Evidence for S284L mutation of the CHRNA4 in a white family with autosomal dominant nocturnal frontal lobe epilepsy

PURPOSE: To identify mutations of the neuronal nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a group of white patients. METHODS: A group of 47 patients from 21 unrelated families with ADNFLE were screened for mutations in CHRNA4. Clinical features and EEG findings in the patients were consistent with those reported in the literature for other affected families. The entire gene was amplified from genomic DNA by polymerase chain reaction (PCR) followed by multitemperature single-strand conformation polymorphism analysis (MSSCP) and sequencing. RESULTS: A c.851C>T transition in exon 5 of CHRNA4 was identified in three affected individuals from two generations of the same family, but not in the remaining patients or in 100 healthy volunteers. This mutation caused an S284L substitution in the transmembrane domain M2 segment of the alpha4 subunit of the neuronal nicotinic acetylcholine receptor. The same mutation had previously been detected in a single Japanese family with ADNFLE, and in an Australian woman with a sporadic form of NFLE. CONCLUSIONS: This is the first report of an occurrence of c.851C>T transition in a white family with ADNFLE.     

Electroclinical picture of autosomal dominant nocturnal frontal lobe epilepsy in a Japanese family

PURPOSE: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is the first described partial epilepsy syndrome known to be due to a single gene mutation. We found a first Japanese ADNFLE family with a novel mutation of the neuronal nicotinic acetylcholine receptor (nAChR) alpha4 subunit (CHRNA4) gene. The aim of this report is precisely to describe the electroclinical manifestations of ADNFLE in this family and to compare these findings with those of other families reported previously in the literature. METHODS: Three affected family members were investigated electroclinically by close clinical observation, interictal EEG, video-EEG monitoring, magnetic resonance imaging, and single-photon-emission tomography. Information about other affected family members was obtained from either the spouse or the parents. Mutations within the CHRNA4 gene were examined in seven family members. RESULTS: The clinical manifestations and diagnostic findings in the members of this family were consistent with ADNFLE. However, there were intrafamilial and interfamilial variations in clinical features. The seizures of the patients were brief tonic seizures, with hyperventilation in children and secondarily generalized tonic-clonic convulsions in adults. The onset of the children's seizures began in infancy and early childhood. The children's seizures were sometimes provoked by movement and sound stimulation, and did not respond to antiepileptic drugs. On the other hand, the adults' seizures disappeared spontaneously or were easily controlled with carbamazepine. Three children showed hyperactivity, and two children had mild mental retardation. All patients had impaired consciousness during their seizures and no auras. A novel missense mutation (c755C>T) in exon 5 of the CHRNA4 gene was found in four affected family members. CONCLUSIONS: The electroclinical pictures of a Japanese family with ADNFLE were basically the same as those of other families reported, but with slight differences. ADNFLE is probably not uncommon, and it is very likely that there are unidentified patients with this inherited disorder in Japan.     

Independent occurrence of the CHRNA4 Ser248Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy

PURPOSE: To describe the clinical features of a family from Northern Norway in which autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is associated with a Ser248Phe amino acid exchange in the second transmembrane domain of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4). We also tested for evidence of a de novo mutation or founder effect by comparing haplotypes with the original Australian family where the Ser248Phe mutation was first described. METHODS: Clinical details were obtained from 19 family members. Personal interviews and genetic analysis were carried out in 17. Parts of the coding region of CHRNA4 were sequenced, and two known polymorphisms (bp555/FokI, bp594/CfoI) were typed by restriction analysis. RESULTS: Eleven individuals had ADNFLE. The haplotypes of the mutation-carrying alleles of affected individuals from the Northern Norwegian and the Australian ADNFLE family are different. The phenotypic expressions are remarkably similar. CONCLUSIONS: The Ser248Phe mutation occurred independently in both families. Given the rarity of the disease, this suggests that not only the position of a mutation in the coding sequence but also the type of an amino acid exchange is important for the etiology of ADNFLE. The phenotypic similarity of these two families with different genetic backgrounds suggests that the Ser248Phe mutation largely determines the phenotype, with relatively little influence of other background genes.     

A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation

BACKGROUND: A Korean family had distinctive clinical and neuroimaging features and carried the same genetic mutation that was found in a previously described Japanese kindred with autosomal dominant nocturnal frontal lobe epilepsy. OBJECTIVE: To describe the first Korean family with autosomal dominant nocturnal frontal lobe epilepsy. METHODS: Members of a large family, including 9 affected individuals from 3 generations, underwent a comprehensive genetic, clinical, electroencephalographic, neuropsychological, and neuroimaging evaluation. Affected members were tested for possible mutations in transmembrane regions 1 through 3 of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4) by direct sequencing and subsequent restriction analysis. RESULTS: Seizures began in childhood, presenting as nocturnal episodes of staring, confusion, shouting, perioral movements, unintelligible speech, and hand waving. Some patients had ictal or interictal epileptiform activity in the temporal and/or frontocentral areas. Neurological examination and brain magnetic resonance imaging results showed no abnormalities, except that all patients available for testing had mild to moderate mental retardation. Fluorodeoxyglucose F 18 with positron emission tomography showed mild decreased glucose uptake in the superior and middle frontal regions, more so on the left than on the right. Patient response to carbamazepine was poor. All affected members were heterozygous for the CHRNA4 Ser252Leu mutation. CONCLUSIONS: Disorders associated with mutations in the transmembrane region 2 of CHRNA4 are genetically and phenotypically heterogeneous. Distinctive features of this kindred include (1) mental retardation in all affected members available for testing, (2) abnormal brain findings on fluorodeoxyglucose F 18 with positron emission tomography, (3) poor response to carbamazepine, and (4) full penetrance.     

A Case of Unverricht-Lundborg Type Progressive Myoclonus Epilepsy Confirmed by Cystatin B Gene Mutation

Purpose : Autosomal dominant nocturnal frontal lobe epilepsy (AD- NFLE) is a newly recognized partial epilepsy first reported by Scheffer ct al. Thc aim of our work is to describc the clinical picture of thc disease found for the first time in a Japanese fiunily.
Method: Affected members were investigated electroclinically, and thc mutations within ncuronal nicotinic acctylcholinc rcceptor alpha-4 subunit (CHRNA4) gene were examined.
Results : All affccted members presented clusters of brief tonic seizures, secondarily generalized, which occurred exclusively in sleep. The scimrc symptomatology and clcctrocnccphalographic findings were compatible with those of ADNFLE. None of the members had aura prcccding the scizure and nonc was aware of the seizure. They all had the same point mutation in the CHRNA4 gene, although intrafiamilial variations of seizure severity such as onset, frequency, and response to therapy were noted.
Conclusions : We described the first instances of ADNFLE in a Japanese family with a novel missense mutation of exon 5 of the CHRNA4 gene. It was a C to T transition and replaces serine in the second mcmbranc-spanning domain (M2) with lcucine (scr 252 LCU). We suggest that intra-familial heterogeneity is one of the important aspects or ADNFLE.     

Further evidence of genetic heterogeneity in families with autosomal dominant nocturnal frontal lobe epilepsy

PURPOSE: Mutations in the genes encoding the alfa(2), alfa(4) and beta(2) subunits of the neuronal nicotinic acetylcholine receptor (nAChR) play a causative role in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Moreover, variations in the promoter of the corticotropic-releasing hormone gene (CRH) were also associated with ADNFLE. Here, we investigated whether nine brain-expressed genes (CHRNA2, CHRNA3, CHRNA4, CHRNA5, CHRNA6, CHRNA7, CHRNB2, CHRNB3, CHRNB4), encoding distinct nAChR subunits, and CRH are associated with the disease in three distinct ADNFLE families from Southern Italy. METHODS: There were 14 living affected individuals (9 women), ranging in age from 14 to 57 years, pertaining to three unrelated families. Age at onset of seizures clustered around 9 years of age (range from 7 and 16 years, mean: 9.1 years+/-3.8). All affected individuals manifested nocturnal partial seizures of frontal lobe origin, which were well controlled by medications. Exon 5 of CHRNA4 and CHRNB2 genes, harboring all the known mutations, was sequenced in the probands. Then, we performed a linkage study on 13 affected and 26 non-affected individuals belonging to the three families with microsatellite markers and an intragenic polymorphisms encompassing the chromosome localization of the nAChR subunit genes and of the CRH gene. RESULTS: Mutational and linkage analyses allowed us to exclude the involvement of all known nAChR subunit genes and of the CRH gene in ADNFLE in our families. CONCLUSION: Our results further illustrate the considerable genetic heterogeneity for such a syndrome, despite the quite homogeneous clinical picture. It is therefore reasonable to hypothesize that at least another gene not belonging to the nAChR gene family, in addition to CRH, is involved in the pathogenesis of ADNFLE.     

Autosomal dominant nocturnal frontal lobe epilepsy in a Spanish family with a Ser252Phe mutation in the CHRNA4 gene.

BACKGROUND: A large family with autosomal dominant nocturnal frontal lobe epilepsy from the south of Spain was studied. The clinical appearance of the disease in this family, which included 28 members, of whom 11 were affected and 2 were obligate carriers, was identical to that previously described in an Australian family and a Norwegian family, in which mutations in exon 5 of the CHRNA4 gene were found. METHODS: Following DNA extraction, the family was genotyped with 4 fluorescent markers flanking the locus to the CHRNA4 gene on chromosome 20q13.3, and lod score computations were performed. The exon 5 of the CHRNA4 gene was amplified between nucleotides 535 and 825 and polymerase chain reaction products were purified and sequenced directly. RESULTS: The same missense mutation as that found in the Australian family, C-->T, which causes the replacement of a serine with phenylalanine in amino acid 252 in exon 5, was detected. This mutation segregated with the disorder in all 11 affected members, in the 2 obligate carriers, and in 1 asymptomatic sibling, and was not found in 1 spouse and 1 daughter. Neither of the 2 polymorphisms found in a series of families with epilepsy were found in our sample [corrected]. CONCLUSIONS: These data confirm the clinical homogeneity in the phenotypic expression of autosomal dominant nocturnal frontal lobe epilepsy caused by mutation in the CHRNA4 gene, and the pathogenic role of the Ser252Phe mutation in this disorder.     

Phenotypic comparison of two Scottish families with mutations in different genes causing autosomal dominant nocturnal frontal lobe epilepsy

PURPOSE: Mutations in genes coding for the alpha 4 and beta 2 subunits of the neuronal nicotinic acetylcholine receptor receptor (CHRN) are known to cause autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Here we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN. METHODS: All affected family members underwent a detailed clinical evaluation and review of available EEG, neuroimaging, and videotapes of seizures. The molecular study of family D is reported here; family S has a previously reported mutation in the beta 2 subunit of CHRN. RESULTS: A total of 16 individuals with ADNFLE were identified in the two families. In both families, seizure semiology, age at seizure onset, and the natural history of the seizure disorder was similar. Intrafamilial variation in terms of severity of epilepsy syndrome was present in both families. A significant number of individuals from each family had a history of psychological problems. The molecular study of family D revealed a Ser248Phe mutation in the alpha 4 subunit of CHRN. CONCLUSIONS: The epilepsy phenotype is not distinguishable in the two families who have ADNFLE as a result of mutations in genes coding for different CHRN subunits. This is likely to be due to the similar functional consequences of each mutation on the CHRN receptor.     

Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor alpha 4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes

To date five mutations in two major constituents of neuronal nicotinic acetylcholine receptor (nAChR) in the brain, i.e. alpha4 and beta2 subunits, have been identified to be associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Among them, only Ser284Leu, a point mutation in alpha4 subunit identified in ADNFLE as well as in a sporadic case with nocturnal frontal lobe epilepsy, remains to be characterized electrophysiologically. We examined the properties of rat nAChR harboring Ser284Leu reconstituted on Xenopus oocytes. Currents elicited in response to application of acetylcholine to oocytes expressing wild type or mutant nAChR were measured by a standard two-microelectrode voltage clamp method. Compared with wild-type nAChR, the mutant nAChR had a comparable EC(50) value for acetylcholine whereas it showed faster desensitization and lower Cs(+)/Na(+) permeability ratio. Ser284Phe, a putative mutation constructed for comparison, exhibited similar properties. These findings indicate that Ser(284) plays an important role in gating of nAChR along with Thr(276) and Ser(280), and suggest that mutation at Ser(284) could reduce nAChR activity similar to other mutations of alpha4 subunit found in ADNFLE.     

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy: An Electroclinical Study of a Norwegian Family with Ten Affected Members

Summary: Purpose: The aim of the study was to describe in detail the electroclinical findings associated with a mutation in the acetylcholine receptor in a Norwegian family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Furthermore, we compared the clinical features associated with this mutation with those of an Australian family with a different mutation at the same locus, as well as with those of eight Italian families with ADNFLE and without a verified mutation in this gene. Methods: We obtained medical records from all of the 10 known affected members of the Norwegian family. A personal interview and a clinical neurologic examination were carried out in six of them. Interictal and ictal scalp EEG recordings were obtained in eight and three, respectively, computed tomography/magnetic resonance imaging (CT/MRI) in five, and blood samples for genetic analysis in seven individuals. The clinical features after an insertion of a leucine residue in the α4 subunit of the neuronal nicotinic acetylcholine receptor are examined. Furthermore, the clinical features that accompany this insertion and the clinical features associated with a missense mutation (Ser248Phe) in the same gene were compared. Results: All the affected individuals had a seizure semiology consistent with frontal lobe seizures. Their seizures started in childhood (mean age, 8 years) and were often misinterpreted as benign nocturnal parasomnias, nocturnal paroxysmal dystonia, or a psychiatric disorder. The affected family members were of normal intellect and showed no abnormalities at neurologic and neuroradiologic examinations. Interictal scalp EEG registrations were mostly normal, ictal scalp EEG registrations in three individuals revealed left frontal low-voltage epileptiform discharges in two, and only shallow arousal preceding the attack in one. Although the seizure susceptibility varied among the affected individuals, the epilepsy course was mostly benign. Conclusions: Patients with ADNFLE, either with the 776ins3 mutation or the Ser248Phe mutation, and those without any recognized mutation in the acetylcholine receptor, have strikingly homogeneous phenotypes, and it seems difficult to separate them on clinical grounds.     

Autosomal dominant nocturnal frontal lobe epilepsy with a mutation in the CHRNB2 gene

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; MIM 600513) has been associated with mutations in the genes coding for the alfa-4 (CHRNA4), beta-2 (CHRNB2), and alpha-2 (CHRNA2) subunits of the neuronal nicotinic acetylcholine receptor (nAChR) and for the corticotropin-releasing hormone (CRH). A four-generation ADNFLE family with six affected members was identified. All affected members presented the clinical characteristics of ADNFLE. Interictal awake and sleep EEG recordings showed no epileptiform abnormalities. Ictal video-EEG recordings showed focal seizures with frontal lobe semiology. Mutation analysis of the CHRNB2 gene revealed a c.859G>A transition (Val287Met) within the second transmembrane domain, identical to that previously described in a Scottish ADNFLE family. To our knowledge, this is the third family reported presenting a mutation in CHRNB2. The clinical phenotype appears similar to that described with mutations in CHRNA4, suggesting that mutations in these two subunits lead to similar functional alterations of the nAChR.     

Refined mapping of CHRNA3/A5/B4 gene cluster and its implications in ADNFLE

The chromosome 15q24 region, containing the CHRNA3/A5/B4 gene cluster, coding for the alpha3, alpha5 and beta4 subunits of neuronal nicotinic acetylcholine receptors, has been reported to be linked to autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in one family. However, nor the gene nor the mutation involved have been identified. We report the refined mapping of CHRNA3/A5/B4 cluster. Segregation analyses of CHRNA3/A5/B4 polymorphisms in families showing recombinations for 15q24 G?en?ethon STR markers allowed to position the cluster in a 0.6 cM interval, between STRs D15S1027 and D15S1005. This location is external to the 15q24-ADNFLE-linked region, therefore excluding the involvement of this cluster in the pathogenesis of ADNFLE in the 15q24-linked family. Moreover, these data provide more precise information for further linkage studies.     

Autism in siblings with autosomal dominant nocturnal frontal lobe epilepsy

In 1999, Hirose et al. reported a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with a neuronal nicotinic acetylcholine receptor α4 subunit mutation (S252L). We followed the siblings of this family, and found that the elder brother had Asperger’s disorder without mental retardation (MR) and the younger brother had autistic disorder with profound MR. The clinical epileptic features of the siblings were very similar, and both had deficits in socialization, but their cognitive development differed markedly. It thus seems that epilepsy is the direct phenotype of the S252L mutation, whereas other various factors modulate the cognitive and social development. No patients with ADNFLE have previously been reported to have autism spectrum disorder or profound MR.     

A new locus for autosomal dominant nocturnal frontal lobe epilepsy maps to chromosome 1

BACKGROUND: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is caused by mutations in the alpha4 subunit of the neuronal nicotinic acetylcholine receptor (CHRNA4) gene, mapping on chromosome 20q13.2. A second ADNFLE locus was mapped on chromosome 15q24. OBJECTIVE: To report a new third ADNFLE locus on chromosome 1 in a large Italian family. METHODS: The authors performed a clinical and genetic study in a large, three-generation ADNFLE family from southern Italy, including eight affected individuals and three obligate carriers. RESULTS: The age at onset of seizures was around 9 years of age and all affected individuals manifested nocturnal partial seizures of frontal lobe origin. Interictal awake and sleep EEG recordings showed no definite epileptiform abnormalities in most patients. Ictal video-EEG showed that the attacks were partial seizures with a frontal lobe semiology. Intellectual and neurologic examinations, and brain CT or MRI results were always normal. Carbamazepine was effective in all treated patients. Exclusion mapping of the known loci linked to ADNFLE-ENFL1, and ENFL2, on chromosomes 20q13.2 and 15q24-was performed on the pedigree before starting the genome-wide linkage analysis. The whole genome scan mapping allowed the identification of a new ADNFLE locus spanning the pericentromeric region of chromosome 1. CONCLUSIONS: The authors provided evidence for a third locus associated to autosomal dominant nocturnal frontal lobe epilepsy on chromosome 1. Among the known genes mapping within this critical region, the ss2 subunit of the nicotinic receptor (CHRNB2) represents the most obvious candidate.     

A de novo mutation in sporadic nocturnal frontal lobe epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy is sometimes due to mutations in CHRNA4. The commoner presentation of sporadic nocturnal frontal lobe epilepsy has not been associated with genetic defects. A 30-year-old woman diagnosed as having sporadic nocturnal frontal lobe epilepsy was found to have a de novo Ser252Leu CHRNA4 mutation. A pattern is emerging of site-specific mutation within the second transmembrane domain of CHRNA4 in association with autosomal dominant nocturnal frontal lobe epilepsy and sporadic nocturnal frontal lobe epilepsy in families with different ethnic backgrounds.     

Association of the neuronal nicotinic acetylcholine receptor subunit alpha4 polymorphisms with febrile convulsions

PURPOSE: The alpha4-subunit gene of the neuronal nicotinic acetylcholine receptor (CHRNA4) has been identified as the first gene underlying an idiopathic partial epilepsy syndrome in human autosomal-dominant nocturnal frontal lobe epilepsy. Studies provided evidence that the protein coded by CHRNA4 is one of the most abundant subunits of the neuronal nicotinic acetylcholine receptors in mammalian brains, and mutations of CHRNA4 seem to cause neuronal excitation. The CHRNA4 gene may have a role in the development of febrile convulsions (FCs), the majority of childhood seizures. This study assessed the distribution of genotypes of CHRNA4 in patients with FCs. METHODS: A total of 102 children with FCs and 80 normal control subjects were included in the study. Polymerase chain reaction was used to identify the C/T polymorphism of the CHRNA4 gene. Genotypes and allelic frequencies for the CHRNA4 gene polymorphisms in both groups were compared. RESULTS: The number of individuals with heterozygous CHRNA4 (Ser543Ser)-C/T genotype was significantly greater (60.8% vs. 32.5%; p = 0.001), and the CHRNA4 (Ser543Ser)-T allele frequency was significantly higher (p = 0.001), in patients with FCs compared with healthy controls. The odds ratio for developing FCs in individuals with the CHRNA4 (Ser543Ser)-CT genotype was 3.77 compared with individuals with two copies of the CHRNA4 (Ser543Ser)-C allele. CONCLUSIONS: This study demonstrated an association between the CHRNA4 gene and FCs. Individuals with the T allele had a higher incidence of FCs. These data suggest that the CHRNA4 gene or a closely linked gene might be one of the susceptibility factors for FCs.     

Exclusion of linkage of nine neuronal nicotinic acetylcholine receptor subunit genes expressed in brain in autosomal dominant nocturnal frontal lobe epilepsy in four unrelated families

Members of the ligand-gated neuronal nicotinic acetylcholine receptor (nAChR) gene family (CHRNA4 and CHRNB2, coding for the α4 and β2 subunits, respectively) are involved in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). However, ADNFLE is genetically heterogeneous and mutations in CHRNA4 and CHRNB2 account for only a minority of ADNFLE cases. Additional nAChR subunits expressed in the brain are candidates for this epilepsy. The involvement of all genes coding for brain-expressed nAChR subunits, with known chromosome localization (CHRNB2, 1q21; CHRNA2, 8p21; CHRNA6, CHRNB3, 8p11.2; CHRNA7, 15q14; CHRNA5/A3/B4, 15q24 and CHRNA4, 20q13.2) was investigated in four unrelated ADNFLE Italian families for at least three generations. Families were selected on the basis of anamnestic and videopolysomnographic analyses. Individuals were typed for polymorphic markers located in the above mentioned chromosome regions. Linkage and mutation analyses were performed. In none of the families was linkage between ADNFLE and the analysed chromosome regions detected. These findings support the hypothesis that genes different from those coding for α2-7 and β2-4 neuronal nAChR subunits could be responsible for ADNFLE. Received: 17 July 2001 Received in revised form: 21 January 2002 Accepted: 29 January 2002     

Evidence for a fourth locus for autosomal dominant nocturnal frontal lobe epilepsy

Mutations responsible for autosomal dominant nocturnal frontal lobe epilepsy have been identified in two members of the neuronal nicotinic acetylcholine receptor gene family: CHRNA4(ENFL1 locus) and CHRNB2 (ENFL3 locus) coding for alpha4 and beta2 subunit, respectively. However, mutations in these genes account for only a minority (less than 10%) of cases. For a third ADNFLE locus (ENFL2) on chromosome 15q24 the gene was not identified. The involvement of the three loci in the pathogenesis of ADNFLE was investigated in 12 unrelated Italian families, selected on the basis of anamnestic and video-polysomnographic data. Compliant family members were typed for polymorphic markers spanning the analyzed chromosome regions. Linkage analyses excluded association of all chromosome regions with ADNFLE in 72% of cases. In two, four and one families it was impossible to ascertain or exclude association with ENFL1, ENFL2, or ENFL3, respectively, however, no mutations have been detected in the nicotinic receptor genes located in these regions. These data strongly suggest that ENFL1, ENFL2 and ENFL3 are minor loci for the disease and point to the existence of at least a fourth locus for ADNFLE.     

The identification of a novel mutation of nicotinic acetylcholine receptor gene CHRNB2 in a Chinese patient: Its possible implication in non-familial nocturnal frontal lobe epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is partly caused by mutations in the nicotinic acetylcholine receptor (nAChR) genes CHRNA4, CHRNB2, and CHRNA2. Cases of non-familial nocturnal frontal lobe epilepsy (NFLE) are more common than the familial type and the phenotypes of the two are similar. CHRNA4 mutations have been found in sporadic NFLE, but no mutation in CHRNB2 or CHRNA2 have been reported. To analyze the genetic features of sporadic NFLE, we designed mutation screening of exon 5 of CHRNA4, exon 5 of CHRNB2, and exon 6 of CHRNA2, mutations in which are associated with ADFLE. We screened a group of 105 Chinese sporadic NFLE cases and identified a novel CHRNB2 mutation, V337G, in an evolutionary conserved region of the intracellular loop between transmembrane domains M3 and M4 in one patient. This mutation was not observed in the control group of 200 subjects. Bioinformatics analysis indicated that the mutation altered the hydrophobicity and secondary structure of the protein. To the best of our knowledge, this study established for the first time that CHRNB2 is potentially associated with non-familial NFLE patient. No mutations in CHRNA4 or CHRNA2 were revealed by our screening method.