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Brain & Development May 2009Severe myoclonic epilepsy (SMEI) or Dravet syndrome is caused by mutations of the SCN1A gene that encodes voltage-gated sodium channel alpha-1 subunit. Recently, we... (Review)
Review
Severe myoclonic epilepsy (SMEI) or Dravet syndrome is caused by mutations of the SCN1A gene that encodes voltage-gated sodium channel alpha-1 subunit. Recently, we generated and characterized a knock-in (KI) mice with an SCN1A nonsense mutation that appeared in three independent SMEI patients. The SCN1A-KI mice well reproduced the SMEI disease phenotypes. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. In heterozygous knock-in mice, trains of evoked action potentials in inhibitory neurons exhibited pronounced spike amplitude decrement late in the burst but not in pyramidal neurons. We further showed that in wild-type mice the Nav1.1 protein is expressed dominantly in axons and moderately in somata of parbalbumin (PV) - positive inhibitory interneurons. Our immunohistochemical observations of the Nav1.1 are clearly distinct to the previous studies, and our findings has corrected the view of the Nav1.1 protein distribution. The data indicate that Nav1.1 plays critical roles in the spike output from PV interneurons and further, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice. These information should contribute to the understanding of molecular pathomechanism of SMEI and to develop its effective therapies.
Topics: Action Potentials; Animals; Brain; Brain Chemistry; Disease Models, Animal; Epilepsies, Myoclonic; Genetic Predisposition to Disease; Humans; Infant; Interneurons; Mice; NAV1.1 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Neural Inhibition; Sodium Channels
PubMed: 19203854
DOI: 10.1016/j.braindev.2008.11.015 -
Brain & Development Nov 2001The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no... (Review)
Review
The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no etiology is found on imaging and metabolic studies, and genetic factors are important. Myoclonic-astatic epilepsy (MAE) and severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome, are epileptic encephalopathies where multiple seizure types begin in the first few years of life associated with developmental slowing. Clinical and molecular genetic studies of the families of probands with MAE and SMEI suggest a genetic basis. MAE was originally identified as part of the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus (GEFS(+)). Recent clinical genetic studies suggest that SMEI forms the most severe end of the spectrum of the GEFS(+). GEFS(+) has now been associated with molecular defects in three sodium channel subunit genes and a GABA subunit gene. Molecular defects of these genes have been identified in patients with MAE and SMEI. Interestingly, the molecular defects in MAE have been found in the setting of large GEFS(+) pedigrees, whereas, more severe truncation mutations arising de novo have been identified in patients with SMEI. It is likely that future molecular studies will shed light on the interaction of a number of genes, possibly related to the same or different ion channels, which result in a severe phenotype such as MAE and SMEI.
Topics: Epilepsies, Myoclonic; Epilepsy, Generalized; Humans; Infant; Mutation; Sodium Channels
PubMed: 11701287
DOI: 10.1016/s0387-7604(01)00272-8 -
Neuromuscular Disorders : NMD Oct 2022Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare inherited autosomal recessive disease due to bi-allelic mutations in the ASAH1 gene.... (Review)
Review
Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) is a rare inherited autosomal recessive disease due to bi-allelic mutations in the ASAH1 gene. SMA-PME is characterized by progressive muscle weakness from three to seven years of age, accompanied by epilepsy, intractable seizures, and sometimes sensorineural hearing loss. To the best of our knowledge, 47 cases have been reported. The present study reports five patients from four different families affected by SMA-PME characterized by progressive myoclonic epilepsy, proximal weakness, and lower motor neuron disease, as proven by electrodiagnostic studies. Genetic analysis identified two different mutations in the ASAH1 (NM_177924.4) gene, a previously reported pathogenic variant, c.125C>T (p.Thr42Met), and a novel likely pathogenic variant c.109C>A (p.Pro37Thr). In addition to reporting a novel pathogenic variant in the ASAH1 gene causing SMA-PME disease, this study compares the signs, phenotypic, and genetic findings of the case series with previous reports and discusses some symptomatic treatments.
Topics: Humans; Myoclonic Epilepsies, Progressive; Muscular Atrophy, Spinal; Mutation; Motor Neuron Disease
PubMed: 36309462
DOI: 10.1016/j.nmd.2022.08.002 -
Epilepsia Mar 2024KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a...
OBJECTIVE
KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort.
METHODS
Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized.
RESULTS
Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years).
SIGNIFICANCE
This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.
Topics: Adolescent; Child; Child, Preschool; Humans; Infant; Young Adult; Electroencephalography; Epilepsies, Myoclonic; Myoclonic Epilepsies, Progressive; Potassium Channels; Seizures; Unverricht-Lundborg Syndrome
PubMed: 38231304
DOI: 10.1111/epi.17880 -
Revista de NeurologiaThe purpose of this study is to survey the data from the literature on the subject of the possible genetic origin of severe myoclonic epilepsy in infancy (SMEI). (Review)
Review
AIMS
The purpose of this study is to survey the data from the literature on the subject of the possible genetic origin of severe myoclonic epilepsy in infancy (SMEI).
DEVELOPMENT
SMEI must inevitably be included within the phenotype of febrile seizures, which is made up of febrile seizures, febrile seizures plus, generalized epilepsy with febrile seizures plus, myoclonic astatic epilepsy and SMEI itself. We describe the five gene loci localized in children with febrile seizures (FEB 1 5), the three genes identified in patients with generalized epilepsy with febrile seizures plus (GEFS+ 1 3) and the de novo mutations of gene SCN1A that have been identified to date in children with SMEI.
CONCLUSIONS
SMEI, the severest form of the phenotypic spectrum of febrile seizures plus, is a channelopathy that is produced de novo, that is, during meiosis. Its prognosis may be conditioned by the kinds of mutations it is due to, and which are very different to those that induce other, more benign epileptic syndromes from the same phenotypic spectrum.
Topics: Chromosomes, Human; Epilepsies, Myoclonic; Humans; Infant; Phenotype; Seizures, Febrile; Sodium Channels
PubMed: 12861511
DOI: No ID Found -
Journal of Molecular Neuroscience : MN Sep 2021Progressive myoclonic epilepsy is a group of neurodegenerative diseases with complex clinical and genetic heterogeneity, which is associated with spontaneous or... (Review)
Review
Progressive myoclonic epilepsy is a group of neurodegenerative diseases with complex clinical and genetic heterogeneity, which is associated with spontaneous or action-induced myoclonus and progressive neurodegeneration. Since 2020, 4 families with progressive myoclonic epilepsy-11 [OMIM#618876] have been reported with a very limited spectrum of SEMA6B pathogenic variants. In our study, whole-exome sequencing was used in a proband from a nonconsanguineous Chinese family presenting with growth retardation and recurrent atonic seizures. A deletion mutation (c.1960_1978del, p.Leu654Argfs*25) in the last exon of SEMA6B was detected, which is a de novo variant and pathogenic. The new genetic evidence we reported here strengthened the gene-disease relationship, and the gene curation level between SEMA6B and progressive myoclonic epilepsy-11 became "strong" following the ClinGen SOP. Therefore, the results of this study broaden the mutation spectrum of SEMA6B in different ethnic groups and strengthen the gene-disease relationship between SEMA6B and progressive myoclonic epilepsy-11.
Topics: Child; Female; Gene Deletion; Humans; Myoclonic Epilepsies, Progressive; Phenotype; Semaphorins
PubMed: 34218423
DOI: 10.1007/s12031-021-01880-0 -
Epileptic Disorders : International... Sep 2016Progressive myoclonic epilepsy associated with KCTD7 mutations has been reported in 19 patients from 12 families. Patients show homozygous mutations in the coding... (Review)
Review
Progressive myoclonic epilepsy associated with KCTD7 mutations has been reported in 19 patients from 12 families. Patients show homozygous mutations in the coding regions of the KCTD7 gene. The disease starts in infancy. Patients typically show an initial severe epileptic disorder, with abundant epileptiform discharges on EEG and myoclonic seizures in the foreground, associated with cognitive regression and ataxia. Continuous multifocal myoclonus aggravated by action is observed in more than half of the cases. After a few years, the disease tends to stabilize and long survival can be expected. Some patients remain able to walk independently. The severity of the disease is variable from one patient to another, even within the same family. It is hypothesized that the epileptic disorder may influence the neurological regression observed in patients.
Topics: Humans; Myoclonic Epilepsies, Progressive; Potassium Channels
PubMed: 27629772
DOI: 10.1684/epd.2016.0856 -
A&A Practice Sep 2021
Topics: Documentation; Epilepsies, Myoclonic; Humans; MERRF Syndrome; Mutation
PubMed: 34529593
DOI: 10.1213/XAA.0000000000001525 -
Acta Neurologica Belgica Sep 2004'Severe myoclonic epilepsy in infancy' or Dravet syndrome is a clear example of the impact of severe epilepsy on the developing child. Presenting with febrile seizures... (Review)
Review
'Severe myoclonic epilepsy in infancy' or Dravet syndrome is a clear example of the impact of severe epilepsy on the developing child. Presenting with febrile seizures in infancy, children later on develop a severe epileptic syndrome with mental retardation. Nearly all children have life-threatening status epilepticus during the first two years of life. The clinical diagnosis can now be confirmed by DNA-analysis in a majority of patients. Most patients have a de novo mutation in the alfa subunit of the neuronal sodium channel SCN1A. In the past few years' treatment of severe myoclonic epilepsy in infancy has changed. Prevention of seizures, avoiding anti-epileptic drugs which only block sodium channels, a simple combination of two major anti-epileptic drugs (sodium valproate and topiramate) and a strict acute seizure treatment significantly improve the quality of life for these patients. Long-term follow up is necessary to evaluate if we can also improve the development possibilities for these children.
Topics: Child, Preschool; Electroencephalography; Epilepsies, Myoclonic; Humans; Infant
PubMed: 15508261
DOI: No ID Found -
Ugeskrift For Laeger Jan 1996Progressive myoclonic epilepsy (PME) is a syndrome characterized by myoclonias, epilepsy, progressive dementia and other neurological deficits. PME may be caused by... (Review)
Review
Progressive myoclonic epilepsy (PME) is a syndrome characterized by myoclonias, epilepsy, progressive dementia and other neurological deficits. PME may be caused by various, rare, incompletely elucidated genetic diseases, and is characterized by age at onset, duration, clinical and pathoanatomical abnormalities. There is ethnic and geographic variation in the frequency of the syndrome. The diseases are frequently autosomal recessive. Research in PME leads to a better understanding of the neurobiological processes of epilepsy. PME should be considered in cases of severe myoclonic epilepsy, progressive neurological disability and poor effect of antiepileptic treatment, and biopsies from skin, mucosa or muscle should be performed. Centralization of treatment of these rare diseases is recommended.
Topics: Adult; Child; Epilepsies, Myoclonic; Female; Humans; Male
PubMed: 8553486
DOI: No ID Found