Elsevier

Epilepsy & Behavior

Volume 17, Issue 4, April 2010, Pages 531-535
Epilepsy & Behavior

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

https://doi.org/10.1016/j.yebeh.2010.01.168Get rights and content

Abstract

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a nonlesional condition associated with mutation of the gene coding for the α4 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 ADNFLE. 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.

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.

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