Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014544 (epilepsy)
 64,704 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epilepsy affects at least 2% of the population at some time in their lives. The epilepsies are a heterogeneous group of disorders, many with an inherited component. Although specific genes have been identified in a few rare diseases causing seizures as part of a more diffuse brain disorder, the molecular pathology of the common idiopathic epilepsies is still unknown. Linkage has been reported for some generalised epilepsy syndromes, but only very recently for familial partial epilepsy syndromes. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a partial epilepsy causing frequent, violent, brief seizures at night, usually beginning in childhood. The gene for ADNFLE maps to chromosome 20q13.2-q13.3 in one large Australian kindred. The neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) maps to the same region of 20q (ref. 12) and the gene is expressed in all layers of the frontal cortex. We screened affected family members for mutations within CHRNA4 and found a missense mutation that replaces serine with phenylalanine at codon 248, a strongly conserved amino acid residue in the second transmembrane domain. The mutation is present in all 21 available affected family members and in four obligate carriers, but not in 333 healthy control subjects.
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PMID:A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. 755 Mar 50

The epilepsy gene map has been refined and extended with new information concerning benign familial neonatal convulsions, benign familial infantile convulsions, Unverricht-Lundborg disease, epilepsy with progressive mental retardation and juvenile myoclonic epilepsy. Understanding of the molecular basis of paroxysmal disorders affecting the central nervous system has been revolutionalized with the identification of mutations in genes for the neurotransmitter receptors, GLRA1 and CHRNA4, and a voltage-gated potassium channel, KCNA1, as causes of inherited neurological disease.
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PMID:Genetics of the epilepsies. 762 May 86

The human neuronal nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) is located in the candidate region for three different phenotypes: benign familial neonatal convulsions, autosomal dominant nocturnal frontal lobe epilepsy, and low-voltage EEG. Recently, a missense mutation in transmembrane domain 2 of CHRNA4 was found to be associated with autosomal dominant nocturnal frontal lobe epilepsy in one extended pedigree. We have determined the genomic organization of CHRNA4, which consists of six exons distributed over approximately 17 kb of genomic DNA. The nucleotide sequence obtained from the genomic regions adjacent to the exon boundaries enabled us to develop a set of primer pairs for PCR amplification of the complete coding region. The sequence analysis provides the basis for a comprehensive mutation screening of CHRNA4 in the above-mentioned phenotypes and possibly in other types of idiopathic epilepsies.
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PMID:Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4). 883 59

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first, and to date only, idiopathic epilepsy for which a specific mutation has been found. A missense mutation in the critical M2 domain of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) has been recently identified in one large Australian pedigree. Here we describe a novel mutation in the M2 domain of the CHRNA4 gene in a Norwegian family. Three nucleotides (GCT) were inserted at nucleotide position 776 into the coding region for the C-terminal end of the M2 domain. Physiological investigations of the receptor reconstituted with the mutated CHRNA4 subunit reveal that this insertion does not prevent the receptor function but increases its apparent affinity for ACh. In addition, this mutant receptor shows a significantly lower calcium permeability that, at the cellular level, may correspond to a loss of function. Comparison of the two mutations identified so far in families with ADNFLE illustrates that different mutations can result in similar phenotypes.
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PMID:An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. 917 43

Benign Familial Neonatal Convulsions (BFNC) is an epileptic disorder with an autosomal dominant mode of transmission. It has been shown that about 80% of BFNC pedigrees are linked to a genetic defect on chromosome 20q13.3. A candidate gene for the epilepsies, the gene coding for the alpha4 subunit of the nicotinic cholinergic receptor (CHRNA4), has previously been localized on chromosome 20. Here we report a single point mutation converting a serine codon to a stop codon in the exon 5 of CHRNA4, in one BFNC family. Identification of CHRNA4 as the defective gene in 20q-BFNC represents the first example of a human idiopathic epilepsy caused by a mutation directly affecting a neurotransmitter receptor in the central nervous system.
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PMID:A nonsense mutation in the alpha4 subunit of the nicotinic acetylcholine receptor (CHRNA4) cosegregates with 20q-linked benign neonatal familial convulsions (EBNI) 921 91

The epilepsies are a group of disorders characterised by recurrent seizures caused by episodes of abnormal neuronal hyperexcitability involving the brain. Up to 60 million people are affected worldwide and genetic factors may contribute to the aetiology in up to 40% of patients. The most common human genetic epilepsies display a complex pattern of inheritance. These are categorised as idiopathic in the absence of detectable structural or metabolic abnormalities. Juvenile myoclonic epilepsy (JME) is a distinctive and common variety of familial idiopathic generalised epilepsy (IGE) with a prevalence of 0.5-1.0 per 1000 and a ratio of sibling risk to population prevalence (lambda(s)) of 42. The molecular genetic basis of these familial idiopathic epilepsies is entirely unknown, but a mutation in the gene CHRNA4, encoding the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR), was recently identified in a rare Mendelian variety of idiopathic epilepsy. Chromosomal regions harbouring genes for nAChR subunits were therefore tested for linkage to the JME trait in 34 pedigrees. Significant evidence for linkage with heterogeneity was found to polymorphic loci encompassing the region in which the gene encoding the alpha7 subunit of nAChR (CHRNA7) maps on chromosome 15q14 (HLOD = 4.4 at alpha = 0.65; Z(all) = 2.94, P = 0.0005). This major locus contributes to genetic susceptibility to JME in a majority of the families studied.
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PMID:Genetic mapping of a major susceptibility locus for juvenile myoclonic epilepsy on chromosome 15q. 925 80

The alpha4 subunit gene of the neuronal nicotinic acetylcholine receptor (CHRNA4) has recently been identified as the first gene underlying an idiopathic partial epilepsy syndrome in human, autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE). CHRNA4 is located in the candidate region for benign familial neonatal convulsions and low-voltage EEG on chromosome 20q. In the present study, we examined the possible role of CHRNA4 in common subtypes of idiopathic generalized epilepsy (IGE), comprising childhood and juvenile absence epilepsy and juvenile myoclonic epilepsy (JME), by systematically screening the coding region of the gene for sequence variants. We present here a population-based association study testing the hypothesis that variants of the CHRNA4 gene confer genetic susceptibility to common subtypes of IGE. The missense mutation (Ser248Phe), associated with ADNFLE, and four silent polymorphisms in the CHRNA4 gene were genotyped in 103 IGE patients and 92 controls by polymerase chain reaction and subsequent restriction analysis. Without correction for multiple testing, the frequency of the T-allele of the silent CfoI bp595 polymorphism was increased in the entire group of IGE patients (f(T) = 0.085) compared to that in the controls (f(T) = 0.027). The allelic association was not restricted to any subgroup of IGE with either JME or idiopathic absence epilepsies. This result suggests that variation of the CHRNA4 gene, or so-far-undetected sequence variants near the CHRNA4 locus, confer susceptibility to the common IGE syndromes.
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PMID:Possible association of a silent polymorphism in the neuronal nicotinic acetylcholine receptor subunit alpha4 with common idiopathic generalized epilepsies. 925 83

A number of clinical and aetiological studies have been performed, during the last 30 years, on patients with abnormal nocturnal motor and behavioural phenomena. The aetiological conclusions of these studies were often conflicting, suggesting either an epileptic or a non-epileptic origin. Among the clinical characteristics of these patients, the familial clustering was one thoroughly accepted. A nocturnal familial form of frontal lobe epilepsy (autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE), often misdiagnosed as parasomnia, has been recently described in some families. In one large Australian kindred, a missense mutation in the second transmembrane domain of the neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4) gene, located on chromosome 20 q13.2-13.3, has been reported to be associated with nocturnal frontal lobe epilepsy. We performed an extensive clinical and video-polysomnographic study in 40 patients complaining of repeated abnormal nocturnal motor and/or behavioural phenomena, from 30 unrelated Italian families. Thirty-eight patients had an electroclinical picture strongly suggesting the diagnosis of ADNFLE. They had a wide clinical spectrum, ranging from nocturnal enuresis to sleep-related violent behaviour, thus including all the main features of the so-called 'typical' parasomnias. The video-polysomnographic recording confirmed the wide spectrum of abnormal manifestations, including sudden awakenings with dystonic/ dyskinetic movements (in 42.1% of patients), complex behaviours (13.2%) and sleep-related violent behaviour (5.3%). The EEG findings showed ictal epileptiform abnormalities predominantly over frontal areas in 31.6% of patients. In another 47.4% of patients the EEG showed ictal rhythmic slow activity over anterior areas. Only 18.4% of the patients had already received a correct diagnosis of epilepsy. In 73.3% of the patients treated with anti-epileptic drugs the seizures were readily controlled. Pedigree analysis on 28 of the families was consistent with autosomal dominant transmission with reduced penetrance (81%). DNAs from 20 representative affected individuals were sequenced in order to check for the presence of the missense mutation in the CHRNA4 gene found in the Australian kindred affected by ADNFLE. Nucleotide sequence analysis did not reveal the presence of this mutation, but it did confirm the presence of two other base substitutions, not leading to amino acid changes. These two intragenic polymorphisms, together with a closely linked restriction fragment length polymorphism at the D20S20 locus, have been used for linkage analysis of ADNFLE to the terminal region of the long arm of chromosome 20 in five compliant families. The results allowed us to exclude linkage of ADNFLE to this chromosomal region in these families, thus confirming the locus heterogeneity of the disorder. Large and full video-polysomnographical studies are of the utmost importance in order to clarify the real prevalence of both nocturnal frontal lobe epilepsy and parasomnias, and to provide a correct therapy.
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PMID:Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome. 954

Autosomal dominant nocturnal frontal-lobe epilepsy (ADNFLE) is a recently identified partial epilepsy in which two different mutations have been described in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4). An additional seven families are presented in which ADNFLE is unlinked to the CHRNA4 region on chromosome 20q13.2. Seven additional sporadic cases showed no evidence of defective CHRNA4. One of the families showed evidence of linkage to 15q24, close to the CHRNA3/CHRNA5/CHRNB4 cluster (maximum LOD score of 3.01 with D15S152). Recombination between ADNFLE and CHRNA4, linkage to 15q24 in one family, and exclusion from 15q24 and 20q13.2 in others demonstrate genetic heterogeneity with at least three different genes for ADNFLE. The CHRNA4 gene and the two known CHRNA4 mutations are responsible for only a minority of ADNFLE. Although the ADNFLE phenotype is clinically homogeneous, there appear to be a variety of molecular defects responsible for this disorder, which will provide a challenge to the understanding of the basic mechanism of epileptogenesis.
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PMID:Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24. 975 5

The alpha4-subunit gene (CHRNA4) of the neuronal nicotinic acetylcholine receptor (nAChR) subunit family has recently been identified in two families as the gene responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a rare monogenic idiopathic epilepsy. As a result of this finding, other subunits of the neuronal nAChR gene family are being considered as candidate genes for ADNFLE in families not linked to CHRNA4 and for other idiopathic epilepsies. Alpha4-subunits often assemble together with beta2-subunits (gene symbol CHRNB2) to build heteromeric nAChRs. The gene encoding another abundant AChR subunit, the alpha3-subunit gene (CHRNA3), is present with those encoding two other subunits, CHRNB4 and CHRNA5, in a gene cluster whose functional role is still unclear. Here we provide the information on the genomic structures of both the CHRNB2 and the CHRNA3 genes that is necessary for comprehensive mutational analyses, and we refine the genomic assignment of CHRNB2 on chromosome 1.
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PMID:The structures of the human neuronal nicotinic acetylcholine receptor beta2- and alpha3-subunit genes (CHRNB2 and CHRNA3). 992 97


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