Autosomal dominant nocturnal frontal lobe epilepsy and mild memory impairment associated with CHRNB2 mutation I312M in the neuronal nicotinic acetylcholine receptor

Certain paroxysmal nocturnal behaviors have been established as features of nocturnal frontal lobe epilepsy (NFLE). Despite insight into its genetics, the majority of patients with NFLE are not linked to a known mutation and clinical diagnosis remains a challenge. We describe a family presenting with stereotyped nocturnal arousals from non-rapid eye movement sleep, bilateral hand posturing, and pelvic thrusting in the mother, but subtle motor activity in the daughter, and minimal or no epileptiform EEG discharges. Despite normal IQ, there were moderate and severe verbal memory deficits in the mother and daughter, respectively. Genetic testing revealed the CHRNB2 mutation I312M in transmembrane region 3 (M3) of the neuronal nicotinic acetylcholine receptor. Phenotypic similarities in unrelated families suggest the determining role of this mutation in NFLE, whereas different inter- and intrafamilial cognitive profiles point to other factors. The absence of clear motor features of NFLE in the daughter emphasizes the shortcomings of current clinical criteria and the potential for genetic testing to further guide clinical diagnostic criteria.     

常染色体显性遗传夜间额叶癫痫

常染色体显性遗传性夜间额叶癫痫（autosomal dominant nocturnal frontal epilepsy，ADNFLE）是一种常染色体显性遗传的特发性局灶性癫痫综合征，1994年首先由Scheffer等描述，夜间成串的运动症状发作为最显著的临床特征。1995年Steinlein等首先发现其致病基因，是第一个被发现由基因变异引起的特发性癫痫综合征。本文对其临床特点、遗传学及发病机制的研究进展加以综述。     

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.     

A new Chrna4 mutation with low penetrance in nocturnal frontal lobe epilepsy

PURPOSE: To identify and characterize the mutation(s) causing nocturnal frontal lobe epilepsy in a German extended family. METHODS: Neuronal nicotinic acetylcholine receptor (nAChR) subunit genes were screened by direct sequencing. Once a CHRNA4 mutation was identified, its biophysical and pharmacologic properties were characterized by expression experiments in Xenopus oocytes. RESULTS: We report a new CHRNA4 mutation, causing a alpha4-T265I amino acid exchange at the extracellular end of the second transmembrane domain (TM). Functional studies of alpha4-T265I revealed an increased ACh sensitivity of the mutated receptors. alpha4-T265I is associated with an unusual low penetrance of the epilepsy phenotype. Sequencing of the TM1-TM3 parts of the 1 known nAChR subunits did not support a two-locus model involving a second nAChR sequence variation. CONCLUSIONS: nAChR mutations found in familial epilepsy are not always associated with an autosomal dominant mode of inheritance. alpha4-T265I is the first nAChR allele showing a markedly reduced penetrance consistent with a major gene effect. The low penetrance of the mutation is probably caused by unknown genetic or environmental factors or both.     

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.     

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.     

Autosomal dominant nocturnal frontal lobe epilepsy: the syndrome]

The identification of the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) in 1994 was rapidly followed by that of other familial forms of non lesional partial epilepsies (familial temporal lobe epilepsy, autosomal dominant partial epilepsy with variable foci). Since then around forty families with ADNFLE have been described, most of them having only 3 or 4 affected individuals. The epilepsy usually begins during childhood (mean age at onset: 11 years). The seizures mainly consist of motor elements which can be dystonic, tonic or hyperkinetic (bipedal automatisms, pelvic thrashing movements...), often preceded by a non specific aura. They are brief and frequent, taking place at night, in clusters. Some patients also present some diurnal seizures. One third of the patients report the occurrence of rare secondarily generalized tonic-clonic seizures. There is a large intra-familial variability as to age of onset, intensity of the manifestations and the course of the epilepsy. During the period of highest frequency of seizures, some patients may present moderate neuropsychological disturbances concordant with frontal dysfunctioning, or transitory behavioral disorders. The seizures often subside with age and may even disappear at adulthood. The most effective antiepileptic drug is carbamazepine, however pharmacoresistance is seen in 20 to 30 p. 100 of the cases. Interictal EEG shows non specific epileptiform anomalies with a frontal predominance, often seen solely on sleep recording, in more than half of all patients. Ictal EEG does not always give evidence of definite ictal discharges. The clinical heterogeneity of ADNFLE as it is especially observed in very variable types of auras which are non localizing, aside form the EEG's own limits, makes it difficult to localize the primary epileptic focus with certainty in the frontal lobe in all cases. In all, the clinical and electrical spectrum of ADNFLE is large, and the topographical identification of these familial frontal lobe epilepsies sets the same problems as for sporadic, classical cryptogenic frontal lobe epilepsies.     

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.     

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.     

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.     

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.     

额叶癫痫的手术治疗

目的总结并分析顽固性额叶癫痫患者手术治疗的效果、手术方式和经验。方法回顾性分析2003年3月至2009年4月在我院接受手术治疗的116例顽固性额叶癫痫患者的临床及脑电图特征、手术方式和疗效。结果随访1～6年,平均2.6年。疗效根据Engel的标准进行评定,其中I级（癫痫发作消失）49例（42.2%）;Ⅱ级（癫痫发作频率减少≥90%）36例（31.0%）;Ⅲ级（癫痫发作频率减少≥75%）19例（16.4%）;Ⅳ级（癫痫发作频率减少〈75%或与术前相近）12例（10.3%）。本组总有效（Ⅰ、Ⅱ、Ⅲ级）率为89.7%;效果优良（Ⅰ、Ⅱ级）率为73.3%。此外,患者术前所伴有的精神和行为异常在术后多数患者有所改善。术后无严重并发症及手术死亡。结论对于顽固性额叶癫痫,准确定位原发致痫灶并采用合理的手术方式彻底处理痫灶是手术成功的关键。必要时应采用颅内埋藏电极来寻找原发致痫灶。     

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.     

Neuropsychological function in patients with a single gene mutation associated with autosomal dominant nocturnal frontal lobe epilepsy

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the α4 nicotinic acetylcholine receptor (nAChR). The nAChR modulates aspects of memory and attention. We examined the neuropsychological phenotype of ADNFLE, with a particular emphasis on understanding the impact on frontal lobe functions. We used standard clinical tests as well as focused measures of frontal lobe function in a well-defined group of patients with ADNFLE. Their performance was compared with that of a group of age-, sex-, and education-matched control participants. Patients with ADNFLE showed impairments on tasks requiring cognitive flexibility against a background of well-preserved intellectual abilities. In accord with existing research, verbal memory impairments were identified in the patient group; the level of impairment on these tasks correlated with disease-related factors. In our study of ADNFLE associated with one mutation, cognitive flexibility appears to be the core cognitive deficit.     

Widespread cortical thinning in children with frontal lobe epilepsy

Purpose: Spread of seizure activity outside the frontal lobe due to cortico‐cortical connections can result in alteration in the cortex beyond the frontal lobe in children with intractable frontal lobe epilepsy (FLE). The aim of this study was to identify regions of reduced cortical thickness in children with intractable FLE. Methods: High‐resolution volumetric T₁‐weighted imaging was performed on 17 children with FLE, who were being evaluated for epilepsy surgery, and 26 age‐matched healthy controls. The cortical thickness of 12 patients with left FLE and 5 patients with right FLE was compared to controls. The clusters of cortical thinning were regressed against age of seizure onset, duration of epilepsy, seizure frequency, and number of medications. Key Findings: In children with left FLE, cortical thinning was present in the left superior frontal, paracentral, precuneus, cingulate, inferior parietal, supramarginal, postcentral, and superior temporal gyri, as well as in the right superior and middle frontal, medial orbitofrontal, supramarginal, postcentral, banks of superior temporal sulcus, and parahippocampal gyri. In children with right FLE, cortical thinning was present in the right precentral, postcentral, transverse temporal, parahippocampal, lingual, and lateral occipital gyri, as well as in the left superior frontal, inferior parietal, postcentral, superior temporal, posterior cingulate, and lingual gyri. In children with left FLE, following exclusion of one outlier, there was no significant association between age at seizure onset, duration of epilepsy, seizure frequency and number of medications with clusters of cortical thinning. In children with right FLE, age at seizure onset, duration of epilepsy, frequency of seizures, and number of medications were not associated with clusters of cortical thinning within the right and left hemispheres. Significance: Cortical changes were present in the frontal and extrafrontal cortex in children with intractable FLE. These changes may be related to spread of seizure activity, large epileptogenic zones involving both frontal and extrafrontal lobes, and development of secondary epileptogenic zones that over time lead to cortical abnormality. Further studies correlating cortical changes with neurocognitive measures are needed to determine if the cortical changes relate to cognitive function.     

Nocturnal hypermotor seizures, suggesting frontal lobe epilepsy, can originate in the insula

PURPOSE: To report three patients with drug-resistant nocturnal hypermotor seizures (NHSs), no detectable brain lesion, and clinically defined nocturnal frontal lobe epilepsy (NFLE) or autosomal dominant NLFE (ADNFLE), whose intracerebral EEG ictal onset primarily involved the insula, rather than the mesial or orbital frontal cortex. METHODS: Fourteen to 15 intracerebral electrodes were implanted in each patient, primarily sampling the frontal lobes with 80 to 91 recording leads covering the most likely side of seizure onset, and two to six leads placed within the ipsilateral insula. Electrical stimulation was used to test the epileptic threshold of frontal and insular brain regions at the various recording sites. RESULTS: In all three patients, a low-voltage fast activity was recorded within the anterosuperior aspect of the insula at ictal onset, either in isolation, or extending to the nearby frontal operculum in the ADNFLE patient. The role of the insula was further supported in all three patients either by the presence of high-amplitude spikes that clearly predominated over that region (n = 2) or by triggering the patient's typical aura or seizure when applying an electrical stimulation at that site, selectively (n = 2). CONCLUSIONS: The anterosuperior portion of the insula might play a pivotal role in generating nocturnal hypermotor seizures in some patients with nonlesional drug-resistant epilepsy suggesting NFLE or ADNFLE. Whether these patients are amenable to successful surgery remain an open issue.     

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.