A Korean Kindred With Autosomal Dominant Nocturnal Frontal Lobe Epilepsy and Mental Retardation

Cho, Yong Won; Motamedi, Gholam K.; Laufenberg, Iris; Sohn, Sung Il; Lim, Jeong Geun; Lee, Hyung; Yi, Sang Doe; Lee, Ju Hwa; Kim, Dae Kwang; Reba, Richard C.; Gaillard, William D.; Theodore, William H.; Lesser, Ronald P.; Steinlein, Ortrud K.

doi:10.1001/archneur.60.11.1625

Cited by 75 publications

(41 citation statements)

References 24 publications

(19 reference statements)

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“…This variability may be family, and thus presumably nAChR gene mutation, dependent. Cho and colleagues described a different family with ADNFLE (CHRNA4 mutation) and markedly impaired general intellectual skills [33]. Similarly, we found that severe ADNFLE can be associated with marked psychiatric disability and intellectual impairment [34].…”

Section: Discussionsupporting

confidence: 65%

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: Discussionsupporting

confidence: 65%

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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“…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) sleep.…”

mentioning

confidence: 99%

“…Whereas the frontal lobe origin, adolescent onset, and clusters of nocturnal, hyperkinetic motor seizures are signatures of this disorder, the ADNFLE seizure phenotype shows incomplete penetrance and can present with (6,8) or without (4, 9) intra-and interfamilial variation in expressivity.…”

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.

184

205

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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...

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“…[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 study of the Australian and Norwegian family 14 showed no genetic connection.…”

Section: Introductionmentioning

confidence: 99%

“…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][13][14][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 study of the Australian and Norwegian family 14 showed no genetic connection.…”

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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A Korean Kindred With Autosomal Dominant Nocturnal Frontal Lobe Epilepsy and Mental Retardation

Cited by 75 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

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

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

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