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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder characterized by seizures, myoclonus and progression to cerebellar ataxia. EPM1 arises due to mutations in the cystatin B (CSTB) gene which encodes a cysteine proteinase inhibitor. Only a minority of EPM1 alleles carry point mutations, while the majority contain large expansions of the dodecamer CCCCGCCCCGCG repeat which is present at two to three copies in normal individuals. The dodecamer repeat is located in the 5' flanking region of the CSTB gene, presumably in its promoter. The pathological repeat expansion results in a reduction in CSTB mRNA, which may be cell specific. To elucidate the mechanism of this reduction of gene expression, we have studied the putative CSTB promoter in vitro. A 3.8 kb fragment, containing the putative promoter with a 600 bp repeat expansion, showed a 2- to 4-fold reduction in luciferase activity compared with an identical fragment with a normal repeat; this reduction was observed only in certain cell types. Introduction of heterologous DNA fragments of 730 and 1000 bp into the normal promoter, instead of the repeat expansion, showed similarly reduced activity. Terminal deletions of the promoter implicate a putative AP-1 binding site, upstream of the repeat, in CSTB transcription activation. We propose that a novel mechanism of pathogenesis, the altering of the spacing of transcription factor binding sites from each other and/or the transcription initiation site due to repeat expansion, is among the causes of reduction in CSTB expression and thus EPM1.
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PMID:Altered spacing of promoter elements due to the dodecamer repeat expansion contributes to reduced expression of the cystatin B gene in EPM1. 1044 45

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1) is characterized by onset at age 6-15 years, stimulus-sensitive myoclonus, tonic-clonic seizures, and typical EEG findings, with marked sensitivity to photic stimulation. Previously the course of the disease was progressive throughout the life, and no biochemical or pathologic marker existed for the diagnosis of EPM1. With modern anticonvulsive therapy, the prognosis has improved significantly, the symptoms are nowadays relatively well controlled, and the disease may not always progress. Moreover, the molecular genetic findings have now made possible an etiologic diagnosis of EPM1. The positional cloning strategy was applied to identify the gene whose defects are responsible for EPM1. The underlying gene encodes cystatin B, a cysteine protease inhibitor. The major mutation worldwide is an unstable expansion of a dodecamer minisatellite repeat unit in the promoter region of the cystatin B gene. In addition, five "minor" mutations have been described. Cystatin B mutations are now known to account for both Mediterranean myoclonus and for "Baltic" myoclonus, described mainly from Finland, thus solving a long-term controversy and proving that these two disorders are one single disease entity. The pathogenetic mechanisms in EPM1 are yet unknown, but in the majority of patients, a reduced level of the cystatin B gene product seems to be the primary mechanism in the pathology. Understanding the molecular pathogenesis of EPM1 may lead to the development of specific therapies for the disease.
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PMID:Progressive myoclonus epilepsy of Unverricht-Lundborg type. 1044 47

Among the epilepsies, the progressive myoclonus epilepsies (PMEs) form a heterogeneous group of rare diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration, particularly dementia and ataxia. The success of the Human Genome Project and the fact that most PMEs are inherited through a mendelian or mitochondrial mode have resulted in important advances in the definition of the molecular basis of PME. The gene defects for the most common forms of PME (Unverricht-Lundborg disease, the neuronal ceroid lipofuscinoses, Lafora disease, type I sialidosis, and myoclonus epilepsy with ragged-red fibers) have been either identified or mapped to specific chromosome sites. Unverricht-Lundborg disease has been shown to be caused by mutations in the gene that codes for cystatin B, an inhibitor of cysteine protease. The most common mutation in Unverricht-Lundborg disease is an expansion of a dodecamer repeat located in a noncoding region upstream of the transcription start site of the cystatin B gene, making it the first human disease associated with instability of a dodecamer repeat. Juvenile neuronal ceroid lipofuscinosis is caused by mutations in the CLN3 gene, a gene of unknown function that encodes a 438-amino-acid protein of possible mitochondrial location. Other forms of neuronal ceroid lipofuscinosis that occur as PME and Lafora disease have been mapped by means of linkage analysis, but the corresponding gene defects remain unknown. Sialidosis has been shown to be caused by mutations in the sialidase gene, and myoclonus epilepsy with ragged-red fibers is well known to be caused by mutations in the mitochondrial gene that codes for tRNA(Lys). How the different PME gene defects described produce the various PME phenotypes, including epileptic seizures, remains unknown. The development of animal models that bear these mutations is needed to increase our knowledge of the basic mechanisms involved in the PMEs. This knowledge should lead to the development of new and effective forms of therapy, which are especially lacking for the PMEs.
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PMID:The molecular genetic bases of the progressive myoclonus epilepsies. 1051 28

Progressive myoclonic epilepsies are rare, genetically transmitted diseases characterized by epileptic seizures, myoclonus, and progressive neurologic deterioration. Unverricht-Lundborg disease, Lafora's disease, neuronal ceroid lipofuscinosis, mitochondrial disorders, and sialidosis are included in this group. Lafora's disease is a progressive disorder of the central nervous system with onset in the late first or second decade of life and is inherited in an autosomal-recessive pattern. The first clinical manifestation is generalized tonic-clonic seizures, myoclonus, or both, usually seen between the ages of 11 and 18 years. The other clinical manifestations are progressive dementia and limb ataxia. Diagnosis is based on showing the typical inclusions in the brain, liver, skin, or muscle tissue specimens. The case of a 6-year-old male patient, who was admitted with the clinical findings of third-degree atrioventricular block and dementia and eventually diagnosed with Lafora's disease, is presented.
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PMID:A case of Lafora's disease associated with cardiac arrhythmia. 1059 53

Loss of function mutations in the gene encoding the cysteine protease inhibitor, cystatin B (CSTB), are responsible for the primary defect in human progressive myoclonus epilepsy (EPM1). CSTB inhibits the cathepsins B, H, L and S by tight reversible binding, but little is known regarding its localization and physiological function in the brain and the relation between the depletion of the CSTB protein and the clinical symptoms in EPM1. We have analysed the expression of mRNA and protein for CSTB in the adult rat brain using in situ hybridization and immunocytochemistry. In the control brains, the CSTB gene was differentially expressed with the highest levels in the hippocampal formation and reticular thalamic nucleus, and moderate levels in amygdala, thalamus, hypothalamus and cortical areas. Detectable levels of CSTB were found in virtually all forebrain neurons but not in glial cells. Following 40 rapidly recurring seizures evoked by hippocampal kindling stimulations, CSTB mRNA expression showed marked bilateral increases in the dentate granule cell layer, CA1 and CA4 pyramidal layers, amygdala, and piriform and parietal cortices. Maximum levels were detected at 6 or 24 h, and expression had reached control values at 1 week post-seizures. The changes of mRNA expression were accompanied by transient elevations (at 6-24 h) of CSTB protein in the same brain areas. These findings demonstrate that seizure activity leads to rapid and widespread increases of the synthesis of CSTB in forebrain neurons. We propose that the upregulation of CSTB following seizures may counteract apoptosis by binding cysteine proteases.
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PMID:Seizures induce widespread upregulation of cystatin B, the gene mutated in progressive myoclonus epilepsy, in rat forebrain neurons. 1079 46

A genetic contribution to aetiology is estimated to be present in up to 40% of patients with epilepsy. It is useful to categorise genetic epilepsies according to the mechanisms of inheritance into Mendelian disorders, non-mendelian or 'complex' disorders, and chromosomal disorders. Over 200 Mendelian diseases include epilepsy as part of the phenotype, and the genes for a number of these have been identified recently. These include autosomal recessive progressive myoclonic epilepsies such as Unverricht-Lundborg disease, Lafora disease and the neuronal ceroid lipofuscinoses, and three autosomal dominant idiopathic epilepsies. The last named have been shown to arise from mutations in ion channel genes. Autosomal dominant nocturnal frontal lobe epilepsy is caused by mutations in CHRNA4, benign familial neonatal convulsions by mutations in KCNQ2 and KCNQ3, and generalised epilepsy with febrile seizures plus by mutations in SCN1B. 'Complex', familial epilepsies are more difficult to analyse, but evidence has been obtained for loci predisposing to juvenile myoclonic epilepsy on chromosome 6p and 15q. Lastly, the genes underlying several spike-wave epilepsies in mice have been cloned, and three of these encode sub-units of voltage-gated calcium channels.
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PMID:Impact of our understanding of the genetic aetiology of epilepsy. 1089 63

Our understanding of the genetic basis of epilepsy is progressing at a rapid pace. Gene mutations causing several of the inherited epilepsies have been mapped, and several more are likely to be added in coming years. In this review, we summarize the available information on the genetic basis of human epilepsies and epilepsy syndromes, emphasizing how genetic defects may correlate with the pathophysiological mechanisms of brain hyperexcitability. Mutations leading to epilepsy have been identified in genes encoding voltage- and ligand-gated ion channels (benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, generalized epilepsy with febrile seizures "plus"), neurotransmitter receptors (Angelman syndrome), the molecular cascade of cellular energy production (myoclonic epilepsy with ragged red fibers), and proteins without a known role in neuronal excitability (Unverricht-Lundborg disease). Gene defects can lead to epilepsy by altering multiple and diverse aspects of neuronal function.
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PMID:Epilepsy genes: the link between molecular dysfunction and pathophysiology. 1110 93

The aim of this paper is to report a patient with late-onset myoclonic epilepsy in Down's syndrome (LOMEDS) as a differential diagnosis of adult-onset progressive myoclonic epilepsies. A 55-year-old male with Down's syndrome (DS) is described who developed progressively frequent myoclonus and generalized myoclonic-tonic seizures (GMTSs) at the age of 52. EEG recordings demonstrated background slowing and generalized polyspike-wave discharges occasionally associated with myoclonic jerks, leading to the classification of primary generalized epileptic myoclonus. Descriptions of late-onset epilepsy in DS patients are rare. However, a review of the pertinent literature revealed at least two other cases of elderly DS patients developing progressive myoclonic epilepsy after the onset of dementia. We suggest that late-onset myoclonic epilepsy in Down's syndrome as characterized here should be considered in the differential diagnosis of adult-onset myoclonic epilepsies. LOMEDS apparently shares features with myoclonic epilepsy in Alzheimer's disease (AD) and Unverricht-Lundborg disease (ULD) caused by a mutation on chromosome 21. Since life expectation of DS patients has markedly increased, LOMEDS may be more frequent than currently acknowledged.
Seizure 2001 Jun
PMID:Late-onset myoclonic epilepsy in Down's syndrome (LOMEDS). 1146 28

Loss-of-function mutations in the cystatin B (Cstb) gene cause a neurological disorder known as Unverricht-Lundborg disease (EPM1) in human patients. Mice that lack Cstb provide a mammalian model for EPM1 by displaying progressive ataxia and myoclonic seizures. We analyzed RNAs from brains of Cstb-deficient mice by using modified differential display, oligonucleotide microarray hybridization and quantitative reverse transcriptase polymerase chain reaction to examine the molecular consequences of the lack of Cstb. We identified seven genes that have consistently increased transcript levels in neurological tissues from the knockout mice. These genes are cathepsin S, C1q B-chain of complement (C1qB), beta2-microglobulin, glial fibrillary acidic protein (Gfap), apolipoprotein D, fibronectin 1 and metallothionein II, which are expected to be involved in increased proteolysis, apoptosis and glial activation. The molecular changes in Cstb-deficient mice are consistent with the pathology found in the mouse model and may provide clues towards the identification of therapeutic points of intervention for EPM1 patients.
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PMID:Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes. 1155 22

The progressive myoclonic epilepsies are a rare but extremely debilitating group of disorders that are difficult to diagnose and even harder to treat. They represent a heterogeneous subgroup of those with secondary generalized epilepsy. Efficacy of treatment is often measured in terms of slowing a patient's inevitable decline. Reviewed here are the classification of progressive myoclonic epilepsies, features of myoclonic seizures, the five most prevalent progressive myoclonic epilepsy syndromes-Unverricht-Lundborg disease, myoclonus epilepsy with ragged red fibers (MERRF) mitochondrial disease, Lafora's disease, neuronal ceroid lipofuscinoses, and sialidoses-and current treatment options.
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PMID:Progressive myoclonic epilepsies. 1191 69


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