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

Frings mice are a model of generalized epilepsy and have seizures in response to loud noises. This phenotype is due to the autosomal recessive inheritance of a single gene on mouse chromosome 13. Here we report the fine genetic and physical mapping of the locus. Sequencing of the region led to identification of a novel gene; mutant mice are homozygous for a single base pair deletion that leads to premature termination of the encoded protein. Interestingly, the mRNA levels of this gene in various tissues are so low that the cDNA has eluded detection by standard library screening approaches. Study of the MASS1 protein will lead to new insights into regulation of neuronal excitability and a new pathway through which dysfunction can lead to epilepsy.
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PMID:A novel gene causing a mendelian audiogenic mouse epilepsy. 1154 6

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant progressive disorder characterized by ataxia, seizures and anticipation, mapped to chromosome 22q13.3. We have found that the mutation of SCA10 is an unstable and massive expansion (800-4,500 repeats) of the ATTCT pentanucleotide repeat in intron 9 of SCA 10 (also known as E46L), a novel gene of unknown function. The mutation, so far, has only been found in the population of the Mexican descent with a founder effect supported by haplotype data. The expansion size of the repeat inversely correlates with age of disease onset and SCA10 is highly expressed throughout the central nervous system. Expanded ATTCT repeats in SCA10 patients show repeat size instability in their somatic and germline cells as well as time-dependent instability in blood. This novel type of microsatellite repeat expansion is the largest found to date in human diseases. Its epidemiological, clinical, genetic and pathophysiological features need to be further investigated.
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PMID:[Spinocerebellar ataxia type 10 (SCA10): a disease caused by a novel pentanucleotide repeat expansion]. 1223 14

Cerebral cavernous malformations (CCMs) are congenital vascular anomalies of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. Mutations in the gene KRIT1 are responsible for type 1 CCM (CCM1). We report that a novel gene, MGC4607, exhibits eight different mutations in nine families with type 2 CCM (CCM2). MGC4607, similar to the KRIT1 binding partner ICAP1alpha, encodes a protein with a phosphotyrosine-binding domain. This protein may be part of the complex pathway of integrin signaling that, when perturbed, causes abnormal vascular morphogenesis in the brain, leading to CCM formation.
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PMID:Mutations in a gene encoding a novel protein containing a phosphotyrosine-binding domain cause type 2 cerebral cavernous malformations. 1462 91

Spinocerebellar ataxia type 10 (SCA10) is an autosomal dominant disorder characterized by ataxia, seizures, and anticipation. It is caused by an expanded ATTCT pentanucleotide repeat in intron 9 of a novel gene, designated "SCA10." The ATTCT expansion in SCA10 represents a novel class of microsatellite repeat and is one of the largest found to cause human diseases. The expanded ATTCT repeat is unstably transmitted from generation to generation, and an inverse correlation has been observed between size of repeat and age at onset. In this multifamily study, we investigated the intergenerational instability, somatic and germline mosaicism, and age-dependent repeat-size changes of the expanded ATTCT repeat. Our results showed that (1) the expanded ATTCT repeats are highly unstable when paternally transmitted, whereas maternal transmission resulted in significantly smaller changes in repeat size; (2) blood leukocytes, lymphoblastoid cells, buccal cells, and sperm have a variable degree of mosaicism in ATTCT expansion; (3) the length of the expanded repeat was not observed to change in individuals over a 5-year period; and (4) clinically determined anticipation is sometimes associated with intergenerational contraction rather than expansion of the ATTCT repeat.
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PMID:Somatic and germline instability of the ATTCT repeat in spinocerebellar ataxia type 10. 1512 63

Spinocerebellar ataxia type 10 (SCA10) is a dominantly inherited ataxia caused by expansion of ATTCT pentanucleotide repeat in intron 9 of a novel gene, E46L, on chromosome 22q13.3. SCA10 is a complex neurodegenerative condition. Initial studies characterized SCA10 as pure cerebellar ataxia associated with seizures. Recent identification of new SCA10 families revealed more diverse phenotypes, including polyneuropathy, pyramidal signs, cognitive and neuropsychiatric impairment. Moreover, several families manifest with ataxia without seizures. Thus a complete clinical spectrum is emerging. Progress has also been made in understanding the molecular and genetic mechanisms of pathogenesis. The length of expanded ATTCT repeats is variable in different tissues and highly unstable during paternal transmission, revealing complex genetic and pathogenetic processes. Under torsional stress, ATTCT repeats form unpaired DNA structure and may serve as an erroneous DNA replication origin, potentially contributing to repeat instability and aberrant cell cycle entry. E46L is a cytoplasmic protein with unknown function. Reduced expression of E46L in primary neuronal cultures from cerebellum and cortex by small interfering RNAs (siRNAs) caused increased apoptosis, raising the possibility that reduced expression of E46L might also play an important role in SCA10 pathogenesis.
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PMID:Recent progress in spinocerebellar ataxia type-10 (SCA10). 1589 57

Spinocerebellar ataxia type 10 (SCA10) is a dominantly inherited neurodegenerative disease caused by expansion of the ATTCT pentanucleotide repeat in intron 9 of a novel gene, ATXN10, on chromosome 22q13.3. It is clinically characterized by progressive ataxia, seizures, and anticipation, which can vary within and between families. The length of the expanded ATTCT repeats is highly unstable on paternal transmission and shows a variable degree of somatic and germline instabilty, revealing complex SCA10 genetic mechanisms. Moreover, the purity of the expanded repeat element may be a disease modifier. ATTCT repeats have been recently shown to form unpaired DNA structure and may serve as an aberrant DNA replication origin, potentially contributing to repeat instability and cell death. How this untranslated ATTCT expansion leads to neurodegeneration has been still controversial. We discuss several possible pathogenic mechanisms for SCA10, and growing number of evidence indicates a gain-of-function RNA mechanism, similar to the myotonic dystrophies caused by non-coding CTG or CCTG repeat expansions.
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PMID:[Molecular and genetic analysis of spinocerebellar ataxia type 10 (SCA10)]. 1838 26

Spinocerebellar ataxia type 10 (SCA10) is a dominantly inherited neurodegenerative disease caused by expansion of the ATTCT pentanucleotide repeat in intron 9 of a novel gene, ATXN10, on chromosome 22q13.3. It is clinically characterized by progressive ataxia, seizures, and anticipation, which can vary within and between families. The length of the expanded ATTCT repeats is highly unstable on paternal transmission and shows a variable degree of somatic and germline instabilty, revealing complex SCA10 genetic mechanisms. How this untranslated ATTCT expansion leads to neurodegeneration has been still controversial. Growing number of evidence indicates a gain-of-function RNA mechanism, similar to the myotonic dystrophies caused by non-coding CTG or CCTG repeat expansions.
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PMID:[Molecular and genetic analysis of spinocerebellar ataxia type 10 (SCA10)]. 1919 92

The N-methyl-d-aspartate receptor (NMDAR) is critically involved in learning and memory, neuronal survival, as well as neuroexcitotoxicity and seizures. We hypothesize that even mild reductions in the numbers of hippocampal NMDARs could impair learning and memory, whereas increasing receptor activity would facilitate learning but reduce seizure threshold. We developed novel gene transfer strategies assisted by an adeno-associated viral vector 1/2 to bi-directionally modulate expression levels of the NR1 protein in rat hippocampus. Functional consequences of the altered NR1 expression were examined in the acute seizure model, and on normal processes of fear memory and neurogenesis. We found that knocking down NR1 protected against seizures at the expense of impaired learning, as predicted. Paradoxically, NR1 overexpression not only increased fear memory and neurogenesis, but also delayed onset of more severe seizures. In conclusion, the observed consequences of NR1 knockdown and overexpression underscore NMDAR requirement for neuronal plasticity, and are in agreement with its dichotomous functions.
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PMID:Knockdown and overexpression of NR1 modulates NMDA receptor function. 1939 26

Brain-lung-thyroid disease is a rare familial disorder caused by mutations in thyroid transcription factor 1, a gene that regulates neuronal migration. We report the clinical features of ten patients from a single family with a novel gene mutation, including observations regarding treatment. Neurologic features of the kindred included developmental delay, learning difficulties, psychosis, chorea, and dystonia. Three patients had a history of seizure, which has not been previously reported in genetically confirmed cases. Low-dose dopamine-receptor blocking drugs were poorly tolerated in 2 patients who received this therapy, levodopa improved chorea in 3 of 4 children, and diazepam was markedly effective in a single adult patient. Chorea related to brain-lung-thyroid disease appears to respond paradoxically to antidopaminergic drugs. The unusual therapeutic response seen in our patients and others may help elucidate how disease-related migratory deficits affect neural pathways associated with motor control.
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PMID:Brain-lung-thyroid disease: clinical features of a kindred with a novel thyroid transcription factor 1 mutation. 2181 2

We report a case of an infant with unique and unreported combinations of brain anomalies. The patient showed distinctive facial findings, severe delay in psychomotor development, cranial nerve palsy and seizures. Brain magnetic resonance imaging performed at 5 days of age revealed complex brain malformations, including heterotopia around the mesial wall of lateral ventricles, dysmorphic cingulate gyrus, and enlarged midbrain tectum. The patient unexpectedly died at 13 months of age. Postmortem pathological findings included a polymicrogyric cingulate cortex, periventricular nodular heterotopia, basal ganglia and thalamic anomalies, and dysmorphic midbrain tectum. Potential candidate genes showed no abnormalities by traditional PCR-based sequencing. Whole-exome sequencing confirmed the presence of novel gene variants for filamin B (FLNB), guanylate binding protein family member 6, and chromosome X open reading frame 59, which adapt to the autosomal recessive mode or X-linked recessive mode. Although immunohistochemical analysis confirmed the expression of FLNB protein in the vessel walls and white matter in autopsied specimens, there may be functional relevance of the compound heterozygous FLNB variants during brain development.
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PMID:Whole-exome sequencing of a unique brain malformation with periventricular heterotopia, cingulate polymicrogyria and midbrain tectal hyperplasia. 2324 Sep 87


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