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.     

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     

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.     

Mutations in familial nocturnal frontal lobe epilepsy might be associated with distinct neurological phenotypes

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare familial seizure disorder caused by mutations in at least two different subunit genes of the neuronal nicotinic acetylcholine receptor (nAChR), CHRNA4 and CHRNB2. ADNFLE was initially described as a "pure" seizure disorder with a mostly benign course. We have analysed the clinical features of 19 ADNFLE families from 12 countries with a total of 150 patients and grouped them with respect to their nAChR mutations. These data suggest that certain nAChR mutations might be associated with an increased risk for major neurological symptoms such as mental retardation, schizophrenia-like symptoms or marked cognitive deficits, but the risk for these disorders seems to be low for most other ADNFLE mutations. The functional data confirm that the mutations differ from each other with respect to the size of their gain-of function effects and other biopharmacological characteristics although these functional changes are not predictive for the severity of the clinical phenotype.     

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.     

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.     

Mutational analysis of nicotinic acetylcholine receptor beta2 subunit gene (CHRNB2) in a representative cohort of Italian probands affected by autosomal dominant nocturnal frontal lobe epilepsy

Twenty-four autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) probands were analyzed for the presence of V287L and V287M mutations in the CHRNB2 gene, which have been recently associated with the disease. In all patients, the involvement of the two additional loci reported as being associated with ADNFLE (CHRNA4 gene and chromosome 15q24 region) had been previously excluded. Mutational screening was performed by sequencing a polymerase chain reaction-amplified CHRNB2 DNA fragment, spanning the whole exon 5, which contains the V287L and V287M mutations and codes for approximately 65% of the mature protein. In none of the patients were mutations in the analyzed region of CHRNB2 found. These data, obtained in the largest ADNFLE cohort so far analyzed, demonstrate the rarity of the identified CHRNB2 mutations in ADNFLE patients.     

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.     

A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy

OBJECTIVE: To identify the mutation responsible for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in a nonwhite family. BACKGROUND: ADNFLE is newly recognized as an entity of idiopathic partial epilepsy. Recently, two different mutations of the neuronal nicotinic acetylcholine receptor alpha4 subunit (CHRNA4) gene were identified in a white family as a cause of ADNFLE. METHODS: Four affected and three unaffected individuals in three generations of a Japanese family with ADNFLE, and 100 unrelated healthy Japanese volunteers were studied. Clinical features and EEG findings in affected individuals were consistent with those of ADNFLE reported in white families with ADNFLE. Mutations within the CHRNA4 gene were screened for using single-strand conformation polymorphism analysis (SSCA) and were determined by direct sequencing. The mutation identified was sought in volunteers by the amplification refractory mutation system. RESULTS: A C-to-T exchange (C755T) was found in exon 5 of the CHRNA4 gene on one allele of affected individuals. C755T segregated in affected individuals and was not found in 200 alleles obtained from the volunteers. C755T replaced serine 252 (Ser252) in the second membrane-spanning domain (M2) of CHRNA4 with a leucine. Ser252 is conserved characteristically in the alpha-subunit of acetylcholine receptor and is considered to play an important role in channel function. CONCLUSION: C755T is a novel missense mutation of the CHRNA4 gene causing autosomal dominant nocturnal frontal lobe epilepsy in this Japanese family.     

The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits

Mutations in nAChRs are found in a rare form of nocturnal frontal lobe epilepsy (ADNFLE). Previously, some nAChR mutations have been described that are associated with additional neurological features such as psychiatric disorders or cognitive defects. Here, we report a new CHRNB2 mutation located in transmembrane region 3 (M3), outside the known ADNFLE mutation cluster. The CHRNB2 mutation I312M, which occurred de novo in twins, markedly increases the receptor's sensitivity to acetylcholine. Phenotypically, the mutation is associated not only with typical ADNFLE, but also with distinct deficits in memory. The cognitive problems are most obvious in tasks requiring the organization and storage of verbal information.     

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.     

Severe autosomal dominant nocturnal frontal lobe epilepsy associated with psychiatric disorders and intellectual disability

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a relatively benign epilepsy syndrome with few comorbidities. Here we describe two families with unusually severe ADNFLE, with associated psychiatric, behavioral, and cognitive features. Detailed clinical data on 17 affected individuals were obtained, and genotyping of microsatellite markers, linkage analysis, and sequencing of candidate genes was performed. The severe ADNFLE phenotype in these families was often refractory to treatment, with status epilepticus occurring in 24% of subjects. Psychiatric or behavioral disorders occurred in 53%, with intellectual disability in 24%, and developmental regression in two individuals. No mutations were identified in alpha4, alpha2, or beta2 nAChR subunits. In one family there was evidence of linkage to a region of 15q24 without nAChR subunit genes. In conclusion, severe ADNFLE has significant medical, psychiatric, and intellectual morbidity. The molecular basis of severe ADNFLE is unknown but may involve non-nAChR-related mechanisms.     

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.     

Autosomal dominant nocturnal frontal lobe epilepsy

Abstract. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an idiopathic epilepsy, with a spectrum of clinical manifestations, ranging from brief, stereotyped, sudden arousals to more complex dystonic–dyskinetic seizures. Video–polysomnography allows a correct differential diagnosis. There is no difference between sporadic nocturnal frontal lobe epilepsy (NFLE) and ADNFLE in the clinical and neurophysiological findings. ADNFLE is the first idiopathic epilepsy for which a genetic basis has been identified. Mutations have been found in two genes (CHRNA4 and CHRNB2) coding for neuronal nicotinic receptor subunits (4 and 2, respectively). Contrasting data have been reported on the effect of these mutations on the functionality of the receptor.Moreover, the incomplete data on the neuronal network/s in which this receptor is involved, make difficult the understanding of the genotype–phenotype correlation. This is an overview on the clinical and genetic aspects of ADNFLE including a discussion of some open questions on the role of the neuronal nicotinic receptor subunit mutations in the pathogenesis of this form of epilepsy.     

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.     

夜发性额叶癫痫三家系临床和遗传学特征

目的 分析夜发性额叶癫痫3个家系的临床、脑电图和遗传学特征.方法 在3个夜发性额叶癫痫家系患者及部分亲属中收集临床、脑电图及神经影像学等资料,并采用测序方法筛查烟碱型乙酰胆碱受体(nAChR)α4、β2和α2亚单位编码基因(CHRNA4、CHRNB2和CHRNA2).结果 3个家系中有6例患者(其中男5例),平均年龄(20.5±11.5)岁,平均发病年龄(7.3±5.5)岁,临床表现为夜发性额叶发作,具体发作类型包括姿势性发作2例,躯体自动症发作4例,最多每夜发作6次.发作间期、发作期视频脑电图2例患者表现为正常或动作伪差,2例表现为前部导联慢波节律,3例出现前部导联棘波、棘慢波及尖波.神经系统及神经影像检查未见异常.抗癫痫药物治疗反应良好.CHRNA4、CHRNB2和CHRNA2部分序列(包含跨膜区1～3)筛查未见突变.结论 夜发性额叶癫痫是一种遗传异质性癫痫综合征.     

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.     

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.     

Two new putative susceptibility loci for ADNFLE

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) has been up to now considered a simple Mendelian trait caused by mutations in neuronal nicotinic acetylcholine receptor (nAChR) subunit genes. We previously demonstrated that in a three-generation Italian family the disease was unlinked to all known ADNFLE loci as well as to all known brain-expressed nAChR subunits. The genome-wide linkage analysis here presented performed on this family points to the existence of two new putative ADNFLE loci on chromosomes 3p22-p24 and 8q11.2-q21.1. These findings, together with several ADNFLE characteristics, suggest that this epilepsy could be, at least in the above family, a complex disorder. In particular, we propose and discuss the hypothesis of a digenic transmission of the disease.