Vulnerability to paroxysmal oscillations in delayed neural networks: a basis for nocturnal frontal lobe epilepsy?
Ontology highlight
ABSTRACT:
SUBMITTER: Quan A
PROVIDER: S-EPMC3258285 | biostudies-other | 2011 Dec
REPOSITORIES: biostudies-other
Similar Datasets
Project description:We assessed the mutation frequency in nicotinic acetylcholine receptor (nAChR) subunits CHRNA4, CHRNB2, and CHRNA2 in a cohort including autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and sporadic nocturnal frontal lobe epilepsy (NFLE). Upon finding a novel mutation in CHRNA2 in a large family, we tested in vitro its functional effects.We sequenced all the coding exons and their flanking intronic regions in 150 probands (73 NFLE, 77 ADNFLE), in most of whom diagnosis had been validated by EEG recording of seizures. Upon finding a missense mutation in CHRNA2, we measured whole-cell currents in human embryonic kidney cells in both wild-type and mutant ?2?4 and ?2?2 nAChR subtypes stimulated with nicotine.We found a c.889A>T (p.Ile297Phe) mutation in the proband (?0.6% of the whole cohort) of a large ADNFLE family (1.2% of familial cases) and confirmed its segregation in all 6 living affected individuals. Video-EEG studies demonstrated sleep-related paroxysmal epileptic arousals in all mutation carriers. Oxcarbazepine treatment was effective in all. Whole-cell current density was reduced to about 40% in heterozygosity and to 0% in homozygosity, with minor effects on channel permeability and sensitivity to nicotine.ADNFLE had previously been associated with CHRNA2 dysfunction in one family, in which a gain of function mutation was demonstrated. We confirm the causative role of CHRNA2 mutations in ADNFLE and demonstrate that also loss of function of ?2 nAChRs may have pathogenic effects. CHRNA2 mutations are a rare cause of ADNFLE but this gene should be included in mutation screening.
| S-EPMC4408286 | biostudies-literature
Project description:OBJECTIVE: Nocturnal frontal lobe epilepsy (NFLE) can be sporadic or autosomal dominant; some families have nicotinic acetylcholine receptor subunit mutations. We report a novel autosomal recessive phenotype in a single family and identify the causative gene. METHODS: Whole exome sequencing data was used to map the family, thereby narrowing exome search space, and then to identify the mutation. RESULTS: Linkage analysis using exome sequence data from two affected and two unaffected subjects showed homozygous linkage peaks on chromosomes 7, 8, 13, and 14 with maximum LOD scores between 1.5 and 1.93. Exome variant filtering under these peaks revealed that the affected siblings were homozygous for a novel splice site mutation (c.93+2T>C) in the PRIMA1 gene on chromosome 14. No additional PRIMA1 mutations were found in 300 other NFLE cases. The c.93+2T>C mutation was shown to lead to skipping of the first coding exon of the PRIMA1 mRNA using a minigene system. INTERPRETATION: PRIMA1 is a transmembrane protein that anchors acetylcholinesterase (AChE), an enzyme hydrolyzing acetycholine, to membrane rafts of neurons. PRiMA knockout mice have reduction of AChE and accumulation of acetylcholine at the synapse; our minigene analysis suggests that the c.93+2T>C mutation leads to knockout of PRIMA1. Mutations with gain of function effects in acetylcholine receptor subunits cause autosomal dominant NFLE. Thus, enhanced cholinergic responses are the likely cause of the severe NFLE and intellectual disability segregating in this family, representing the first recessive case to be reported and the first PRIMA1 mutation implicated in disease.
| S-EPMC4554443 | biostudies-literature
Project description:ObjectiveTo present findings on a series of cases of sporadic nocturnal frontal lobe epilepsy (NFLE), a form of NFLE that is infrequently reported, in contrast to familial (autosomal dominant) NFLE. Both forms of NFLE need to be distinguished from parasomnias, nocturnal temporal lobe epilepsy, and other nocturnal disorders.MethodsEight consecutive cases of sporadic NFLE were evaluated at a sleep clinic in Taiwan. All patients had clinical evaluations, daytime waking and sleeping EEGs, brain MRIs, and overnight video-polysomnography (vPSG) with seizure montage.ResultsGender was equal (four males, four females); mean age was 18.4 yrs (range, 7-41 yrs). Age of NFLE onset was by puberty. Premorbid history was negative for any neurologic, medical or psychiatric disorder. NFLE subtypes: nocturnal paroxysmal dystonia, n=6; paroxysmal arousals, n=2. MRI brain scan abnormalities with clinical correlates were found in one patient. Daytime awake EEGs were negative for ictal/interictal activity in all patients, but two patients had daytime sleep EEGs with interictal epileptiform EEG activity. During vPSG studies, three of eight patients with NFLE seizure events had concurrent epileptiform EEG activity, and two patients had interictal epileptiform EEG activity during their vPSG studies. No case had a spontaneous remission. Anticonvulsant therapy was highly effective in all eight cases (>75% reduction in seizure frequency).DiscussionThese cases confirm that sporadic NFLE closely resembles familial NFLE, and comprises a set of distinct clinical manifestations, with variable intensity, and variable scalp EEG epileptiform abnormalities across sleep and wakefulness, which have previously been identified in Caucasian patients from Europe and North America.
| S-EPMC4559607 | biostudies-literature
Project description:ObjectiveMost cases of sudden unexpected death in epilepsy (SUDEP) follow a seizure, and most deaths occur while people are in bed, presumably sleeping. Nocturnal seizures are reported to be a risk factor for SUDEP. People with nocturnal frontal lobe epilepsy (NFLE) have seizures predominantly or exclusively during sleep, often many times per night. The present study aimed to assess whether NFLE represents a high-risk condition for SUDEP.MethodsThe present study retrospectively assessed the incidence of SUDEP in a cohort reconstructed from a dedicated database of consecutive patients referred to the Epilepsy and Sleep Centres of the Institute of Neurological Sciences of Bologna from 1980 to 2012 with: (1) a diagnosis of NFLE, (2) at least 90% of seizures during sleep, and (3) at least one-year of follow-up.ResultsOne hundred and three people were included. The median time from seizure onset to last observation was 26 years, equal to a follow-up of 2789 person-years. One person died of SUDEP during the follow-up period. The incidence rate of SUDEP was 0.36 per 1000 person-years (95% CI 0.01 to 2.0).ConclusionsThe incidence of SUDEP in the participant population was not higher than the rates previously reported in prevalent epilepsy populations (0.4 to 2.3 per 1000 person-years). The low prevalence of SUDEP might reflect the low occurrence of generalised tonic-clonic seizures in people with NFLE.
| S-EPMC4350853 | biostudies-literature
Project description:ObjectiveTo describe the anatomo-electro-clinical findings of patients with nocturnal hypermotor seizures (NHS) preceded by auditory symptoms, to evaluate the localizing value of auditory aura.MethodsOur database of 165 patients with nocturnal frontal lobe epilepsy (NFLE) diagnosis confirmed by videopolysomnography (VPSG) was reviewed, selecting those who reported an auditory aura as the initial ictal symptom in at least two NHS during their lifetime.ResultsEleven patients were selected (seven males, four females). According to the anatomo-electro-clinical data, three groups were identified. Group 1 [defined epileptogenic zone (EZ)]: three subjects were studied with stereo-EEG. The EZ lay in the left superior temporal gyrus in two cases, whereas in the third case seizures arose from a dysplastic lesion located in the left temporal lobe. One of these three patients underwent left Heschl's gyrus resection, and is currently seizure-free. Group 2 (presumed EZ): three cases in which a presumed EZ was identified; in the left temporal lobe in two cases and in the left temporal lobe extending to the insula in one subject. Group 3 (uncertain EZ): five cases had anatomo-electro-clinical correlations discordant.ConclusionsThis work suggests that auditory aura may be a helpful anamnestic feature suggesting an extra-frontal seizure origin. This finding could guide secondary investigations to improve diagnostic definition and selection of candidates for surgical treatment.
| S-EPMC4247377 | biostudies-literature
Project description:Previously characterized nicotinic acetylcholine receptor (nAChR) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)-associated mutations are found in α2, α4 and β2 subunit transmembrane (TM) domains. They predominantly increase ACh potency and, for β2-subunit mutants, increase macroscopic currents. Two recently-identified mutations, α4(R336H) and β2(V337G), located in the intracellular cytoplasmic loop (C2) have been associated with non-familial NFLE. Effects of these mutations on α4β2-nAChR function and expression were studied for the first time, using two-electrode voltage clamp recordings in Xenopus laevis oocytes. Biased-ratio preparations elucidated the mutations' effects at alternate isoforms: high-sensitivity [HS; (α4)2(β2)3] or low-sensitivity [LS; (α4)3(β2)2] via 1:10 or 30:1 [α4:β2] cRNA injection ratios, respectively. An unbiased (1:1 [α4:β2] cRNA) injection ratio was also used to study potential shifts in isoform expression. α4(R336H)-containing receptors showed significant increases in maximal ACh-induced currents (Imax) in all preparations (140% increase compared to wild type control). β2(V337G)-containing receptors significantly increased Imax in the LS-favoring preparation (20% increase compared to control). Expression of either mutation consistently produced enrichment of HS-isoform expression in all preparations. α4β2-nAChR harboring either NFLE mutant subunit showed unchanged ACh, sazetidine-A, nicotine, cytisine and mecamylamine potency. However, both mutant subunits enhanced partial agonist efficacies in the LS-biased preparation. Using β2-subunit-specific [(125)I]mAb 295 immunolabeling, nAChR cell-surface expression was determined. Antibody binding studies revealed that the β2(V337G) mutation tended to reduce cell-surface expression, and function per receptor was significantly increased by either NFLE mutant subunit in HS-favoring preparations. These findings identify both common and differing features between TM- and C2-domain AD/NFLE-associated mutations. As we discuss, the shared features may be particularly salient to AD/NFLE etiology.
| S-EPMC4698238 | biostudies-literature
Project description:Study objectivesTo describe the semiological features of NREM arousal parasomnias in detail and identify features that can be used to reliably distinguish parasomnias from nocturnal frontal lobe epilepsy (NFLE).DesignSystematic semiologial evaluation of parasomnias and NFLE seizures recorded on video-EEG monitoring.Patients120 events (57 parasomnias, 63 NFLE seizures) from 44 subjects (14 males). Interventions. The presence or absence of 68 elemental clinical features was determined in parasomnias and NFLE seizures. Qualitative analysis of behavior patterns and ictal EEG was undertaken. Statistical analysis was undertaken using established techniques.ResultsElemental clinical features strongly favoring parasomnias included: interactive behavior, failure to wake after event, and indistinct offset (all P < 0.001). Cluster analysis confirmed differences in both the frequency and combination of elemental features in parasomnias and NFLE. A diagnostic decision tree generated from these data correctly classified 94% of events. While sleep stage at onset was discriminatory (82% of seizures occurred during stage 1 or 2 sleep, with 100% of parasomnias occurring from stage 3 or 4 sleep), ictal EEG features were less useful. Video analysis of parasomnias identified three principal behavioral patterns: arousal behavior (92% of events); non-agitated motor behavior (72%); distressed emotional behavior (51%).ConclusionsOur results broadly support the concept of confusion arousals, somnambulism and night terrors as prototypical behavior patterns of NREM parasomnias, but as a hierarchical continuum rather than distinct entities. Our observations provide an evidence base to assist in the clinical diagnosis of NREM parasomnias, and their distinction from NFLE seizures, on semiological grounds.
| S-EPMC2786048 | biostudies-literature
Project description:Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is an uncommon, idiopathic partial epilepsy characterized by clusters of motor seizures occurring in sleep. We describe a mutation of the beta2 subunit of the nicotinic acetylcholine receptor, effecting a V287M substitution within the M2 domain. The mutation, in an evolutionary conserved region of CHRNB2, is associated with ADNFLE in a Scottish family. Functional receptors with the V287M mutation are highly expressed in Xenopus oocytes and characterized by an approximately 10-fold increase in acetylcholine sensitivity. CHRNB2 is a new gene for idiopathic epilepsy, the second acetylcholine receptor subunit implicated in ADNFLE.
| S-EPMC1234917 | biostudies-literature
Project description:Mutations in genes coding for subunits of the neuronal nicotinic acetylcholine receptor (nAChR) have been involved in familial sleep-related hypermotor epilepsy (also named autosomal dominant nocturnal frontal lobe epilepsy, ADNFLE). Most of these mutations reside in CHRNA4 and CHRNB2 genes, coding for the ?4 and ?2 nAChR subunits, respectively. Two mutations with contrasting functional effects were also identified in the CHRNA2 gene coding for the ?2 subunit. Here, we report the third mutation in the CHRNA2, found in a patient showing ADNFLE. The patient was examined by scalp EEG, contrast-enhanced brain magnetic resonance imaging (MRI), and nocturnal video-polysomnographic recording. All exons and the exon-intron boundaries of CHRNA2, CHRNA4, CHRNB2, CRH, KCNT1 were amplified and Sanger sequenced. In the proband, we found a c.754T>C (p.Tyr252His) missense mutation located in the N-terminal ligand-binding domain and inherited from the mother. Functional studies were performed by transient co-expression of ?2 and ?2 Tyr252His , with either ?2 or ?4, in human embryonic kidney (HEK293) cells. Equimolar amounts of subunits expression were obtained by using F2A-based multi-cistronic constructs encoding for the genes relative to the nAChR subunits of interest and for the enhanced green fluorescent protein. The mutation reduced the maximal currents by approximately 80% in response to saturating concentrations of nicotine in homo- and heterozygous form, in both the ?2?4 and ?2?2 nAChR subtypes. The effect was accompanied by a strong right-shift of the concentration-response to nicotine. Similar effects were observed using ACh. Negligible effects were produced by ?2Tyr252His on the current reversal potential. Moreover, binding of (±)-[3H]Epibatidine revealed an approximately 10-fold decrease of both Kd and Bmax (bound ligand in saturating conditions), in cells expressing ?2Tyr252His. The reduced Bmax and whole-cell currents were not caused by a decrease in mutant receptor expression, as minor effects were produced by ?2Tyr252His on the level of transcripts and the membrane expression of ?2?4 nAChR. Overall, these results suggest that ?2Tyr252His strongly reduced the number of channels bound to the agonist, without significantly altering the overall channel expression. We conclude that mutations in CHRNA2 are more commonly linked to ADNFLE than previously thought, and may cause a loss-of-function phenotype.
| S-EPMC6379349 | biostudies-literature
Project description: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.
| S-EPMC1377480 | biostudies-other