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

Bertrand, Daniel; Elmslie, Frances; Hughes, Elaine; Trounce, J. R.; Sander, Thomas; Bertrand, Sonia; Steinlein, Ortrud K.

doi:10.1016/j.nbd.2005.05.013

Cited by 95 publications

(73 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Like the current study, verbal learning impairments have been identified previously in patients with ADNFLE. This included patients with S248F mutation [16] and twins with a novel mutation of the b2 nAChR [17]. The latter had significant impairments of general intellectual skills and other aspects of verbal functions.…”

Section: Discussionmentioning

confidence: 99%

“…The frontal lobe aspects of the disorder raise the possibility that associated cognitive dysfunction may be observed. Research on a pair of monozygotic twins with a mutation of the b2 nAChR found impaired verbal memory abilities [17]. Recent data on a group of 11 patients with known nAChR subunit mutations (three CHRNA4 and one CHRNB2 mutation) [16] showed impaired memory and executive function as well as impaired intellectual abilities in 5 patients.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

Wood¹,

Saling²,

Fedi³

et al. 2010

Epilepsy & Behavior

View full text Add to dashboard Cite

a b s t r a c tAutosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the a4 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 ADN-FLE. 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.Crown

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Wood¹,

Saling²,

Fedi³

et al. 2010

Epilepsy & Behavior

View full text Add to dashboard Cite

show abstract

“…CBZ reduces both the frequency and complexity of nocturnal seizures in more than 60% of patients with ADNFLE/NFLE, including those with S280F and insL mutations [28,30,31]. However, some cases (especially, individuals with S284L [32][33][34], T293I [35], V287M [36] and I312M [37]) are resistant to CBZ but respond to other antiepileptic drugs such as acetazolamide, benzodiazepine (BZP), topiramate and zonisamide (ZNS), or antiepileptic drugs-resistant [28,30,32,33,36,38,39]. (The amino acid numbering of CHRNA4 mutations used here is based on the deduced amino acid sequence of human α4 subunit and accordingly differs from those in the original articles that were based on the Torpedo sequence and nomenclature system).…”

Section: Criteria For Predictive Validity (Table 4)mentioning

confidence: 99%

Validation criteria for genetic animal models of epilepsy

Okada

Zhu

Yoshida

et al. 2010

E&S

View full text Add to dashboard Cite

In the past decades, several mutant genes that encode ion channel subunit proteins or their functionally-related proteins have been identified in pedigrees of idiopathic epilepsy. To explore the pathogenesis and pathophysiology of epilepsy syndrome, the functional abnormalities of transmission in genetic animal models bearing the mutant genes identified in pedigrees of idiopathic epilepsy should be analyzed. In spite of these efforts, it is important to identify the most suitable genetic animal models for exploration of epileptogenesis and ictogenesis, as well as the development of novel antiepileptic drugs. In the literature on genetic epileptic animal models, there is no systematic discussion on how to assess the validation criteria for such models. In this review, we describe the validation criteria for genetic animal models of epilepsy.

show abstract

“…A candidate gene for the third locus (ENFL2, 15q24) has not been identified. Considerable clinical and genetic data now provide a strong link between the ADNFLE syndrome and six mutations located within the pore-forming, second transmembrane domain of the ␣4 (S252F, ϩL264, S256L, T265I) and ␤2 (V287L, V287M) nAChR subunits (2), as well as a single mutation located in the third transmembrane domain of the ␤2 subunit (I312M) (3).…”

mentioning

confidence: 99%

Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

Klaassen

Glykys

Maguire

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

186

205

View full text Add to dashboard Cite

Selected mutations in the human ␣4 or ␤2 neuronal nicotinic acetylcholine receptor subunit genes cosegregate with a partial epilepsy syndrome known as autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). To examine possible mechanisms underlying this inherited epilepsy, we engineered two ADNFLE mutations (Chrna4 S252F and Chrna4 ؉L264 ) in mice. Heterozygous ADNFLE mutant mice show persistent, abnormal cortical electroencephalograms with prominent delta and theta frequencies, exhibit frequent spontaneous seizures, and show an increased sensitivity to the proconvulsant action of nicotine. Relative to WT, electrophysiological recordings from ADNFLE mouse layer II͞III cortical pyramidal cells reveal a >20-fold increase in nicotineevoked inhibitory postsynaptic currents with no effect on excitatory postsynaptic currents. i.p. injection of a subthreshold dose of picrotoxin, a use-dependent ␥-aminobutyric acid receptor antagonist, reduces cortical electroencephalogram delta power and transiently inhibits spontaneous seizure activity in ADNFLE mutant mice. Our studies suggest that the mechanism underlying ADNFLE seizures may involve inhibitory synchronization of cortical networks via activation of mutant ␣4-containing nicotinic acetylcholine receptors located on the presynaptic terminals and somatodendritic compartments of cortical GABAergic interneurons.cortex ͉ GABAegic interneuron ͉ nicotinic acetylcholine receptor E pilepsy is a common neurological disorder affecting Ϸ1% of the population worldwide. Over the past decade, several idiopathic epilepsies have been identified that show single-gene inheritance. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was the first idiopathic epilepsy for which specific mutations were described (1). Segregation and subsequent linkage analyses of ADNFLE families led to the assignment of candidate genetic loci and ultimately to the identification of specific mutations. Two of the three loci associated with this partial epilepsy (ENFL1, 20q13.3 and ENFL3, 1p21) map to neuronal nicotinic acetylcholine receptor (nAChR) subunit genes ␣4 and ␤2 (CHRNB2), respectively. A candidate gene for the third locus (ENFL2, 15q24) has not been identified. Considerable clinical and genetic data now provide a strong link between the ADNFLE syndrome and six mutations located within the pore-forming, second transmembrane domain of the ␣4 (S252F, ϩL264, S256L, T265I) and ␤2 (V287L, V287M) nAChR subunits (2), as well as a single mutation located in the third transmembrane domain of the ␤2 subunit (I312M) (3).In most patients with ADNFLE, seizure onset occurs during adolescence with symptoms persisting into adulthood. Affected individuals typically present without adverse neurological symptoms other than seizures, although several reports describe ADNFLE patients with a concomitant history of psychiatric problems (4, 5), cognitive deficits (3), or mental retardation (6). Clinical features of ADNFLE include clusters of brief seizures that initiate during non-rapid eye movement (NREM) sle...

show abstract

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

Cited by 95 publications

References 24 publications

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

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

Validation criteria for genetic animal models of epilepsy

Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

Contact Info

Product

Resources

About