Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036572 (seizures)
 80,221 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated cortical functions of two Unverricht-Lundborg disease (ULD) patients suffering from myoclonic jerks, but no generalized tonic-clonic seizures. Somatosensory cortical responses were recorded to median nerve stimuli and coherence was calculated between cortical and muscle signals during isometric contraction of hand muscle. In contrast to ULD patients with generalized tonic-clonic seizures, responses of the primary somatosensory (SI) cortex were only slightly enhanced in the left and normal in the right hemisphere, and no early responses were observed in the ipsilateral SI. Cortex-muscle coherence was remarkably enhanced. We conclude that in ULD patients without generalized tonic-clonic seizures, both the excitability of the SI and transcallosal conduction are relatively normal, probably decreasing susceptibility to generalized seizures. Disturbed cortical control of muscle contraction indicates selective alteration of the motor cortex activation.
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PMID:Cortical sensorimotor alterations in Unverricht-Lundborg disease patients without generalized seizures. 1195 May 3

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 the 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 2002 Apr
PMID:Late-onset myoclonic epilepsy in Down's syndrome (LOMEDS). 1218 65

Serum glutathione levels were assessed in a patient with genetically proven Unverricht-Lundborg disease (ULD) before and during treatment with the antioxidant N-acetylcysteine (NAC). Glutathione levels were low before treatment, and increased during treatment. This increase was mirrored by an improvement in seizures, but not in myoclonus or ataxia. Three other patients with clinically determined ULD showed a variable response and some notable side effects during treatment with NAC.
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PMID:N-acetylcysteine and Unverricht-Lundborg disease: variable response and possible side effects. 1242 4

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a recessively inherited neurodegenerative disease caused by loss-of-function mutations in the gene encoding cystatin B, a cysteine protease inhibitor. Mice with disruptions in this gene display myoclonic seizures, progressive ataxia, and cerebellar pathology closely paralleling EPMI in humans. To provide further insight into our understanding of EPM1, we report pathological findings in brains from cystatin B-deficient mice. In addition to confirming the loss of cerebellar granular cell neurons by apoptosis, we identified additional neuronal apoptosis in young mutant mice (3-4 months old) within the hippocampal formation and entorhinal cortex. In older mutant mice (16-18 months old), there was also gliosis most marked in the presubiculum and parasubiculum of the hippocampal formation, as well as the entorhinal cortex, neocortex, and striatum. Furthermore, widespread white matter gliosis was also noted, which may be a secondary phenomenon. Within the cerebral cortex, cellular atrophy was a prominent finding in the superficial neurons of the prosubiculum. Finally, we show that mutant mice in either a "seizure-prone" or "seizure-resistant" genetic background display similar neuropathological changes. These findings indicate that neuronal atrophy is an important consequence of cystatin-B deficiency independent of seizure events, suggesting a physiological role for this protein in the maintenance of normal neuronal structure.
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PMID:Neuropathological changes in a mouse model of progressive myoclonus epilepsy: cystatin B deficiency and Unverricht-Lundborg disease. 1248 71

Research on human inherited diseases provides a powerful tool to identify an intrinsically important subset of genes vital to healthy functioning of the organism. Progressive myoclonus epilepsies (PMEs) are a group of rare inherited disorders characterized by the association of epilepsy, myoclonus and progressive neurological deterioration. Significant progress has been made in elucidating the molecular background of PMEs. Here, progress towards understanding the molecular pathogenesis of PMEs is reviewed using the most common single cause of PME, Unverricht-Lundborg disease, as an example. Mutations in the gene encoding cystatin B (CSTB), a cysteine protease inhibitor, are responsible for the primary defect in Unverricht-Lundborg disease. CSTB-deficient mice, produced by targeted disruption of the mouse Cstb gene, display a phenotype similar to the human disease, with progressive ataxia and myoclonic seizures. The mice show neuronal atrophy, apoptosis and gliosis as well as increased expression of apoptosis and glial activation genes. Although significant advances towards understanding the molecular basis of Unverricht-Lundborg disease have been achieved, the physiological function of CSTB and the molecular pathogenesis of the disease remain unknown.
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PMID:Molecular background of progressive myoclonus epilepsy. 1285 62

The inherited epilepsy Unverricht-Lundborg disease (EPM1) is caused by loss-of-function mutations in the cysteine protease inhibitor, cystatin B. Because cystatin B inhibits a class of lysosomal cysteine proteases called cathepsins, we hypothesized that increased proteolysis by one or more of these cathepsins is likely to be responsible for the seizure, ataxia, and neuronal apoptosis phenotypes characteristic of EPM1. To test this hypothesis and to identify which cysteine cathepsins contribute to EPM1, we have genetically removed three candidate cathepsins from cystatin B-deficient mice and tested for rescue of their EPM1 phenotypes. Whereas removal of cathepsins L or S from cystatin B-deficient mice did not ameliorate any aspect of the EPM1 phenotype, removal of cathepsin B resulted in a 36-89% reduction in the amount of cerebellar granule cell apoptosis depending on mouse age. The incidence of an incompletely penetrant eye phenotype was also reduced upon removal of cathepsin B. Because the apoptosis and eye phenotypes were not abolished completely and the ataxia and seizure phenotypes experienced by cystatin B-deficient animals were not diminished, this suggests that another molecule besides cathepsin B is also responsible for the pathogenesis, or that another molecule can partially compensate for cathepsin B function. These findings establish cathepsin B as a contributor to the apoptotic phenotype of cystatin B-deficient mice and humans with EPM1. They also suggest that the identification of cathepsin B substrates may further reveal the molecular basis for EPM1.
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PMID:Cathepsin B but not cathepsins L or S contributes to the pathogenesis of Unverricht-Lundborg progressive myoclonus epilepsy (EPM1). 1291 16

Progressive myoclonus epilepsy 1 (EPM1) or Unverricht-Lundborg disease is a human autosomal recessive neurodegenerative disorder caused by mutations in cystatin B (CSTB). The CSTB gene maps to human chromosome 21 and encodes an inhibitor of lysosomal cysteine proteases. Five point mutations have been found, two of which are seen in numerous unrelated patients. However, the main CSTB mutation in EPM1, even among patients of different ethnic origins, is an expansion of a dodecamer repeat (CCCCGCCCCGCG) in the 5' flanking area of CSTB. Most normal alleles contain either two or three repeats, while rarer normal alleles that are highly unstable contain between 12 and 17 repeats. Mutant expanded alleles have been reported to contain between 30 and 80 copies and are also highly unstable, particularly via parental transmission. There is no apparent correlation between mutant repeat length and disease phenotype. While the repeat expansion is outside the CSTB transcriptional unit, it results in a marked decrease in CSTB expression, at least in certain cell types in vitro. CSTB homozygous knockout mice show some parallels to the phenotype of human EPM1 including myoclonic seizures, development of ataxia and neuropathological changes associated with cell loss via apoptosis. Loss of CSTB function due to mutations is consistent with the observed neurodegenerative pathology and phenotype, but the functional link to the epileptic phenotype of EPM1 remains largely unknown.
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PMID:The epilepsy, the protease inhibitor and the dodecamer: progressive myoclonus epilepsy, cystatin b and a 12-mer repeat expansion. 1452 83

Loss-of-function mutations in the cystatin B (CSTB), a cysteine protease inhibitor, gene underlie progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1), characterized by myoclonic and tonic-clonic seizures, ataxia and a progressive course. A minisatellite repeat expansion in the promoter region of the CSTB gene is the most common mutation in EPM1 patients and leads to reduced mRNA levels. Seven other mutations altering the structure of CSTB, or predicting altered splicing, have been described. Using a novel monoclonal CSTB antibody and organelle-specific markers in human primary myoblasts, we show here that endogenous CSTB localizes not only to the nucleus and cytoplasm but also associates with lysosomes. Upon differentiation to myotubes, CSTB becomes excluded from the nucleus and lysosomes, suggesting that the subcellular distribution of CSTB is dependent on the differentiation status of the cell. Four patient mutations altering the CSTB polypeptide were transiently expressed in BHK-21 cells. The p.Lys73fsX2-truncated mutant protein shows diffuse cytoplasmic and nuclear distribution, whereas p.Arg68X is rapidly degraded. Two missense mutations, the previously described p.Gly4Arg affecting the highly conserved glycine, critical for cathepsin binding, and a novel mutation, p.Gln71Pro, fail to associate with lysosomes. These data imply an important lysosome-associated physiological function for CSTB and suggest that loss of this association contributes to the molecular pathogenesis of EPM1.
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PMID:Loss of lysosomal association of cystatin B proteins representing progressive myoclonus epilepsy, EPM1, mutations. 1548 48

Progressive myoclonic epilepsies (PMEs) are a group of rare disorders characterized by the occurrence of seizures, myoclonus, and progressive neurological dysfunction. This article discusses epidemiology, genetics, pathology, clinical manifestations, EEG characteristics, methods of diagnosis and treatment of the most common causes of PME, including Unverricht-Lundborg Disease (Baltic Myoclonus), MERRF, neuronal ceroid lipofuscinosis, dentatorubropallidoluysan atrophy, Gaucher disease, Lafora disease, and sialidosis. The aim of this paper is to provide clinicians with useful clinical information in order to facilitate the diagnosis and treatment of these rare diseases.
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PMID:Progressive myoclonic epilepsy. 1554 6

Progressive myoclonus epilepsy (PME) has a number of causes, of which Unverricht-Lundborg disease (ULD) is the most common. ULD has previously been mapped to a locus on chromosome 21 (EPM1). Subsequently, mutations in the cystatin B gene have been found in most cases. In the present work we identified an inbred Arab family with a clinical pattern compatible with ULD, but mutations in the cystatin B gene were absent. We sought to characterize the clinical and molecular features of the disorder. The family was studied by multiple field trips to their town to clarify details of the complex consanguineous relationships and to personally examine the family. DNA was collected for subsequent molecular analyses from 21 individuals. A genome-wide screen was performed using 811 microsatellite markers. Homozygosity mapping was used to identify loci of interest. There were eight affected individuals. Clinical onset was at 7.3 +/- 1.5 years with myoclonic or tonic-clonic seizures. All had myoclonus that progressed in severity over time and seven had tonic-clonic seizures. Ataxia, in addition to myoclonus, occurred in all. Detailed cognitive assessment was not possible, but there was no significant progressive dementia. There was intrafamily variation in severity; three required wheelchairs in adult life; the others could walk unaided. MRI, muscle and skin biopsies on one individual were unremarkable. We mapped the family to a 15-megabase region at the pericentromeric region of chromosome 12 with a maximum lod score of 6.32. Although the phenotype of individual subjects was typical of ULD, the mean age of onset (7.3 years versus 11 years for ULD) was younger. The locus on chromosome 12 does not contain genes for any other form of PME, nor does it have genes known to be related to cystatin B. This represents a new form of PME and we have designated the locus as EPM1B.
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PMID:A new clinical and molecular form of Unverricht-Lundborg disease localized by homozygosity mapping. 1563 28


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