Neuropsychological function in patients with a single gene mutation associated with autosomal dominant nocturnal frontal lobe epilepsy
Introduction
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 α(2–10) and β(2–4) subunits and are widespread throughout the brain. Initial human and animal evidence of a role for these receptors in fundamental and higher-level aspects of cognition has been reported, but a definitive view is yet to emerge. Administration of nicotine to abstinent smokers improves general alertness, attention, and vigilance [4], [5]. Nicotine improves performance on vigilance tasks [6], [7], inhibition of prepotent responses [8], and verbal learning [9] in nonsmokers. Effects such as these, however, are thought to reflect an influence on general alertness, rather than the primary influence of specific cognitive domains [10], [11]. Administration of nicotine or nicotinic drugs might also facilitate attention and memory in patients with dementia of the Alzheimer type [12]. The predominant effect of nAChR ligands in experimental animals appears to be on memory processing [6], [13], and the α7 and α4β2 receptors have been implicated in mediating these effects [5].
In the current study we examined individuals with a missense mutation, S248F, of the CHRNA4 gene that encodes the α4 subunit of the nAChR [3], [14]. Patients with this mutation have ADNFLE, a distinctive syndrome associated with mutations of three acetylcholine receptor subunit genes, CHRNA4, CHRNB2, CHRNA2, in different families [15]. The majority of mutations have been found in CHRNA4. Patients with ADNFLE experience clusters of nocturnal seizures arising from the frontal lobes [14], and reduced right prefrontal receptor density and hypometabolism are observed on PET [16]. 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 β2 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.
The aim of the current study was to characterize neurocognitive function in patients with ADNFLE caused by the same CHRNA4 mutation, tapping a range of functions that are heavily dependent on frontal lobe integrity. We hypothesized that aspects of executive function would be impaired in the patient group.
Section snippets
Participants
Inclusion criteria were a confirmed mutation of the CHRNA4 (S248F) gene, English as the first language, and absence of other neurological or cognitive disorders. Clinical features of the nine eligible participants from a single large family [14], [18] are summarized in Table 1. At the current assessment, a detailed clinical history and neurological examination were obtained by M.F. and I.E.S., and the participants’ medical records were reviewed and the most recent carbamazepine serum level
Results
The nine patients and nine controls were well matched on age and general intellectual abilities (all P > 0.05). The mean age of the mutation group was 40.1 years (SD = 15.0, range = 16–63), and that for controls was 39.3 years (SD = 14.6, range = 15–64).
Discussion
In contrast to previous research in patients with ADNFLE, our study involves a single group, which was homogeneous with respect to the underlying causative mutation. Family members with the S248F CHRNA4 subunit mutation were impaired on tasks that require flexible adaptation to, and monitoring of, cognitive demands. In particular, performance was impaired on Color–Word Interference, object alternation, Controlled Oral Word Association Test, and Part B of the Trail Making Test, implicating a
Ethical approval
We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Conflict of interest statement
None of the authors has any conflict of interest to disclose.
Acknowledgments
The contributions of family members, control participants, and Ms. Danya Vears are gratefully acknowledged. This work was supported by National Health and Medical Research Council of Australia program funding to S.F.B., I.E.S., and D.C.R. and postdoctoral training fellowship funding (ID 251755) to A.G.W.
References (35)
- et al.
Increased sensitivity of the neuronal nicotinic receptor α2 subunit causes familial epilepsy with nocturnal wandering and ictal fear
Am J Hum Genet
(2006) - et al.
Mecamylamine blocks enhancement of reference memory but not working memory produced by post-training injection of nicotine in rats tested on the radial arm maze
Behav Brain Res
(2002) - et al.
Neuronal nicotinic acetylcholine receptors: from the genetic analysis to neurological diseases
Biochem Pharmacol
(2008) - et al.
Neuropsychological disturbances in frontal lobe epilepsy due to mutated nicotinic receptors
Epilepsy Behav
(2009) - et al.
The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits
Neurobiol Dis
(2005) - et al.
Autosomal dominant frontal lobe epilepsy misdiagnosed as sleep disorder
Lancet
(1994) - et al.
A neurocognitive account of frontal lobe involvement in orthographic lexical retrieval: an fMRI study
NeuroImage
(2001) Behavioral aspects of frontal lobe epilepsy
Epilepsy Behav
(2001)- et al.
Autosomal dominant nocturnal frontal lobe epilepsy and mild memory impairment associated with CHRNB2 mutation I312M in the neuronal nicotinic acetylcholine receptor
Epilepsy Behav
(2008) - et al.
The nicotinic receptor B2 subunit is mutant in nocturnal frontal lobe epilepsy
Nat Genet
(2000)
A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy
Nat Genet
Nicotine and smoking: a review of effects on human performance
Exp Clin Psychopharmacol
Nicotinic receptor subtypes and cognitive function
J Neurobiol
Transdermal nicotine effects on attention
Psychopharmacology
Nicotine effects on adults with attention-deficit/hyperactivity disorder
Psychopharmacology
Selective effects of nicotine on attentional processes
Psychopharmacology
Effects of transdermal nicotine on attention and memory in healthy elderly non-smokers
Psychopharmacology
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