Seizure 21 (2012) 118–123

Contents lists available at SciVerse ScienceDirect

Seizure

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Mutations in familial nocturnal frontal lobe epilepsy might be associated

with distinct neurological phenotypes

a, b b b

Ortrud K. Steinlein *, Jean-Charles Hoda , Sonia Bertrand , Daniel Bertrand

a

Institute of Human Genetics, University Hospital, Ludwig-Maximilians-University, Goethestr. 29, D-80336 Munich, Germany

b

Department of Neuroscience, Medical Faculty, Centre Me´dical Universitaire, CH-1211 Geneva, Switzerland

A R T I C L E I N F O A B S T R A C T

Article history: Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is a rare familial seizure disorder caused

Received 17 August 2011

by mutations in at least two different subunit genes of the neuronal nicotinic acetylcholine receptor

Received in revised form 12 October 2011

(nAChR), CHRNA4 and CHRNB2. ADNFLE was initially described as a ‘‘pure’’ seizure disorder with a mostly

Accepted 12 October 2011

benign course. We have analysed the clinical features of 19 ADNFLE families from 12 countries with a

total of 150 patients and grouped them with respect to their nAChR mutations. These data suggest that

Keywords:

certain nAChR mutations might be associated with an increased risk for major neurological symptoms

Epilepsy

such as mental retardation, schizophrenia-like symptoms or marked cognitive deficits, but the risk for

ADNFLE

these disorders seems to be low for most other ADNFLE mutations. The functional data confirm that the

Cognition

mutations differ from each other with respect to the size of their gain-of function effects and other

Mental retardation

Acetylcholine receptor biopharmacological characteristics although these functional changes are not predictive for the severity

Electrophysiology of the clinical phenotype.

ß 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

5–10

1. Introduction or cognitive deficits have been described only in a few families.

So far it is unknown if these additional features occur by chance, or

Epilepsies affect about 1% of the population, rendering it one of if they are indeed causally related to specific nAChR mutations. The

the most common neurological disorders. Most non-lesional systematic analysis of the clinical variability presented here

epilepsies arise on an oligogenic or polygenic background, but suggests that the risk for additional major neurological and

several seizure disorders are known to segregate in a Mendelian psychiatric features might be increased for ADNFLE patients with

fashion. These rare monogenic epilepsies are valuable models for certain nAChR mutations but rare for the carriers of most other

scientific approaches and have already helped to uncover parts of mutations. The functional studies show that ADNFLE mutations

the various pathomechanisms underlying epileptogenesis. Auto- differ from each other with respect to their biopharmacological

somal dominant nocturnal frontal lobe epilepsy (ADNFLE) has a characteristics but that no obvious correlation can be detected

special role within this group of monogenic epilepsies because it between the severity of the clinical phenotypes and the respective

was the first epilepsy in humans for which specific mutations were changes in receptor function.

identified. So far, mutations in at least two genes, CHRNA4 and

CHRNB2 encoding the a4 and b2 subunits of the neuronal nicotinic 2. Methods

acetylcholine receptor (nAChR), are known to give rise to

1,2

ADNFLE. These mutations cause a clinical phenotype that was 2.1. Subjects

initially described as a ‘‘pure’’ epilepsy characterized by nocturnal

seizures that arise mostly from non-REM sleep. In the original Clinical data from 20 ADNFLE families with known nAChR

family 27 individuals were affected and, except for the seizures, no mutations were either taken from the histories of families

neurological symptoms, psychiatric disturbances or mental diagnosed in our lab (Munich) or collected by reviewing the

3

deficiencies were reported. Subsequent studies indicated that relevant literature (for references see Table 1). The study protocol

borderline intelligence or mild deficits in executive tasks are not was approved by the institutional review board and informed

4

uncommon in ADNFLE patients. However, major neurological consent was given from the participants.

features such as schizophrenia-like symptoms, mental retardation

2.2. Mutation construct

* Corresponding author. Tel.: +49 89 5160 4468; fax: +49 89 5160 4470. CHRNA4 and CHRNB2 mutations were introduced by PCR-based

E-mail address: [email protected] (O.K. Steinlein). site-directed mutagenesis (QuikChange II site-directed mutagene-

1059-1311/$ – see front matter ß 2011 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.seizure.2011.10.003 Table 1 Summary of clinical data for ADNFLE families.

Gene Mutation Ethnic origin Number of clinically affected Neurological/psychiatric features Antiepileptic drug treatment (n)/sei- References individuals (f/m) other than NFLE (n/t) zure severity (n)/drug efficiency (n) 1,16–18 CHRNA4 S248F (S280F) British-Australian 27 (18/9) CBZ average 690 mg (NA), MD (11)/ controlled in most patients (NA) Spanish 11 (7/4) CBZ 600–1000 mg (4), VPA 700 mg (1), NT (2), NA (4)/controlled (6), poorly controlled (2) Norwegian 22 (10/12) Mild mental retardation (1/22) NA/controlled (10), uncontrolled (1), Psychiatric disorder, unclassified (1/22) SRI (6), NA (5) Scottish 7 (4/3) Psychological problems (NA) NA (1), NT (6)/SRI (6), severe (1) 6–8,23,25 S252L (S284L) Japanese 5 (2/3) Mild mental retardation (3/5) CBZ NA (1), MD (2), NT (1), NA (1)/ Early childhood onset of epilepsy (3/5) controlled (1), SRI (1), poorly controlled (2), NA (1) Lebanese 2 (1/1) Low average intellect (1/2) NA/poorly controlled (1), NA (1) Early childhood onset of epilepsy (2/2) Korean 9 (7/2) Mild to moderate mental retardation (7 CBZ (1), MD (5), NT (1), NA (2)/SRI (1), out of 9 available for testing) improvement (3), poorly controlled (3)

Polish 3(1/2) Early childhood onset of epilepsy (2/3) MD (2), NT (1)/poorly controlled (3) O.K. 5,9

776ins3 (865-873insGCT) Norwegian 11 (5/6) Schizophrenia (1/11) NA Steinlein Negative symptoms of schizophrenia (1/11)

Recurrent psychosis (1/11) et

Psychiatric disorder, unspecified (3/11) al.

(5 family members were not available /

for testing) Seizure T265I (T293I) German 2 (0/2) CBZ 2400 mg (1), CBZ NA (1)/ 19 improvement (1), poorly controlled (1)

R308H (R336H) Chinese 1 (0/1) NA MD (1)/poorly controlled (1) 13 21

(2012) CHRNB2 V287L Italian 8 (2/6) CBZ 400–800 mg (6), NT (2)/controlled 2,22 (6), SRI (1), mild (1)

V287M Scottish 10 (6/4) Psychological problems mentioned, CBZ NA (4), MD (3), NT (3)/SRI (NA), 18,20,21 118–123 numbers not specified poorly controlled (1) Spanish 6 (3/3) CBZ NA (2), PB 150 mg (1), NT (3), NA (1)/SRI (1), improved (1), controlled (2), poorly controlled (1), NA (1) 15 L301V Turkish Cypriot 3 (2/1) CBZ NA (1), NT (2)/SRI (1), mild (1) poorly controlled (1) V308A Scottish 5 (4/1) LTG NA (1)/controlled (1) 15 German 4 (2/2) CBZ NA (2)/controlled (2) I312M English 2 (2/0) Low average intellect with significant MD (2)/controlled (2) 10,24 memory deficits (verbal) (2/2) Korean 2 (2/0) Psychiatric episode with delusional NA ideas (1/2) Normal intelligence with moderate memory deficits (verbal) (1/2) Normal intelligence with significant memory deficits (verbal/visual) (1/2) 14 CHRNA2 I279N Italian 10 (8/2) NA NA/controlled (2), poorly controlled (8) ADNFLE mutations frequently associated with additional major neurological or psychiatric symptoms are given in bold. Mutations are named as in the original references, for CHRNA4 numberings according to reference sequences (NP_000735.1, NP_000739.1) are given in brackets; NA, data not available; NT, not currently treated; n, number of patients; f/m, female/male; n/t, number of total; MD, patients with more than one drug; SRI, spontaneous remission or improvement. Antiepileptic drugs (number of patients given in brackets): CBZ, carbamazepin; PB, phenobarbital; PHT, phenytoin; LTG, lamotrigine. 119

120 O.K. Steinlein et al. / Seizure 21 (2012) 118–123

sis Kit, Stratagene Europe) into full-length cDNAs as previously CHRNA4-R308H, a recently published but not yet functionally

11 13

described. The correct sequences were confirmed by direct characterized mutation in the second intracellular loop. A single

sequencing. CHRNA2 mutation was described in a family with a clinical

11,14

phenotype resembling ADNFLE. Three CHRNA4 mutations

2.3. Functional studies (776ins3, T265I, R308H) and three CHRNB2 mutations (V287L,

L301V, V308A) have each been found only in a single family, while

Xenopus oocytes were isolated and selected as previously two CHRNA4 mutations (S248F, S252L) were detected in four

11

described. Briefly, oocytes were harvested from mature Xenopus families each, and two (CHRNB2-V287M, CHRNB2-I312M) in two

females following animal ethic rules of Geneva canton, families each. For most patients with CHRNA4 mutations S248F and

1,15–19

Switzerland. Oocytes were isolated by mechanical and enzymatic T265I as well as CHRNB2 mutations V287L, V287M, L301V,

15,18,20–22

action using type I collagenase (Sigma, Basel Switzerland) at 0.2% and V308A no additional major neurological or psychiat-

in a medium deprived of calcium. Stage V and VI oocytes were ric features were reported. A detailed neuropsychological assess-

placed in 96 wells microtiter plates (NUNC) in BARTH medium that ment in 11 patients with three of the above mentioned mutations

contained 88 mM NaCl, 1 mM KCl, 2.4 mM NaHCO3, 10 mM HEPES, (S252L, S248F, T265L) showed borderline intelligence but no

0.82 mM MgSO4Á7H2O, 0.33 mM Ca(NO3)2Á4H2O, 0.41 mM mental retardation in 45% of them and mild deficits in executive

4

CaCl2Á6H2O, adjusted to pH 7.4 with NaOH and complemented functions in all 11 patients. Severe additional neurological or

with kanamycin (20 mg/ml), penicillin (100 U/ml) and streptomy- psychiatric features were diagnosed in most carriers of CHRNA4

5–9,23

cin (100 U/ml). Nuclear injections of 2 ng of cDNAs containing in mutations S252L and 776ins3, and CHRNB2 mutation

12 10,24

equal ratios the genes of interest were performed with a robot, I312M. The CHRNA4 mutation S252L was the only one that

and cells were subsequently maintained at 18 8C. showed an unusual age of onset in 7/19 patients with seizures

starting as early as six months of age, while the average age of

2.4. Recording of nAChR properties onset for all other mutations was mostly within the second half of

the first decade or in the second decade. Only very few patients

Electrophysiological properties of oocytes were determined with mutations other than S252L were reported to have an earlier

3,5

two to five days after cDNA injection by automated two electrode age of onset. Additional major neurological and psychiatric

voltage clamp. During recording oocytes were continuously features tended to be the same with a given mutation but different

superfused with OR2 (control medium) that contained 82.5 mM between mutations. Mental retardation was the main additional

6–

NaCl, 2.5 mM KCl, 2.5 mM CaCl2, 1 mM MgCl2, 5 mM HEPES, symptom described in 10/19 carriers of CHRNA4 mutation S252L,

8,23,25

adjusted to pH 7.4 with NaOH. Unless otherwise stated the holding while at least 6/11 affected family members in the CHRNA4-

potential was À100 mV and experiments were performed at 18 8C. 776ins3 family had serious psychiatric problems including

Data were filtered at 10 Hz and digitized at 100 Hz with an analog schizophrenia-like symptoms (four additional affected individuals

to digital converter (National Instrument). Concentration–activa- from this family refused to be questioned about psychiatric

9

tion curves were fitted using a Hill equation in the form: Y = 1/ problems). The CHRNB2 mutation I312M was associated with

nH

1 + (EC50/x) where: y = the fraction of evoked current, EC50 = con- specific cognitive defects affecting mostly verbal memory in all

centration for 50% activation of the high affinity, nH = the apparent affected members from the two families known to carry this

10,24

cooperativity for the high affinity, x = agonist concentration. For mutation (Table 1).

statistical analysis the unpaired, two-tailed Student’s t-test was

computed either with Excel (Microsoft) or Matlab (mathworks 3.2. Electrophysiological analysis

Inc.).

The normalized dose-response curve of the wildtype a4b2

receptors showed a very low sensitivity for acetylcholine for doses

3. Results

up to 1 mM. Concentrations above 1 mM elicited currents with a

steep increase in amplitude with a maximum reached at 300 M.

3.1. Clinical findings m

In accordance to previous published studies the results were best

15

fitted with the sum of two empirical Hill equations. Compared to

The clinical information of 20 ADNFLE families from 13

the wildtype the two mutations 4S248F/ 2 and 4S252L/ 2

countries with a total of 150 patients is summarized in Table 1. a b a b

showed a much higher affinity for acetylcholine, which was most

More females than males were affected by nocturnal frontal lobe

pronounced in the latter mutation. Referring to the EC50H of the

epilepsy (total, 86 versus 64, CHRNA4, 55 versus 45; CHRNB2, 23

mutated receptors (0.8 for 4S248F/ 2 and 0.75 for 4S252L/ 2)

versus 17; CHRNA2, 8 versus 2). The known mutational spectrum in a b a b

they differed markedly from that of the wildtype receptor (8.5).

ADNFLE includes five CHRNA4 and four CHRNB2 mutations (Fig. 1).

Nonetheless the Hill coefficients for the high-affinity state as well

CHRNA4 mutations are located within or directly adjacent to the

as that for the low affinity state were nearly equal for all three

second transmembrane domain (TM2), while CHRNB2 mutations

receptors (n = 0.9–0.95 and n 1.4, respectively; see Table 2).

are equally distributed between TM2 and TM3. An exception is HH HL

Fig. 1. Position of ADNFLE mutations in CHRNA4 and CHRNB2. Wild type amino acids are underlined and mutated amino acids are written above or below them. For numbering

see legend of Table 1.

O.K. Steinlein et al. / Seizure 21 (2012) 118–123 121

Table 2

to belong to the more benign causes of ADNFLE because the few

Acetylcholine affinity at different ADNFLE mutants.

carriers that have been analysed by neuropsychological tests were

Receptor a EC50H nHH 1 À a EC50L nHL found to have mild cognitive deficits [4] but major psychiatric or

neurological features other than epilepsy were only reported in

a4b2 19 8.4 0.9 81 77 1.4

a4 + a4S248Fb2 75 0.8 0.95 25 62 1.4 two out of 67 patients. The age of onset is within the usual range

a4 + a4S252Lb2 75 0.75 0.95 25 30 1.4 observed for most ADNFLE mutations, and long-time remissions

a4b2 + b2L301V 56 3.8 1.3 44 41 0.9

are not uncommon. The rather benign nature of CHRNA4-S248F

a4b2 + b2V287M 65 0.4 1.6 35 5.3 1

contrasts sharply with the more severe clinical course that seems

a, percentage of receptors in the high-affinity state; EC and n , half-maximal

50H HH to be associated with the adjacent mutation CHRNA4-S252L. At

effective concentration and Hill coefficient for the high-affinity state; EC50L and nHL,

least 11 of the 19 known carriers of this mutation showed

half-maximal effective concentration and Hill coefficient for the low-affinity state.

intellectual capacities that fell into the low normal or the moderate

retarded range. Remarkable is also the unusually low age of onset

Recorded currents of receptors carrying the b2 mutations, a4/ which in three out of four families with CHRNA4-S252L was mostly

6,7,23

b2L301V and a4/b2V287M, were normalized and fitted as in early childhood (six months to two years). The later age of

described above. The highest affinity for ACh was seen for the onset in the third family argues against a causative relationship

a4/b2V287M receptor (EC50H = 0.4) followed by a4/b2L301V between the early onset of epilepsy and the less than favourable

8

(EC50H = 3.8) and finally the wild type a4/b2 with the lowest mental outcome in CHRNA4-S252L patients. It seems more likely

affinity (EC50H of 8.4). In contrast to the alpha-subunit mutations that both features are independent of each other but are both

and to the wildtype receptors, the Hill-coefficients for the high- related to the underlying mutation. Another example for two

affinity state of b2-mutations were generally higher (a4/b2L301V adjacent ADNFLE mutations that differ with respect to their clinical

nHH = 1.3; a4/b2V287M nHH = 1.6) than for the low-affinity state features is the CHRNB2 mutations V308A and I312M. Like CHRNA4-

(L301V nHL = 0.9, V287M nHL = 1.0). The number of receptors in the S248F, mutation CHRNB2-V308A causes a mostly benign type of

high-affinity state was remarkably increased for all four mutations nocturnal frontal lobe epilepsy usually without additional

15

examined in this study (see parameter ‘‘a’’ in Table 2). neurological or psychiatric features. The clinical spectrum

associated with mutation CHRNB2-I312M appears to be much

4. Discussion more severe with all four affected members from two unrelated

families showing clinically relevant deficits in their cognitive

10,24

All but one of the known ADNFLE mutations cluster in small functions, especially in verbal memory. However, unlike the

parts of either CHRNA4 or CHRNB2 (Fig. 1), and several of these S248F and S252L mutations described above, the numbers of

mutations have been identified in two or more unrelated families families and patients with mutations V308A or I312M are still

(Table 1). However, phenotypic comparison is hampered by the rather low and do not allow definite conclusions about the

fact that most of the published families have not been evaluated by phenotypic differences yet.

standardized neuropsychological tests. This renders it difficult to The families carrying the same ADNFLE mutation and sharing

deduce exact risk figures for additional neurological or psychiatric the same associated neurological or psychiatric features are

problems that might be associated with ADNFLE mutations. Mild usually from different countries and are most likely unrelated,

cognitive deficits as they have been reported in a pilot study for a thus a shared genetic background cannot explain the observed

4

small number of patients might often go undetected without associations. The possibility remains that the associated symptoms

careful evaluation, however, major neurological symptoms such as are caused by a not fully penetrant mutation in a second, unknown

mental retardation or schizophrenia-like disorder are likely to be gene. However, the probabilities that such a gene would be

reported. The present study therefore focused solely on such major physically closely linked to the mutated nAChR gene or cose-

symptoms, but it needs to be stressed that for all mutations the gregate with it in a multiplex pedigree by chance are very low,

frequency of associated clinical symptoms might in fact be higher rendering these two possibilities unlikely. Another possibility

than given in Table 1. would be that unknown environmental factors are responsible for

Comparison of the clinical data shows that the percentage of the increased risk for additional major features. Again, this

patients reported to have associated major neurological or explanation is unlikely because the chances are very low that

psychiatric features is rather low for some mutations but quite the same environmental risk factors are present in families

high for others. The data also suggest that these associations are carrying the same mutation but living in countries far apart.

not exclusive as not all carriers of mutations that seem to bear an Furthermore, there are no obvious differences with respect to high

increased risk for major neurological or psychiatric symptoms are drug doses or multiple drug treatment between ADNFLE families

affected by these additional features but a few carriers of putative with a high versus those with a low rate of associated clinical

low-risk mutations are. It is also interesting to note that families features. A causal relationship between the neurological and

carrying the same mutation tend to have an identical pattern of psychiatric features and the respective ADNFLE mutation seems to

accessory major neurological or psychiatric features. In some be the most likely explanation, and it would also fit well with the

families mental retardation was a common feature but no wide range of neuronal dysfunctions and psychiatric disorders

psychiatric disorders were reported while in other families the nAChRs have been implicated in Ref. 26. For example, loss of

opposite pattern was observed (Table 1). The strongest association cholinergic transmission is regarded as a significant cause of

between mutation and clinical phenotype was found for a pair of cognitive decline in patients with Alzheimer’s disease. This

mutations located close together in transmembrane region 2 hypothesis is supported by the reduction and degeneration of

(TM2) of CHRNA4, S248F and S252L. CHRNA4-S248F was the first cholinergic neurons or the reduced amount of cholinergic key

1

mutation discovered in ADNFLE, and has been found in an enzymes like choline acetyltransferase and acetylcholine esterase

27

extended Australian family of British origin as well as in families in post mortem brains of Alzheimer patients. More recently,

16–18

from Spain, Norway and Scotland. With a total of 67 patients it cholinergic dysfunction has been shown to be an early hallmark of

28

is so far the most frequently found ADNFLE mutation. The large cognitive decline. Genetic variants in nAChR subunits have also

number of patients carrying this mutation allows a good found to be associated with psychiatric disorders and behavioural

29

assessment of the clinical variability of major neurological traits. It can therefore be hypothesized that the dysfunction of

symptoms associated with CHRNA4-S248F. This mutation seems nAChRs caused by ADNFLE mutations is probably at the origin of

122 O.K. Steinlein et al. / Seizure 21 (2012) 118–123

Fig. 2. Functional properties of ADNFLE mutations. Dose response curves for controls and mutant receptors. Data points represent normalized mean values Æ S.E.M. Regression

curves were calculated by the sum of two empirical Hill equations. Specific values for the parameters are given in Table 2.

the additional major neurological or psychiatric symptoms 5. Conclusions

observed in several of the patients suffering from this rare genetic

epilepsy. The data presented here suggest that certain ADNFLE mutations

Expression studies demonstrate that, despite their clustering, might be associated with specific risks for additional major

ADNFLE mutations significantly differ from each other with respect neurological or psychiatric symptoms. However, the numbers of

to the changes in biopharmacological properties they induce in affected families are still too low for some of these mutations and

receptor function. All known ADNFLE mutations have in common many of the families included here did not yet underwent a

that, at least in vitro, they cause a gain of function effect by comprehensive neuropsychological examination. Clinicians who

15,30

increasing the receptors sensitivity to acetylcholine. Never- evaluate patients from ADNFLE families should therefore include

theless, the extent of this gain of function effect is not identical for neuropsychological testing whenever possible in order to increase

each mutation (Fig. 2), and they also display individual profiles for our knowledge about the genotype-phenotype correlations in this

several other biopharmacological characteristics. This is best rare disorder.

demonstrated for CHRNA4-S248F and CHRNA4-S252L that, coex-

pressed with wild type CHRNB2, differ from each other with respect

Conflict of interest statement

to their desensitisation kinetics. When ACh test-pulses were given

repeatedly while background ACh concentration was steadily

The authors declare that no financial or non-financial interest

raised, nAChRs with mutation CHRNA4-S248F showed a gradual exist.

increase of desensitisation while CHRNA4-S252L receptors pre-

sented with a nearly complete desensitisation already after the

Acknowledgements

first test-pulse. The effect was found to be most pronounced in

30

experimental setups that did not include wild type CHRNA4,

This work was supported by the Swiss National Science

which makes it difficult to predict how pronounced the effect on

Foundation to DB (3100A0-101787/2) and by the DFG (STE16511-

desensitisation kinetics will be in vivo. Another example for

2, BE 3834/1-2) to OKS and to DB.

functional differences between ADNFLE mutations is CHRNB2-

V287M and CHRNB2-L301V. In the heterozygous state (CHRNB2-

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