidative Stress; Reactive Oxygen Species
PubMed: 20411357
DOI: 10.1007/s12035-010-8123-7 -
Reproductive Sciences (Thousand Oaks,... May 2023Polycystic ovary syndrome (PCOS) is a multi-causal condition. Among the genetic causes, variations in the mitochondrial DNA (mtDNA) are increasingly recognised as... (Review)
Review
Polycystic ovary syndrome (PCOS) is a multi-causal condition. Among the genetic causes, variations in the mitochondrial DNA (mtDNA) are increasingly recognised as causative. PCOS not only occurs in known syndromic mitochondrial disorders due to pathogenic variants in the mtDNA but also in non-syndromic mitochondrial disorders. Additionally, mtDNA variants not causing a multi-system mitochondrial disorder but exclusively PCOS have been reported. Among the syndromic mitochondrial disorders, PCOS has been described in myoclonic epilepsy with ragged-red fibre (MERRF) syndrome. Among the non-syndromic mitochondrial disorders, PCOS has been described in association with insulin resistance. Several other studies suggest that mtDNA point mutations or mtDNA deletions can be associated with PCOS without manifesting in organs other than the ovaries. Evidence from animal studies suggests that function, morphology, and biogenesis of mitochondria in ovarian tissue are generally impaired in PCOS patients. In conclusion, there is increasing evidence that mtDNA variants play a pathophysiological role in the development of PCOS. Further studies are needed to establish the causal link between mtDNA variants and PCOS.
Topics: Female; Humans; Animals; Polycystic Ovary Syndrome; Mitochondria; DNA, Mitochondrial; Mitochondrial Diseases
PubMed: 36221022
DOI: 10.1007/s43032-022-01100-z