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)

A new autosomal recessively inherited disease of the central nervous system involving childhood epilepsy and mental deterioration is described. Twenty three patients (11 males and 12 females) belonging to 11 families from northern Finland have been identified. A common ancestor has been found for nine families. The mean age of onset of epilepsy was 6.7 years (range 5-10 years) and the epilepsy was characterised by generalised tonic-clonic seizures increasing in frequency up to puberty. One third of the patients also had complex partial seizures during childhood. During young adulthood the epileptic activity began to decrease, but complete remission did not occur. Electroencephalography showed progressive slowing of the background activity with relatively scanty epileptiform activity. Out of four ictal recordings the paroxysmal activity was initiated focally in two cases. Clonazepam and sodium valproate had some antiepileptic effect, clonazepam being the more beneficial of the two. Mental development, which was originally normal, began to deteriorate two to five years after the onset of epilepsy, and the deterioration continued during adulthood in spite of good epilepsy control, leading to mental retardation by middle age. The pathogenesis of the disorder, called the Northern epilepsy syndrome, is unknown. Linkage analysis using DNA markers linked to the EPM1 gene for progressive myoclonus epilepsy of Unverricht-Lundborg type showed that the Northern epilepsy syndrome is not allelic to EPM1.
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PMID:Northern epilepsy syndrome: an inherited childhood onset epilepsy with associated mental deterioration. 801 63

Jittery (ji) is a recessive mouse mutation on Chromosome 10 characterized by progressive ataxic gait, dystonic movements, spontaneus seizures, and death by dehydration/starvation before fertility. Recently, a viable neurological recessive mutation, hesitant, was discovered. It is characterized by hesitant, unco-ordinated movements, exaggerated stepping of the hind limbs, and reduced fertility in males. In a complementation test and by genetic mapping we have shown here that hesitant and jittery are allelic. Using several large intersubspecific backcrosses and intercrosses we have genetically mapped ji near the marker Amh and microsatellite markers D10Mit7, D10Mit21, and D10Mit23. The linked region of mouse Chromosome 10 is homologous to human 19p13.3, to which several human ataxia loci have recently been mapped. By excluding genes that map to human 21q22.3 (Pfkl) and 12q23 (Nfyb), we conclude that jittery is not likely to be a genetic mouse model for human Unverricht-Lundborg progressive myoclonus epilepsy (EPM1) on 21q22.3 nor for spinocerebellar ataxia II (SCA2) on 12q22-q24. The closely linked markers presented here will facilitate positional cloning of the ji gene.
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PMID:The neurological mouse mutations jittery and hesitant are allelic and map to the region of mouse chromosome 10 homologous to 19p13.3. 881 88

Progressive myoclonus epilepsy (EPM1) is an autosomal recessive disorder, characterized by severe, stimulus-sensitive myoclonus and tonic-clonic seizures. The EPM1 locus was mapped to within 0.3 cM from PFKL in chromosome 21q22.3. The gene for the proteinase inhibitor cystatin B was recently localized in the EPM1 critical region, and mutations were identified in two EPM1 families. We have identified six nucleotide changes in the cystatin B gene of non-Finnish EPM1 families from northern Africa and Europe. The 426G-->C change in exon 1 results in a Gly4Arg substitution and is the first missense mutation described that is associated with EPM1. Molecular modeling predicts that this substitution severely affects the contact of cystatin B with papain. Mutations in the invariant AG dinucleotides of the acceptor sites of introns 1 and 2 probably result in abnormal splicing. A deletion of two nucleotides in exon 3 produces a frameshift and truncates the protein. Therefore, these four mutations are all predicted to impair the production of functional protein. These mutations were found in 7 of the 29 unrelated EPM1 patients analyzed, in homozygosity in 1, and in heterozygosity in the others. The remaining two sequence changes, 431G-->T and 2575A-->G, probably represent polymorphic variants. In addition, a tandem repeat in the 5' UTR (CCCCGCCCCGCG) is present two or three times in normal alleles. It is peculiar that in the majority of patients no mutations exist within the exons and splice sites of the cystatin B gene.
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PMID:Identification of mutations in cystatin B, the gene responsible for the Unverricht-Lundborg type of progressive myoclonus epilepsy (EPM1). 901 7

Progressive myoclonus epilepsy type 1 (EPM1, also known as Unverricht-Lundborg disease) is an autosomal recessive disorder characterized by progressively worsening myoclonic jerks, frequent generalized tonic-clonic seizures, and a slowly progressive decline in cognition. Recently, two mutations in the cystatin B gene (also known as stefin B, STFB) mapping to 21q22.3 have been implicated in the EPM1 phenotype: a G-->C substitution in the last nucleotide of intron 1 that was predicted to cause a splicing defect in one family, and a C-->T substitution that would change an Arg codon (CGA) to a stop codon (TGA) at amino acid position 68, resulting in a truncated cystatin B protein in two other families. A fourth family showed undetectable amounts of STFB mRNA by northern blot analysis in an affected individual. We present haplotype and mutational analyses of our collection of 20 unrelated EPM1 patients and families from different ethnic groups. We identify four different mutations, the most common of which consists of an unstable approximately 600-900 bp insertion which is resistant to PCR amplification. This insertion maps to a 12-bp polymorphic tandem repeat located in the 5' flanking region of the STFB gene, in the region of the promoter. The size of the insertion varies between different EPM1 chromosomes sharing a common haplotype and a common origin, suggesting some level of meiotic instability over the course of many generations. This dynamic mutation, which appears distinct from conventional trinucleotide repeat expansions, may arise via a novel mechanism related to the instability of tandemly repeated sequences.
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PMID:Unstable insertion in the 5' flanking region of the cystatin B gene is the most common mutation in progressive myoclonus epilepsy type 1, EPM1. 905 46

Progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1; MIM 254800) is an autosomal recessive disorder that occurs with a low frequency in many populations but is more common in Finland and the Mediterranean region. It is characterized by stimulus-sensitive myoclonus and tonic-clonic seizures with onset at age 6-15 years, typical electroencephalographic abnormalities and a variable rate of progression between and within families. Following the initial mapping of the EPM1 gene to chromosome 21 (ref. 6) and the refinement of the critical region to a small interval, positional cloning identified the gene encoding cystatin B (CST6), a cysteine protease inhibitor, as the gene underlying EPM1 (ref. 10). Levels of messenger RNA encoded by CST6 were dramatically decreased in patients. A 3' splice site and a stop codon mutation were identified in three families, leaving most mutations uncharacterized. In this study, we report a novel type of disease-causing mutation, an unstable 15- to 18-mer minisatellite repeat expansion in the putative promoter region of the CST6 gene. The mutation accounts for the majority of EPM1 patients worldwide. Haplotype data are compatible with a single ancestral founder mutation. The length of the repeat array differs between chromosomes and families, but changes in repeat number seem to be comparatively rare events.
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PMID:Unstable minisatellite expansion causing recessively inherited myoclonus epilepsy, EPM1. 909 Mar 86

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a rare, autosomal recessive disorder characterized by onset at age 6-16 years, generalized seizures, incapacitating myoclonus, and variable progression to cerebellar ataxia. The gene that causes EPM1, cystatin B, encodes a cysteine proteinase inhibitor. Only a minority of EPM1 patients carry a point mutation within the transcription unit. The majority of EPM1 alleles contain large expansions of a dodecamer repeat, CCC CGC CCC GCG, located upstream of the 5' transcription start site of the cystatin B gene; normal alleles contain two or three copies of this repeat. All EPM1 alleles with an expansion were resistant to standard PCR amplification. To precisely determine the size of the repeat in affected individuals, we developed a detection protocol involving PCR amplification and subsequent hybridization with an oligonucleotide containing the repeat. The largest detected expansion was approximately 75 copies; the smallest was approximately 30 copies. We identified affected siblings with repeat expansions, of different sizes, on the same haplotype, which confirms the repeat's instability during transmissions. Expansions were observed directly; contractions were deduced by comparison of allele sizes within a family. In a sample of 28 patients, we found no correlation between age at onset of EPM1 and the size of the expanded dodecamer. This suggests that once the dodecamer repeat expands beyond a critical threshold, cystatin B expression is reduced in certain cells, with pathological consequences.
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PMID:A PCR amplification method reveals instability of the dodecamer repeat in progressive myoclonus epilepsy (EPM1) and no correlation between the size of the repeat and age at onset. 952 56

Loss-of-function mutations in the gene (CSTB) encoding human cystatin B, a widely expressed cysteine protease inhibitor, are responsible for a severe neurological disorder known as Unverricht-Lundborg disease (EPM1). The primary cellular events and mechanisms underlying the disease are unknown. We found that mice lacking cystatin B develop myoclonic seizures and ataxia, similar to symptoms seen in the human disease. The principal cytopathology appears to be a loss of cerebellar granule cells, which frequently display condensed nuclei, fragmented DNA and other cellular changes characteristic of apoptosis. This mouse model of EPM1 provides evidence that cystatin B, a non-caspase cysteine protease inhibitor, has a role in preventing cerebellar apoptosis.
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PMID:Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. 980 43

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

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


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