Increased Sensitivity of the Neuronal Nicotinic Receptor α2 Subunit Causes Familial Epilepsy with Nocturnal Wandering and Ictal Fear

Aridon, Paolo; Marini, Carla; Resta, Chiara Di; Brilli, Elisa; Fusco, Maurizio De; Politi, F; Parrini, Elena; Manfredi, Irene; Pisano, Tiziana; Pruna, Dario; Curia, Giulia; Cianchetti, Carlo; Pasqualetti, Massimo; Becchetti, Andrea; Guerrini, Renzo; Casari, Giorgio

doi:10.1086/506459

Cited by 231 publications

(159 citation statements)

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“…Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was the first epilepsy syndrome for which a genetic basis was discovered, and several nicotinic receptor subunit gene mutations have now been reported [1][2][3]. Neuronal nicotinic acetylcholine receptors (nAChRs) are heteropentamers of a(2-10) and b(2-4) subunits and are widespread throughout the brain.…”

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

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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

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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

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“…Expression of α4 mutants in human embryonic kidney cells or Xenopus oocytes had various effects, consistent with either gain or loss of function: increased sensitivity to acetylcholine (gain of function), or decreased Ca 2+ potentiation or accelerated desensitization (loss of function) [131,132]. Whereas β2 mutations showed gain of function by increased sensitivity to acetylcholine or slower desensitization [125], the α2 mutation showed gain of function by increased sensitivity to acetylcholine [128]. The α4 mutations S252F and +L264 engineered in knockin mice [133] induced spontaneous seizures of various types, in some cases similar to those of the human phenotype, but no paroxysmal arousal and dystonia-like manifestations that are typical of ADNFLE; α4 subunit knockout mice showed no spontaneous seizures, but had nicotine-induced dystonic attacks [134].…”

Section: Autosomal Dominant Nocturnal Frontal Lobe Epilepsymentioning

confidence: 99%

“…About 15 mutations in CHRN A4, 5 in CHRNB2 (which encodes the β2-subunit of nAchR), and 1 in CHRNA2 (encoding the neuronal nAchR α2-subunit) have been reported so far [123][124][125][126][127][128][129][130]. These receptors are heteropentameric, consisting of various combinations of subunits.…”

Section: Autosomal Dominant Nocturnal Frontal Lobe Epilepsymentioning

confidence: 99%

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

2014

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Research in genetics of epilepsy represents an area of great interest both for clinical purposes and for understanding the basic mechanisms of epilepsy. Most mutations in epilepsies without structural brain abnormalities have been identified in ion channel genes, but an increasing number of genes involved in a diversity of functional and developmental processes are being recognized through whole exome or genome sequencing. Targeted molecular diagnosis is now available for different forms of epilepsy. The identification of epileptogenic mutations in patients before epilepsy onset and the possibility of developing therapeutic strategies tested in experimental models may facilitate experimental approaches that prevent epilepsy or decrease its severity. Functional analysis is essential for better understanding pathogenic mechanisms and gene interactions. In vitro experimental systems are either cells that usually do not express the protein of interest or neurons in primary cultures. In vivo/ex vivo systems are organisms or preparations obtained from them (e.g., brain slices), which should better model the complexity of brain circuits and actual pathophysiological conditions. Neurons differentiated from induced pluripotent stem cells generated from the skin fibroblasts of patients have recently allowed the study of mutations in human neurons having the genetic background of a given patient. However, there is remarkable complexity underlying epileptogenesis in the clinical dimension, as reflected by the fact that experimental models have not provided yet results having clinical translation and that, with a few exceptions concerning rare conditions, no new curative treatment has emerged from any genetic finding in epilepsy.

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“…6 Clinically available molecular genetic testing reveals mutations in three genes encoding the a4, b2 and a2 subunits of the neuronal nicotinic acetylcholine receptor (CHRNA4, CHRNB2 and CHRNA2, respectively). [7][8][9] Overall mutations are found in less than 20% of individuals with ADNFLE/NFLE phenotypes, suggesting their genetic heterogeneity. 10 Approximately 10-20% of patients have a positive family history and fewer than 5% a negative one.…”

Section: Introductionmentioning

confidence: 99%

Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation

et al. 2011

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Autosomal dominant nocturnal frontal lobe epilepsy is a familial partial epilepsy syndrome and the first human idiopathic epilepsy known to be related to specific gene defects. Clinically available molecular genetic testing reveals mutations in three genes, CHRNA4, CHRNB2 and CHRNA2. Mutations in CHRNA4 have been found in families from different countries; the Ser280Phe in an Australian, Spanish, Norwegian and Scottish families, and the Ser284Leu in a Japanese, Korean, Polish and Lebanese families. Clear evidence for founder effect was not reported among them, including a haplotype study carried out on the Australian and Norwegian families. Japanese and Koreans, because of their geographical closeness and historical interactions, show greater genetic similarities than do the populations of other countries where the mutation is found. Haplotype analysis in the two previously reported families showed, however, independent occurrence of the Ser284Leu mutation. The affected nucleotide was highly conserved and associated with a CpG hypermutable site, while other CHRNA4 mutations were not in mutation hot spots. Association with a CpG site accounts for independent occurrence of the Ser284Leu mutation. Journal of Human Genetics (2011) 56, 609-612; doi:10.1038/jhg.2011.69; published online 14 July 2011Keywords: acetylcholine receptor; autosomal dominant nocturnal frontal lobe epilepsy; epilepsy; founder effect; mutation INTRODUCTIONAutosomal dominant nocturnal frontal lobe epilepsy (ADNFLE; MIM 118504) is a familial partial epilepsy syndrome characterised by clusters of brief frontal lobe motor seizures during drowsiness or sleep. 1,2 Seizures-often misdiagnosed as other nocturnal motor activities such as parasomnia or night terror 1-4 -vary from simple arousals to hyperkinetic activity with tonic or dystonic features. Onset usually occurs during the first two decades (mean age 10 years), but later onset has also been reported. 5 ADNFLE is the first human idiopathic epilepsy known to be related to specific gene defects. 6 Clinically available molecular genetic testing reveals mutations in three genes encoding the a4, b2 and a2 subunits of the neuronal nicotinic acetylcholine receptor (CHRNA4, CHRNB2 and CHRNA2, respectively). 7-9 Overall mutations are found in less than 20% of individuals with ADNFLE/NFLE phenotypes, suggesting their genetic heterogeneity. 10 Approximately 10-20% of patients have a positive family history and fewer than 5% a negative one. 11 Among the four mutations in CHRNA4 (Ser280Phe, Ser284Leu, Leu291dup and Thr293Ile), Ser280Phe and Ser284Leu have been identified in several unrelated families (mutation names may be different from those of previous papers; we use NP_000735.1):the Ser280Phe in an Australian, Spanish, Norwegian and Scottish families, 12-15 and the Ser284Leu in a Japanese, Korean, Polish and Lebanese families. [16][17][18][19] It has been assumed that founder effect is not relevant to ADNFLE, because most of the families studied come from different countries, 20 and a previous haplotype...

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Increased Sensitivity of the Neuronal Nicotinic Receptor α2 Subunit Causes Familial Epilepsy with Nocturnal Wandering and Ictal Fear

Cited by 231 publications

References 28 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

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation

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