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Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Synonym: ADNFLE

, MD, PhD and , MD, PhD.

Author Information
, MD, PhD
Aichi Welfare Center for Persons with Developmental Disabilities
Kasugai, Japan
, MD, PhD
Fukuoka University
Fukuoka, Japan

Initial Posting: ; Last Update: September 20, 2012.

Summary

Disease characteristics. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures, which are often stereotyped and brief (5 seconds to 5 minutes). They vary from simple arousals from sleep to dramatic, often bizarre, hyperkinetic events with tonic or dystonic features. Affected individuals may experience aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Onset ranges from infancy to adulthood. About 80% of individuals develop ADNFLE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidity, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADNFLE is lifelong but not progressive. As an individual reaches middle age, attacks may become milder and less frequent.

Diagnosis/testing. The diagnosis of ADNFLE is made on clinical grounds. A detailed history from the affected individual and witnesses, supplemented if necessary by video-EEG monitoring, is the key to diagnosis. Molecular genetic testing reveals mutations in CHRNA4, CHRNB2, or CHRNA2 in approximately 20% of individuals with a positive family history and fewer than 5% of individuals with a negative family history.

Management. Treatment of manifestations: Carbamazepine is associated with remission in about 70% of individuals, often in relatively low doses. Individuals with ADNFLE associated with the CHRNA4 mutation p.Ser284Leu are more responsive to zonisamide than carbamazepine. Resistance to AEDs, present in about 30% of affected individuals, requires a trial of all appropriate AEDs. Vagal nerve stimulation may be considered for individuals resistant to AEDs.

Surveillance: Reevaluation of EEGs at regular intervals to monitor disease progression.

Evaluation of relatives at risk: A medical history from relatives at risk can identify those with ADNFLE so that treatment can be initiated promptly.

Genetic counseling. ADNFLE is inherited in an autosomal dominant manner. Most individuals diagnosed with ADNFLE have an affected parent. The proportion of cases caused by de novo gene mutations is unknown, as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. Penetrance is estimated at 70% and the risk to each offspring of inheriting the mutant allele is 50%; thus, the chance that the offspring will manifest ADNFLE is (50%)(70%)=35%. Prenatal testing for pregnancies at increased risk is possible.

Diagnosis

Clinical Diagnosis

The clinical diagnostic features of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) include the following:

  • Clusters of seizures with a frontal semiology*
  • Occurrence of seizures predominantly during sleep*
  • Normal clinical neurologic examination
  • Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidity may occur
  • Normal findings on neuroimaging
  • Ictal EEG that may be normal or obscured by movement artifact
  • Interictal EEG that shows infrequent epileptiform discharges
  • Presence of the same disorder in other family members with evidence of an autosomal dominant mode of inheritance [Tassinari & Michelucci 1997, Provini et al 1999, Combi et al 2004]

* History of clusters of brief (5 seconds to 5 minutes) nocturnal motor seizures which are often stereotyped and may include nightmares, verbalizations, sudden limb movements, or other parasomnias (undesirable phenomena that occur mainly or only during sleep). The history may be obtained from the affected individual and witnesses, and supplemented if necessary by video-electroencephalogram (EEG) monitoring.

The diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is established in individuals with the above clinical features and/or a disease-causing mutation in CHRNA4, CHRNB2, or CHRNA2.

Ictal EEG recordings may be normal or may be obscured by movement artifact. Ictal rhythms, if present, are usually sharp waves or repetitive 8-11 Hz spikes. Recruiting patterns and rhythmic theta (bifrontal, unilateral frontal, or with diffuse desynchronization) are occasionally seen [Steinlein et al 1997, Oldani et al 1998, Provini et al 1999, Picard et al 2000]. El Helou et al [2008] suggest that seizures may be initiated by K-complexes.

Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals.

Interictal sleep EEG may show infrequent epileptiform discharges.

Note: The clinical features of ADNFLE are indistinguishable from those of nonfamilial nocturnal frontal lobe epilepsy [Hayman et al 1997, Tenchini et al 1999, Steinlein et al 2000]. The term ADNFLE should only be applied if the family history is positive for other affected individuals and/or if a disease-causing mutation has been identified in either CHRNA4, CHRNB2, or CHRNA2.

Molecular Genetic Testing

Genes. The genes in which mutations are known to cause ADNFLE [Steinlein et al 1997, Hirose et al 1999, Saenz et al 1999, Gambardella et al 2000, Phillips et al 2000, Steinlein et al 2000, Diàz-Otero et al 2001, Phillips et al 2001, Cho et al 2003, Rozycka et al 2003, Aridon et al 2006]:

  • CHRNA4, encoding the α4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR); associated with type 1 ADNFLE
  • CHRNB2, encoding the β2 subunit of the nAChR; associated with type 3 ADNFLE
  • CHRNA2, encoding α2 subunit of the (nAChR; associated with type 4 ADNFLE
  • CRH, encoding corticotropin-releasing hormone

Evidence for locus heterogeneity. Families with the ADNFLE phenotype and without mutations in CHRNA4, CHRNB2, or CHRNA2 have been described, demonstrating genetic heterogeneity [De Marco et al 2007].

  • A potential ADNFLE locus has been mapped in one family to chromosome 15q24, which is close to the sites of the gene cluster encoding the α3, α5, and β4 subunits of the nicotinic acetylcholine receptors (nAChR) (genes: CHRNA3, CHRNA5, and CHRNB4).
  • In other families, linkage to CHRNA4, CHRNB2, CHRNA2, CRH, or the 15q24 locus has not been established, suggesting the existence of additional genes associated with ADNFLE [Phillips et al 1998, Tenchini et al 1999, Cho et al 2003].
  • Absence of linkage to nine other neuronal nicotinic acetylcholine receptor subunit genes expressed in brain was demonstrated in four unrelated Italian families [Bonati et al 2002].

Clinical testing

  • Sequence analysis of CHRNA4, CHRNB2, and CHRNA2 identifies mutations in only approximately 20% of individuals with a positive family history of ADNFLE [Ottman et al 2010] and fewer than 5% of individuals who have no other family members with nocturnal frontal lobe epilepsy. Slightly fewer mutations are reported in CHRNB2 compared to CHRNA4. Mutations in CHRNA2 are rare.

Table 1. Summary of Molecular Genetic Testing Used in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

ADNFLE TypeGene 1Proportion of ADNFLE Attributed to Mutations in This GeneTest MethodMutations Detected 2
Family History
PositiveNegative
1CHRNA410%-20%RareSequence of select exonsSequence variants 3 in exon 5
Sequence analysisSequence variants 3
Deletion / duplication analysis 4Exonic or whole-gene deletion; none reported
3CHRNB2Fewer than in CHRNA4Rare 5Sequence of select exons Sequence variants 3 in exon 5
Sequence analysis Sequence variants 3
Deletion / duplication analysis 4Exonic or whole-gene deletion; none reported
4CHRNA2Rare 60%Sequence analysisSequence variants 3
NACRHUnknown 70%Sequence analysisSequence variants 3

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Reported in one individual [Liu et al 2011]

6. Reported in one family [Aridon et al 2006]

7. Reported in three families [Combi et al 2005]

Testing Strategy

To confirm/establish the diagnosis in a proband detection of a mutation in CHRNA4, CHRNB2, or CHRNA2 is required. Mutations reported to date in CHRNA4 or CHRNB2 are in exon 5 and reported mutations in CHRNA2 are in exon 6. Thus, sequence analysis of these three exons is recommended as a first step. There is not sufficient clinical information to determine which gene should be tested first.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures with a range of manifestations. Within a family, the manifestations of the disorder may vary considerably [Hayman et al 1997]; individuals with subtle manifestations may not present for medical attention. Magnusson et al [2003] reported an increase in psychiatric symptoms in families with ADNFLE. A high incidence of true parasomnias (undesirable phenomena that occur mainly or only during sleep) has been reported in relatives of those with ADNFLE [Provini et al 1999].

Seizures may occur in any stage of sleep [Oldani et al 1996, Steinlein et al 1997, Provini et al 1999], although typically in clusters in non-REM sleep, most commonly in stage two sleep [Oldani et al 1998, Provini et al 1999]. The affected individual often goes back to sleep rapidly after a seizure, only to be awakened by another event. A minority of individuals experience daytime seizures, typically during a period of poor seizure control.

The seizures are often stereotyped and brief (5 seconds to 5 minutes) [Oldani et al 1996, Thomas et al 1998, Nakken et al 1999, Provini et al 1999, Ito et al 2000, Picard et al 2000]. They vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling movements, ballism (flinging or throwing arm movements), and pelvic thrusting movements.

Retained awareness during seizures is common and may cause affected individuals to fear falling asleep. A sense of difficulty breathing and hyperventilation may occur, as well as vocalization, clonic features, urinary incontinence, and secondary generalization.

Some individuals experience an aura, which may be nonspecific or may consist of fear, a shiver, vertigo, or a feeling of falling or being pushed.

The three distinct sub-classifications of seizure types based on clinical features of the seizures (semiology) and their duration [Oldani et al 1998, Provini et al 1999] are “paroxysmal arousals,” “paroxysmal dystonia,” and “episodic wandering.”

ADNFLE is lifelong but not progressive. Onset ranges from infancy to adulthood. About 80% of affected individuals develop ADNFLE in the first two decades of life [Oldani et al 1998, Picard et al 2000]; mean age of onset is ten years. As an individual reaches middle age, attacks may become milder and less frequent. Seizures may vary over time; for example, tonic attacks appearing in early childhood may evolve into seizures with dystonic or hyperkinetic components in later childhood.

Clinical neurologic examination is normal and intellect is usually preserved [Oldani et al 1996, Nakken et al 1999]; however, in some individuals neuropsychological assessment reveals reduced intellect, cognitive deficits, or psychiatric comorbidity [Khatami et al 1998, Provini et al 1999, Picard et al 2000, Cho et al 2003, Wood et al 2010]. Picard et al [2009] found below-normal general intellect in 45% of 11 subjects with special difficulty in executive tasks and concluded that cognitive dysfunction is an integral part of ADNFLE with nicotinic receptor mutations. It is suggested that certain nAChR mutations could be associated with an increased risk for such symptoms [Steinlein et al 2012].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been consistently identified. Steinlein et al [2012] suggested that certain nAchR mutations may be associated with an increased risk for cognitive dysfunction. Marked intrafamilial variation in severity is seen, the reasons for which are unknown.

Penetrance

Penetrance is estimated at 70%.

Anticipation

Anticipation has not been observed.

Prevalence

The number of families with ADNFLE reported exceeds 100 [Picard & Brodtkorb 2007], but no accurate data concerning the prevalence of ADNFLE exist. It is likely that the disorder is underdiagnosed, or in some cases misdiagnosed.

Families with the disorder have been identified in many countries including Australia, Canada, France, Germany, Great Britain, Italy, Japan, Korea, Norway, and Spain [Khatami et al 1998, Oldani et al 1998, Thomas et al 1998, Hirose et al 1999, Nakken et al 1999, Saenz et al 1999, Ito et al 2000, Diàz-Otero et al 2001, Phillips et al 2001, Cho et al 2003].

Differential Diagnosis

The differential diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADFLNE) includes conditions of varied etiology.

Normal sleep is characterized by periodic arousals, and occasionally other sleep-related movements or phenomena such as nightmares [Phillips et al 1998].

Other parasomnias (disorders in which undesirable physical and mental phenomena occur mainly or exclusively during sleep [American Academy of Sleep Medicine 2001]) to be considered include:

  • Pavor nocturnus (night terrors), a common childhood syndrome, is characterized by attacks of extreme fear and distress that occur one or two hours after the child falls asleep. The child is unaware during the attack, which lasts five to ten minutes, and is amnesic for the event the following day [Schenck & Mahowald 2000].
  • Benign somnambulism (sleep walking) is not accompanied by abnormal motor behavior or dystonia and is usually a self-limiting disorder of childhood. Somnambulism is often familial.

Hysteria is often considered because the individual retains awareness during the attacks, which can be bizarre. Clues to the organic nature of attacks are the occurrence during sleep and the stereotyped semiology (sequence of observed events during the attack).

Familial paroxysmal kinesigenic dyskinesia (familial PKD) is characterized by unilateral or bilateral involuntary movements precipitated by other sudden movements such as standing up from a sitting position, being startled, or changes in velocity; attacks include combinations of dystonia, choreoathetosis, and ballism, are sometimes preceded by an aura, and do not involve loss of consciousness. Attacks can be as frequent as 100 per day to as few as one per month. Duration of attacks is typically a few seconds to five minutes, but can be several hours. Familial PKD has been associated with infantile, but not adult-onset, seizures. Age of onset is typically in childhood and adolescence, but ranges from four months to 57 years. Familial PKD is predominantly seen in males.

Mutations in PRRT2 have been reported as causative of a subset of cases of familial PKD. The other gene(s) associated with PKD have not been identified. Inheritance is autosomal dominant.

Familial paroxysmal nonkinesigenic dyskinesia (familial PNKD) is characterized by unilateral or bilateral involuntary movements; attacks are spontaneous or precipitated by alcohol, coffee or tea, excitement, stress fatigue, or chocolate. Attacks involve dystonic posturing with choreic and ballistic movements, are sometimes accompanied by a preceding aura, occur while the individual is awake, and are not associated with seizures. Attacks last minutes to hours and rarely occur more than once per day. Age of onset is typically in childhood or early teens, but can be as late as age 50 years.

MR1, the gene encoding myofibrillogenesis regulator 1, is the only gene known to be associated with familial PNKD. Inheritance is autosomal dominant.

Familial partial epilepsy with variable foci (FPEVF) is a hereditary partial epilepsy syndrome in which some family members may have frontal lobe epilepsy with a nocturnal pattern [Phillips et al 1998, Steinlein 1999]. FPEVF is distinguished by other family members having partial epilepsy emanating from other cortical regions.

Periodic limb movement disorder (nocturnal myoclonus) affects the flexor muscles of the lower limbs and is characterized by segmental motor activity in muscles that recurs every 20-30 seconds. Brief stationary movements may be followed by myoclonic or repetitive clonic jerks that coincide with the periodic K-complexes of light sleep.

Restless legs syndrome is often accompanied by segmental motor activity and may be a spinal cord-mediated disorder.

REM sleep disorders may include prominent motor and verbal manifestations that are often of unknown cause or secondary to other neurologic disorders. REM sleep disorders typically occur in men ages 55-60 years. Polysomnography is a useful diagnostic tool.

Respiratory disorders such as asthma may be considered because of difficulty breathing.

Obstructive sleep apnea may be considered in individuals complaining of daytime sleepiness who are not aware of their nocturnal attacks.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE):

  • In addition to the evaluation for epilepsy, cognitive and behavioral assessment may help determine the extent of disease.
  • Medical genetics consultation is appropriate.

Treatment of Manifestations

Carbamazepine is the antiepileptic drug (AED) of choice for ADNFLE, although no controlled trials have been conducted. In about 70% of individuals with ADFLNE, carbamazepine is associated with remission of seizures, often with relatively low doses. However, individuals with ADNFLE associated with the CHRNA4 mutation p.Ser284Leu respond only partially to carbamazepine and are more responsive to zonisamide [Provini et al 1999, Ito et al 2000, Combi et al 2004].

Resistance to AEDs occurs in about 30% of affected individuals. Intrafamilial variation in pharmaco-responsiveness occurs; therefore, all appropriate AEDs should be tried.

Vagal nerve stimulation may be considered for individuals with resistance to AEDs [Carreño et al 2010].

Surveillance

Annual or biannual evaluation of EEGs to monitor disease progression is appropriate.

Evaluation of Relatives at Risk

A medical history to seek evidence of affected status should be elicited from relatives at risk so that treatment can be initiated if appropriate.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with ADNFLE have an affected parent.
  • A proband with ADNFLE may have the disorder as the result of a de novo mutation. The proportion of cases caused by de novo mutations is unknown, as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. In one report a mother with a de novo mutation passed the condition on to her son [Phillips et al 2000].
  • Recommendations for the evaluation of parents of a child with nocturnal frontal lobe epilepsy and no known family history of NFLE include a detailed clinical and family history and molecular genetic testing, if the mutation in the proband has been identified. In simplex cases (individuals with no known family history of NFLE), the data on heritability are incomplete.

Sibs of a proband. The risk to sibs and offspring of a proband depends on the genetic status of the parents:

  • If one parent has phenotypic features of ADNFLE or has a disease-causing mutation, the risk to each sib of inheriting the mutant allele is 50%. The chance that the sib will manifest ADNFLE is (50%)(70%) = 35%, assuming penetrance of 70%.
  • If neither parent has a disease-causing mutation detectable in DNA, it is presumed that the proband has a de novo gene mutation and the risk to the sibs of the proband depends on the spontaneous mutation rate of the gene involved and the probability of germline mosaicism.

Offspring of a proband

  • The risk to each offspring of a proband of inheriting the mutant allele is 50%.
  • The chance that the offspring will manifest ADNFLE is (50%)(70%)=35%, assuming penetrance of 70%.

Other family members

  • The risk to other family members depends on the genetic status of the proband's parents and the presence of other affected first- or second-degree relatives.
  • If a parent is affected or has a disease-causing mutation, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Other genetic counseling issues. Individuals may not be aware of the significance of their attacks; in some families, individuals may be reluctant to reveal their symptoms [Thomas et al 1998].

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions which (like ADNFLE) do not usually affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified in an affected family member.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • American Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@efa.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Autosomal Dominant Nocturnal Frontal Lobe Epilepsy: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (View All in OMIM)

118502CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 2; CHRNA2
118504CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, ALPHA POLYPEPTIDE 4; CHRNA4
118507CHOLINERGIC RECEPTOR, NEURONAL NICOTINIC, BETA POLYPEPTIDE 2; CHRNB2
122560CORTICOTROPIN-RELEASING HORMONE; CRH
600513EPILEPSY, NOCTURNAL FRONTAL LOBE, 1; ENFL1
603204EPILEPSY, NOCTURNAL FRONTAL LOBE, 2; ENFL2
605375EPILEPSY, NOCTURNAL FRONTAL LOBE, 3; ENFL3
610353EPILEPSY, NOCTURNAL FRONTAL LOBE, 4; ENFL4

Molecular Genetic Pathogenesis

The neuronal nicotinic acetylcholine receptor is a heterologous pentamer comprising various combinations of alpha and beta subunits, encoded by CHRNA4 and CHRNB2, respectively. The most common configuration is (α4)2(β2)3 subunits; that is, two α4 and three β2 subunits.

The receptor is widely distributed in the brain, including the frontal lobes. It is thought that the receptor is a presynaptic modulator of other neurotransmitter systems, including gamma-amino butyric acid (GABA), glutamate, and dopamine, and therefore may have variable effects on excitatory and inhibitory pathways [Kuryatov et al 1997, Bertrand 1999, Buisson et al 1999, Picard et al 1999].

The second transmembrane domain of the receptor forms the ion channel pore and is the site of most of the mutations implicated in ADNFLE. Mutations in CHRNA4 and CHRNB2 associated with ADNFLE occur in highly conserved amino acids and alter the function of the resulting receptors.

Functional studies of different mutations provide conflicting results although an increase in acetylcholine (Ach) sensitivity in vitro is typical for known ADNFLE-associated mutations [Kuryatov et al 1997, Steinlein et al 1997, Bertrand et al 1998, Bertrand 1999, De Fusco et al 2000, Phillips et al 2001, di Corcia et al 2005]; thus, the mechanism whereby the mutations cause ADNFLE is poorly understood.

The corticotropin-releasing hormone is widely distributed throughout the central nervous system. CRH acts as a neurotransmitter or neuromodulator in extrahypothalamic circuits to integrate a multisystem response to stress that controls numerous behaviors including sleep and arousal. Two new nucleotide variations in the promotor region were reported [Combi et al 2005, Shimmin et al 2007].

CHRNA4

Normal allelic variants. CHRNA4 has six exons distributed over approximately 17 kb of genomic DNA [Steinlein et al 1996]. The main part of the coding region is distributed in exon 5 [Steinlein et al 1996]. Normal allelic variants of the CHRN receptor genes have been described [Weiland & Steinlein 1996, Phillips & Mulley 1997].

Pathogenic allelic variants. See Table 2. In a sporadic NFLE case, Chen et al [2009] identified a novel mutation in CHRNA4 that causes an α4-Arg336His amino acid exchange outside the TM, and in the second intracellular loop between the third and fourth transmembrane domains. Certain mutations have been observed in many different countries; these mutations occurred independently [Steinlein et al 2000, Hwang et al 2011].

Table 2. Selected CHRNA4 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.839C>Tp.Ser280Phe 1NM_000744​.5
NP_000735​.1
c.851C>Tp.Ser284Leu 2
c.878C>Tp.Thr293Ile 3
c.870_872dupGCTp.Leu291dup 4
c.1007G>Ap.Arg336His 5

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Four families [Saenz et al 1999, Steinlein et al 2000, McLellan et al 2003]

2. Hirose et al [1999], Rozycka et al [2003]

3. Leniger et al [2003]

4. Steinlein et al [1997]

5. Chen et al [2009]

For more information, see Table A.

Normal gene product. Each nicotinic acetylcholine receptor subunit has a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region [Elliott et al 1996]. The α subunits are characterized by the presence of a pair of cysteine residues (Cys161 and Cys175, NP_000735.1) that are presumed to function as part of the ACh binding site when the α4 subunits are complexed as a heterologous pentamer with the β subunits [Figl et al 1998].

Abnormal gene product. Functional studies of different mutations provide conflicting results, although an increase in ACh sensitivity in vitro is typical for known ADNFLE-causing mutations [Kuryatov et al 1997, Steinlein et al 1997, Bertrand et al 1998, Bertrand 1999, De Fusco et al 2000, Phillips et al 2001]; hence gain of function of nAChR may be a contributing mechanism of developing ADNFLE. Studies on mutated nAchR demonstrated an increased sensitivity to carbamazepine [Picard et al 1999].

CHRNB2

Normal allelic variants. Normal allelic variants of the CHRN receptor genes have been described [Weiland & Steinlein 1996, Phillips & Mulley 1997].

Pathogenic allelic variants. Various mutations resulting in changes in the highly conserved region of the conducting pore or transmembrane domain are described. A novel mutation in CHRNB2, p.Val337Gly, located between transmembrane domains M3 and M4, was identified in a sporadic NFLE case [Liu et al 2011]. See Table 3.

Table 3. Selected CHRNB2 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.859G>Cp.Val287Leu 1NM_000748​.2
NP_000739​.1
c.859G>Tp.Val287Leu 2
c.859G>Ap.Val287Met 3
c.901C>Gp.Leu301Val 4
c.923T>Cp.Val308Ala 4
c.936C>Gp.Ile312Met 5
c.1010T>Gp.Val337Gly 6

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. De Fusco et al [2000]

2. Kurahashi et al [unpublished observation]

3. Diàz-Otero et al [2001], Phillips et al [2001]

4. Hoda et al [2008]

5. Bertrand et al [2005]

6. Liu et al [2011]

For more information, see Table A.

Normal gene product. CHRNB2 encodes the β2 subunit of nAChR. The β2 subunit is composed of 503 amino acids. CHRNB2 is similar to CHRNA4, but the β subunits encoded by the genes are defined by the lack of paired cysteine residues [Elliott et al 1996].

Abnormal gene product. Functional studies of different mutations provide conflicting results, although an increase in ACh sensitivity in vitro is typical for known ADNFLE-associated mutations [Kuryatov et al 1997, Steinlein et al 1997, Bertrand et al 1998, Bertrand 1999, De Fusco et al 2000, Phillips et al 2001]; hence, gain of function of nAChR may be a contributing mechanism of developing ADNFLE.

CHRNA2

Normal allelic variants. CHRNA2 has seven exons distributed over approximately 19 kb of genomic DNA. Normal allelic variants of the CHRN receptor genes have been described [Weiland & Steinlein 1996, Phillips & Mulley 1997].

Pathogenic allelic variants. One mutation resulting in changes in the highly conserved region of the first transmembrane domain is described [Aridon et al 2006]. See Table 4.

Table 4. Selected CHRNA2 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.836T>Ap.Ile279Asn 1NM_000742​.3
NP_000733​.2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Aridon et al [2006]

Normal gene product. CHRNA2 encodes the α2 subunit of nAChR. The α2 subunit is composed of 529 amino acids. CHRNA2 is similar to CHRNA4.

Abnormal gene product. The CHRNA2 mutation increases the receptor sensitivity to acetylcholine, and gain of function of nAChR may be a contributing mechanism of developing ADNFLE [Aridon et al 2006, Hoda et al 2009]. Carbamazepine and oxcarbazepine produce a non-competitive channel inhibition in heteromeric neuronal nicotinic receptors including mutated α2 subunits as well as wild α2 subunits, but the different heteromeric nicotinic receptors exhibit distinct pharmacologic properties [Di Resta et al 2010].

CRH

Normal allelic variants. Normal allelic variants of CRH have been described [Shimmin et al 2007].

Pathogenic allelic variants. Two variants in the promotor region were reported [Combi et al 2005]. See Table 5.

Table 5. Selected CRH Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.-1166G>C
g.67,090,878
NoneNM_000756​.1
NC_000008​.10
c.-1470C>A
g.67,091,183
None

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Normal gene product. CRH is composed of 196 amino acids.

Abnormal gene product. In vitro assays demonstrated that these variants result in altered levels of gene expression. The luciferase assay showed stronger promotor activity for the g.-1470C>A variation, whereas reduction of the promotor activity was detected for the g.-1166G>C mutation [Combi et al 2005].

References

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Chapter Notes

Author History

Judith Adams, MBBS, FRACP; University of Melbourne (2002-2004)
Samuel F Berkovic, MD, FRACP; Epilepsy Research Institute (2002-2010)
Shinichi Hirose, MD, PhD (2010-present)
Hirokazu Kurahashi, MD, PhD (2010-present)
Ingrid E Scheffer, MBBS, FRACP, PhD; Austin and Repatriation Medical Centre (2002-2010)

Revision History

  • 20 September 2012 (me) Comprehensive update posted live
  • 5 April 2010 (me) Comprehensive update posted live
  • 24 June 2004 (me) Comprehensive update posted to live Web site
  • 23 January 2004 (cd) Revision: mutation detection rate
  • 16 May 2002 (me) Review posted to live Web site
  • 22 January 2002 (ja) Original submission
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