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Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Synonym: ADNFLE

, MD, PhD and , MD, PhD.

Author Information

Initial Posting: ; Last Update: March 15, 2018.

Summary

Clinical 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 established in a proband who has suggestive clinical findings combined with a family history that is positive for other affected individuals and/or by the identification of a heterozygous pathogenic variant in CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH on molecular genetic testing.

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 pathogenic variant 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. Adjunctive fenofibrate therapy or 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.

Pregnancy management: Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

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 pathogenic variants 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 pathogenic variant is 50%; thus, the chance that the offspring will manifest ADNFLE is (50% x 70% =) 35%. Prenatal testing for pregnancies at increased risk is possible.

Diagnosis

Suggestive Findings

No formal diagnostic criteria for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have been published. ADNFLE should be suspected in individuals with the following clinical features, EEG findings, neuroimaging, and family history.

Clinical features

  • Clusters of brief (5-second to 5-minute) nocturnal motor seizures that are often stereotyped and may include:
    • Nightmares
    • Verbalizations
    • Sudden limb movements
    • Parasomnias (undesirable phenomena that occur mainly or only during sleep)
  • Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidity may occur
  • Normal clinical neurologic examination

Note: The clinical features of ADNFLE are indistinguishable from those of nonfamilial NFLE [Hayman et al 1997, Tenchini et al 1999, Steinlein et al 2000].

EEG findings

  • Clusters of seizures with a frontal semiology
  • Ictal EEG that may be normal or obscured by movement artifact
  • Interictal EEG that shows infrequent epileptiform discharges

Neuroimaging. Normal findings

Family history

Establishing the Diagnosis

The diagnosis of ADNFLE is established in a proband with the clinical features and findings detailed in Suggestive Findings combined with a family history that is positive for other affected individuals and/or by identification of a heterozygous pathogenic variant in one of the genes listed in Table 1.

Molecular genetic testing approaches can include serial single-gene testing, use of a multigene panel, and more comprehensive genomic testing:

  • Serial single-gene testing is based on the order in which pathogenic variants most commonly occur (i.e., CHRNA4, CHRNB2, KCNT1, DEPDC5, CHRNA2, and CRH).
    If no pathogenic variant is found, deletion/duplication analysis may be considered.
  • A multigene panel that includes CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, CRH, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
  • More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
    For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Gene 1, 2Proportion of ADNFLE Attributed to Pathogenic Variants in This GeneProportion of Pathogenic Variants 3 Detectable by This Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
CHRNA2Rare 6Rare 6None reported 7
CHRNA410%-15% 810%-15% 8
CHRNB2Lower than in CHRNA4 8Lower than in CHRNA4 8
CRHRare 9Rare 9
DEPDC510% 1010% 10
KCNT1<5% 11<5% 11
1.

Genes are listed in alphabetic order.

2.
3.

See Molecular Genetics for information on allelic variants detected in this gene.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

5.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

6.

Reported in two families [Aridon et al 2006, Conti et al 2015]

7.

To date, exon or whole-gene deletions/duplications have not been detected in ADNFLE.

8.

10%-15% of individuals with a family history have pathogenic variants in subunits of nicotinic acetylcholine receptor [Ferini-Strambi et al 2012].

9.
10.
11.

Clinical Characteristics

Clinical Description

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by clusters of nocturnal motor seizures with a range of manifestations.

Nocturnal seizures. The history may be obtained from the affected individual and witnesses, and supplemented if necessary by video-EEG monitoring.

Seizures may occur in any stage of sleep, although typically in clusters in non-REM (NREM) sleep, most commonly in stage 2 sleep [Picard & Scheffer 2012]. The affected individual often goes back to sleep rapidly after a seizure, only to be awakened by another event.

The seizures are often stereotyped and brief (5 seconds to 5 minutes); 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.

The three distinct sub-classifications of seizure types based on clinical features of the seizures (semiology) and their duration are "paroxysmal arousals," "paroxysmal dystonia," and "episodic wandering."

  • Paroxysmal arousal is characterized by abrupt recurrent arousals from NREM sleep associated with a stereotypic motor pattern.
  • Paroxysmal dystonia is characterized by recurrent motor attacks with dystonic-dyskinetic features arising from NREM sleep and usually lasting less than two minutes.
  • Episodic wandering is somnambulic agitated behavior arising from NREM sleep.

The reported frequency ranges from one to 20 attacks each night, a mean of 20 seizures per month; about 60% of the affected individuals reported more than 15 seizures per month.

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 preceding the seizure during sleep and are aware of the onset. Aura may be nonspecific or may consist of numbness in one limb, fear, a shiver, vertigo, or a feeling of falling or being pushed.

Note: A minority of individuals experience daytime seizures, typically during a period of poor seizure control. Some of the seizures reported are paroxysmal dystonia similar to those during sleep, and others are generalized tonic-clonic seizures, generalized atonic seizures, and focal seizures with impairment of consciousness or awareness.

EEG findings

  • Ictal EEG recordings may be normal or may be obscured by movement artifact. Ictal rhythms, if present, are usually sharp waves or repetitive 8- to 11-Hz spikes. Recruiting patterns and rhythmic theta (bifrontal, unilateral frontal, or with diffuse desynchronization) are occasionally seen [Picard & Scheffer 2012]. 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.

Cognitive findings. 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 five (45%) of 11 subjects with special difficulty in executive tasks and concluded that cognitive dysfunction is an integral part of ADNFLE caused by a heterozygous pathogenic variant in the nicotinic receptor (see Phenotype Correlations by Gene).

Magnusson et al [2003] reported an increase in psychiatric symptoms in families with ADNFLE (see Phenotype Correlations by Gene).

Familial variation. Within a family, the manifestations of the disorder may vary considerably; individuals with subtle manifestations may not present for medical attention.

A high incidence of true parasomnias has been reported in relatives of those with ADNFLE [Provini et al 1999]. True parasomnias were distinguished from epileptic seizures because of their age-dependent course, the rarity of episodes, and their being not violent and often not disturbing for the affected individual. They often ended well before the onset of the clear-cut epileptic seizures.

Onset and prognosis. 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; 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.

Phenotype Correlations by Gene

KCNT1. Individuals with heterozygous pathogenic variants in KCNT1 may have a more severe phenotype than those with neuronal nicotinic acetylcholine receptor (nAChR) pathogenic variants [Heron et al 2012]:

  • Affected individuals are more likely to display psychiatric and behavioral problems.
  • Affected individuals are more likely to have a lower age of onset, complete penetrance, and cognitive comorbidities.

Genotype-Phenotype Correlations

Steinlein et al [2012] suggested that certain nAchR pathogenic variants 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%. KCNT1-related ADNFLE demonstrates complete penetrance compared to 60%-80% in nAChR-related ADNFLE.

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 worldwide [Steinlein 2014].

Differential Diagnosis

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

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

Parasomnias (disorders in which undesirable physical and mental phenomena occur mainly or exclusively during sleep [American Academy of Sleep Medicine 2001]) including the following may be considered:

  • 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).

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.

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) the following evaluations are recommended if they have not already been completed:

  • In addition to the evaluation for epilepsy, cognitive and behavioral assessment to help determine the extent of disease
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

In about 70% of individuals with ADNFLE, carbamazepine is associated with remission of seizures, often with relatively low doses. However, individuals with ADNFLE associated with the CHRNA4 pathogenic variant 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].

Exposure to quinidine significantly reduces gain of function for KCNT1 pathogenic variants implicated in ADNFLE and EIMFS [Milligan et al 2014]. Clinical treatment with quinidine was reported in a child with EIMFS [Bearden et al 2014], and correlated with a marked reduction in seizure frequency. In the future, it may be also possible to treat KCNT1-related ADNFLE with quinidine.

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

Adjunctive therapy with fenofibrate reduced seizure frequency in individuals with pharmacoresistant ADNFLE/NFLE in one study [Puligheddu et al 2017].

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

Caregivers

For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy & My Child Toolkit.

Prevention of Secondary Complications

Prompt diagnosis and appropriate treatment for ADNFLE can help prevent morning tiredness and daytime somnolence resulting from sleep fragmentation due to seizure-related arousals.

Surveillance

Serial evaluation of EEGs to monitor disease progression is appropriate.

Evaluation of Relatives at Risk

It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment:

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

Pregnancy Management

In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of antiepileptic medication during pregnancy reduces this risk. However, exposure to antiepileptic medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from antiepileptic medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of antiepileptic medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given antiepileptic drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and www.ClinicalTrialsRegister.eu in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

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 CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH pathogenic variant. The proportion of cases caused by a de novo pathogenic variant 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 pathogenic variant 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 pathogenic variant in the proband has been identified).
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (though theoretically possible, no instances of germline mosaicism have been reported).
  • The family history of some individuals diagnosed with ADNFLE may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

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

  • If one parent has phenotypic features of ADNFLE and/or is known to have a pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%. The chance that the sib will manifest ADNFLE is (50% x 70% =) 35%, assuming penetrance of 70%.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the theoretic possibility of germline mosaicism.

Offspring of a proband

  • Each child of an individual with ADNFLE has a 50% chance of inheriting the pathogenic variant.
  • The chance that the offspring will manifest ADNFLE is (50% x70% =) 35%, assuming penetrance of 70%.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected with ADNFLE or has the pathogenic variant, his or her family members may be 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 [Picard & Scheffer 2012].

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

If the ADNFLE–related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

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. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

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)
  • Canadian Epilepsy Alliance
    Canada
    Phone: 1-866-EPILEPSY (1-866-374-5377)
  • Epilepsy Foundation
    8301 Professional Place East
    Suite 200
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Email: ContactUs@efa.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)

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 from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) 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
608167POTASSIUM CHANNEL, SUBFAMILY T, MEMBER 1; KCNT1
614191DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5

Molecular Genetic Pathogenesis

The genes in which pathogenic variants are known to cause ADNFLE:

  • Genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR):
    • 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
    The neuronal nicotinic acetylcholine receptor is a heterologous pentamer comprising various combinations of alpha and beta subunits, encoded by CHRNA2-CHRNA7 and CHRNB2-CHRNB4, respectively. The most common configuration in thalamus and isocortex is (α4)2(β2)3 subunits (i.e., 2 α4 and 3 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 pathogenic variants implicated in ADNFLE. Pathogenic variants 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 pathogenic variants provide conflicting results, although an increase in acetylcholine (Ach) sensitivity in vitro is typical for known ADNFLE-associated pathogenic variants [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 pathogenic variants cause ADNFLE is poorly understood.
  • KCNT1, encoding a sodium-activated potassium channel; associated with type 5 ADNFLE. Sodium-activated potassium channel encoded by KCNT1 is widely distributed in many regions of the mammalian brain, including the frontal cortex. Its activity contributes to the slow hyperpolarization that follows repetitive firing.
    Mutated channels with pathogenic variants identified in ADNFLE produce voltage-activated currents with higher magnitude compared to wild type, leading to gain of function.
  • DEPDC5, encoding dishevelled, egl-10, and pleckstrin (DEP) domain-containing protein 5. DEPDC5 is a component of GATOR1 (GTPase-activating protein [GAP] activity toward RAGs complex 1), which negatively regulates mTORC1 (mammalian target of rapamycin complex 1) and is expressed ubiquitously in human tissues. Most pathogenic variants are truncating variants that can be expected to result in nonsense-mediated mRNA degradation.
  • CRH, encoding corticotropin-releasing hormone (CRH). CRH is widely distributed throughout the central nervous system; it acts as a neurotransmitter or neuromodulator in extrahypothalamic circuits to integrate a multisystem response to stress that controls numerous behaviors including sleep and arousal. Variations in the promotor [Combi et al 2005] or in the pro-sequence region [Sansoni et al 2013] have been reported. The variant identified in one family with ADNFLE decreases peptide secretion in vitro [Sansoni et al 2013].

CHRNA2

Gene structure. CHRNA2 has seven exons distributed over ~19 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Benign variants have been described [Weiland & Steinlein 1996, Phillips & Mulley 1997].

Pathogenic variants. One pathogenic variant resulting in changes in the highly conserved region of the first transmembrane domain has been described [Aridon et al 2006]. See Table 2.

Table 2.

Selected CHRNA2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein 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 authors. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Normal gene product. CHRNA2 encodes the α2 subunit of nAChR. The α2 subunit is composed of 529 amino acids. CHRNA2 is one of the subunits that form functional nAChRs.

Abnormal gene product. The CHRNA2 pathogenic variant increases the receptor sensitivity to acetylcholine, and gain of function of nAChR may be a contributing mechanism in the development of 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 type α2 subunits, but the different heteromeric nicotinic receptors exhibit distinct pharmacologic properties [Di Resta et al 2010].

CHRNA4

Gene structure. CHRNA4 has six exons distributed over ~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]. For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Benign variants have been described [Weiland & Steinlein 1996, Phillips & Mulley 1997].

Pathogenic variants. See Table 3. In one case of sporadic NFLE Chen et al [2009] identified a novel variant in CHRNA4 that causes an α4-Arg336His amino acid exchange outside the transmembrane domain, and in the second intracellular loop between the third and fourth transmembrane domains. Instances of the same pathogenic variant occurring independently in multiple countries have been reported [Steinlein et al 2000, Hwang et al 2011].

Table 3.

CHRNA4 Pathogenic Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.851C>Tp.Ser284Leu 1NM_000744​.5
NP_000735​.1
c.1007G>Ap.Arg336His 2

Note on variant classification: Variants listed in the table have been provided by the authors. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.
2.

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 pathogenic variants provide conflicting results, although an increase in ACh sensitivity in vitro is typical for known ADNFLE-causing pathogenic variants [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 in the development of ADNFLE. Studies on mutated nAchR demonstrated an increased sensitivity to carbamazepine [Picard et al 1999].

CHRNB2

Gene structure. CHRNB2 has six exons distributed over ~12 kb of genomic DNA. The main part of the coding region is distributed in exon 5. For a detailed summary of gene and protein information, see Table A, Gene.

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

Pathogenic variants. Various pathogenic variants resulting in changes in the highly conserved region of the conducting pore or transmembrane domain are described. A novel variant in CHRNB2 located between transmembrane domains M3 and M4 was identified in a sporadic NFLE case [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 pathogenic variants provide conflicting results, although an increase in ACh sensitivity in vitro is typical for known ADNFLE-associated pathogenic variants [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 in the development of ADNFLE.

CRH

Gene. CRH has two exons; the first one is noncoding (NM_000756.3). For a detailed summary of gene and protein information, see Table A, Gene.

Benign variants. Benign variants have been described [Shimmin et al 2007].

Pathogenic variants. Two variants in the promotor region and one missense variant have been reported [Combi et al 2005, Sansoni et al 2013]. See Table 4.

Table 4.

Selected CRH Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.-365G>C 1None 2NM_000756​.2
c.-669C>A 3None 2
c.89C>Gp.Pro30Arg 4NM_000756​.2
NP_000747​.1

Note on variant classification: Variants listed in the table have been provided by the authors. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

NC_000008​.10:g.67090878C>G (GRCh37); rs72556399

2.
3.

NC_000008​.10:g.67091182G>T (GRCh37); rs12721510

4.

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

Abnormal gene product. In vitro assays demonstrated that the pathogenic variants result in altered levels of gene expression. The luciferase assay showed stronger promotor activity for the c.-669C>A variation, whereas reduction of the promotor activity was detected for the c.-365G>C pathogenic variant [Combi et al 2005].

DEPDC5

Gene structure. DEPDC5 has 43 exons distributed over ~150 kb of genomic DNA. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The majority of the DEPDC5 pathogenic variants detected resulted in premature termination, suggesting haploinsufficiency as the disease mechanism.

Normal gene product. DEPDC5 is composed of 1,603 amino acids and is expressed ubiquitously in human tissues [Dibbens et al 2013]. It contains a DEP homology domain that is present in many proteins of G-protein signaling pathways. DEPDC5 is a component of GATOR1 (GTPase-activating protein [GAP] activity toward RAGs complex 1), which negatively regulates mTORC1 (mammalian target of rapamycin complex 1) [Bar-Peled et al 2013]. The mTOR pathway plays a role in many activities including cell growth, cell proliferation, and metabolism.

Abnormal gene product. Most pathogenic variants are truncating variants that can be expected to result in nonsense-mediated mRNA degradation. Aberrant mTORC1 signaling is known to cause disturbance in neuronal migration and cortical lamination, which has been demonstrated in neuronal migration disorders including tuberous sclerosis. Pathogenic variants in DEPDC5 appear to have a less dramatic effect on mTORC1 signaling but disturb it sufficiently to cause focal epilepsy. Indeed, the phenotype of individuals with DEPDC5 pathogenic variants extends with the identification of variants associated with rolandic epilepsy, unclassified focal epilepsy [Lal et al 2014], and focal epilepsy with brain malformations [Scheffer et al 2014].

KCNT1

Gene structure. KCNT1 has 31 exons distributed over ~90 kb of genomic DNA. There are two relevant transcript variants (the longer NM_020822.2 and the alternate NM_001272003.1). For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Various pathogenic variants resulting in changes in the highly conserved region are described. All of the variants are located within the intracellular region and most alter amino acids within or immediately adjacent to a nicotinamide adenine dinucleotide (NAD+)-binding site. They are identified in Australian (of British heritage), Italian, and Israeli families. See Table 5.

Table 5.

Selected KCNT1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.1193G>Ap.Arg398Gln 1NM_020822​.2
NP_065873​.2
c.2386T>Cp.Tyr796His 1
c.2688G>Ap.Met896Ile 1
c.2782C>Tp.Arg928Cys 1

Note on variant classification: Variants listed in the table have been provided by the authors. 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 (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Normal gene product. KCNT1 (previously known as SLACK, SLO2.2, and KCa4.1) encodes a sodium-activated potassium channel and is composed of 1,235 amino acids [Joiner et al 1998]. KCNT1 channel contains six putative membrane-spanning regions and extended C-terminus. The C-terminal cytoplasmic domain contains several motifs believed to interact with a protein network. One of the proteins is fragile X mental retardation protein (FMRP), a potent stimulator of KCNT1 channel activity [Brown et al 2010].

Abnormal gene product. The electrophysiologic properties of KCNT1 variants identified in patients with ADNFLE were analyzed in vitro [Milligan et al 2014]. All of the variants studied (see Table 5) increase current magnitude leading to gain of function, and in some cases hasten (p.Met896Ile, p.Arg928Cys) or slow (p.Arg398Gln) activation. The mechanisms underlying increased neuronal excitability due to a gain of function of the KCNT1 channels are not known.

References

Literature Cited

  • American Academy of Sleep Medicine. The International Classification of Sleep Disorders, Revised: Diagnostic and Coding Manual. Available online. 2001. Accessed 3-13-18.
  • Aridon P, Marini C, Di Resta C, Brilli E, De Fusco M, Politi F, Parrini E, Manfredi I, Pisano T, Pruna D, Curia G, Cianchetti C, Pasqualetti M, Becchetti A, Guerrini R, Casari G. Increased sensitivity of the neuronal nicotinic receptor alpha 2 subunit causes familial epilepsy with nocturnal wandering and ictal fear. Am J Hum Genet. 2006;79:342–50. [PMC free article: PMC1559502] [PubMed: 16826524]
  • Bar-Peled L, Chantranupong L, Cherniack AD, Chen W W, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science. 2013;340:1100–6. [PMC free article: PMC3728654] [PubMed: 23723238]
  • Bearden D, Strong A, Ehnot J, DiGiovine M, Dlugos D, Goldberg EM. Targeted treatment of migrating partial seizures of infancy with quinidine. Ann Neurol. 2014;76:457–61. [PubMed: 25042079]
  • Bertrand D. Neuronal nicotinic acetylcholine receptors: their properties and alterations in autosomal dominant nocturnal frontal lobe epilepsy. Rev Neurol (Paris). 1999;155:457–62. [PubMed: 10472659]
  • Bertrand S, Weiland S, Berkovic SF, Steinlein OK, Bertrand D. Properties of neuronal nicotinic acetylcholine receptor mutants from humans suffering from autosomal dominant nocturnal frontal lobe epilepsy. Br J Pharmacol. 1998;125:751–60. [PMC free article: PMC1571006] [PubMed: 9831911]
  • Brown MR, Kronengold J, Gazula VR, Chen Y, Strumbos JG, Sigworth FJ, Navaratnam D, Kaczmarek LK. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat Neurosci. 2010;13:819–21. [PMC free article: PMC2893252] [PubMed: 20512134]
  • Buisson B, Curtis L, Betrand D. Neuronal nicotinic acetylcholine receptor and epilepsy. In: Berkovic SF, Genton P, Hirsch E, Picard F, eds. Genetics of Focal Epilepsies. London, UK: John Libbey & Co; 1999:187-202.
  • Carreño M, Garcia-Alvarez D, Maestro I, Fernández S, Donaire A, Boget T, Rumià J, Pintor L, Setoain X. Malignant autosomal dominant frontal lobe epilepsy with repeated episodes of status epilepticus: successful treatment with vagal nerve stimulation. Epileptic Disord. 2010;12:155–8. [PubMed: 20478764]
  • Chen Y, Wu L, Fang Y, He Z, Peng B, Shen Y, Xu Q. A novel mutation of the nicotinic acetylcholine receptor gene CHRNA4 in sporadic nocturnal frontal lobe epilepsy. Epilepsy Res. 2009;83:152–6. [PubMed: 19058950]
  • Cho YW, Motamedi GK, Laufenberg I, Sohn SI, Lim JG, Lee H, Yi SD, Lee JH, Kim DK, Reba R, Gaillard WD, Theodore WH, Lesser RP, Steinlein OK. A Korean kindred with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation. Arch Neurol. 2003;60:1625–32. [PubMed: 14623738]
  • Combi R, Dalpra L, Ferini-Strambi L, Tenchini ML. Frontal lobe epilepsy and mutations of the corticotropin-releasing hormone gene. Ann Neurol. 2005;58:899–904. [PubMed: 16222669]
  • Combi R, Dalpra L, Tenchini ML, Ferini-Strambi L. Autosomal dominant nocturnal frontal lobe epilepsy--a critical overview. J Neurol. 2004;251:923–34. [PubMed: 15316796]
  • Conti V, Aracri P, Chiti L, Brusco S, Mari F, Marini C, Albanese M, Marchi A, Liguori C, Placidi F, Romigi A, Becchetti A, Guerrini R. Nocturnal frontal lobe epilepsy with paroxysmal arousals due to CHRNA2 loss of function. Neurology. 2015;84:1520–8. [PMC free article: PMC4408286] [PubMed: 25770198]
  • De Fusco M, Becchetti A, Patrignani A, Annesi G, Gambardella A, Quattrone A, Ballabio A, Wanke E, Casari G. The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet. 2000;26:275–6. [PubMed: 11062464]
  • Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, Crompton DE, Hughes JN, Bellows ST, Klein KM, Callenbach PM, Corbett MA, Gardner AE, Kivity S, Iona X, Regan BM, Weller CM, Crimmins D, O'Brien TJ, Guerrero-Lopez R, Mulley JC, Dubeau F, Licchetta L, Bisulli F, Cossette P, Thomas PQ, Gecz J, Serratosa J, Brouwer OF, Andermann F, Andermann E, van den Maagdenberg AM, Pandolfo M, Berkovic SF, Scheffer IE. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013;45:546–51. [PubMed: 23542697]
  • di Corcia G, Blasetti A, De Simone M, Verrotti A, Chiarelli F. Recent advances on autosomal dominant nocturnal frontal lobe epilepsy: understanding the nicotinic acetylcholine receptor (nAChR). Eur J Paediatr Neurol. 2005;9:59–66. [PubMed: 15843070]
  • Di Resta C, Ambrosi P, Curia G, Becchetti A. Effect of carbamazepine and oxcarbazepine on wild-type and mutant neuronal nicotinic acetylcholine receptors linked to nocturnal frontal lobe epilepsy. Eur J Pharmacol. 2010;643:13–20. [PubMed: 20561518]
  • El Helou J, Navarro V, Depienne C, Fedirko E, LeGuern E, Baulac M, An-Gourfinkel I, Adam C. K-complex-induced seizures in autosomal dominant nocturnal frontal lobe epilepsy. Clin Neurophysiol. 2008;119:2201–4. [PubMed: 18762450]
  • Elliott KJ, Ellis SB, Berckhan KJ, Urrutia A, Chavez-Noriega LE, Johnson EC, Velicelebi G, Harpold MM. Comparative structure of human neuronal alpha 2-alpha 7 and beta 2-beta 4 nicotinic acetylcholine receptor subunits and functional expression of the alpha 2, alpha 3, alpha 4, alpha 7, beta 2, and beta 4 subunits. J Mol Neurosci. 1996;7:217–28. [PubMed: 8906617]
  • Ferini-Strambi L, Sansoni V, Combi R. Nocturnal frontal lobe epilepsy and the acetylcholine receptor. Neurologist. 2012;18:343–9. [PubMed: 23114665]
  • Figl A, Viseshakul N, Shafaee N, Forsayeth J, Cohen BN. Two mutations linked to nocturnal frontal lobe epilepsy cause use-dependent potentiation of the nicotinic ACh response. J Physiol. 1998;513:655–70. [PMC free article: PMC2231326] [PubMed: 9824708]
  • Hayman M, Scheffer IE, Chinvarun Y, Berlangieri SU, Berkovic SF. Autosomal dominant nocturnal frontal lobe epilepsy: demonstration of focal frontal onset and intrafamilial variation. Neurology. 1997;49:969–75. [PubMed: 9339675]
  • Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, Oliver KL, Mazarib A, Afawi Z, Korczyn A, Plazzi G, Petrou S, Berkovic SF, Scheffer IE, Dibbens LM. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 2012;44:1188–90. [PubMed: 23086396]
  • Hirose S, Iwata H, Akiyoshi H, Kobayashi K, Ito M, Wada K, Kaneko S, Mitsudome A. A novel mutation of CHRNA4 responsible for autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 1999;53:1749–53. [PubMed: 10563623]
  • Hoda JC, Wanischeck M, Bertrand D, Steinlein OK. Pleiotropic functional effects of the first epilepsy-associated mutation in the human CHRNA2 gene. FEBS Lett. 2009;583:1599–604. [PubMed: 19383498]
  • Hwang SK, Makita Y, Kurahashi H, Cho YW, Hirose S. Autosomal dominant nocturnal frontal lobe epilepsy: a genotypic comparative study of Japanese and Korean families carrying the CHRNA4 Ser284Leu mutation. J Hum Genet. 2011;56:609–12. [PubMed: 21753767]
  • Ito M, Kobayashi K, Fujii T, Okuno T, Hirose S, Iwata H, Mitsudome A, Kaneko S. Electroclinical picture of autosomal dominant nocturnal frontal lobe epilepsy in a Japanese family. Epilepsia. 2000;41:52–8. [PubMed: 10643924]
  • Joiner WJ, Tang MD, Wang LY, Dworetzky SI, Boissard CG, Gan L, Gribkoff VK, Kaczmarek LK. Formation of intermediate-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nat Neurosci. 1998;1:462–9. [PubMed: 10196543]
  • Khatami R, Neumann M, Schulz H, Kolmel HW. A family with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation. J Neurol. 1998;245:809–10. [PubMed: 9840354]
  • Kuryatov A, Gerzanich V, Nelson M, Olale F, Lindstrom J. Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca2+ permeability, conductance, and gating of human alpha4beta2 nicotinic acetylcholine receptors. J Neurosci. 1997;17:9035–47. [PubMed: 9364050]
  • Lal D, Reinthaler EM, Schubert J, Muhle H, Riesch E, Kluger G, Jabbari K, Kawalia A, Baumel C, Holthausen H, Hahn A, Feucht M, Neophytou B, Haberlandt E, Becker F, Altmuller J, Thiele H, Lemke JR, Lerche H, Nurnberg P, Sander T, Weber Y, Zimprich F, Neubauer BA. DEPDC5 mutations in genetic focal epilepsies of childhood. Ann Neurol. 2014;75:788–92. [PubMed: 24591017]
  • Liu H, Lu C, Li Z, Zhou S, Li X, Ji L, Lu Q, Lv R, Wu L, Ma X. The identification of a novel mutation of nicotinic acetylcholine receptor gene CHRNB2 in a Chinese patient: Its possible implication in non-familial nocturnal frontal lobe epilepsy. Epilepsy Res. 2011;95:94–9. [PubMed: 21497487]
  • Magnusson A, Stordal E, Brodtkorb E, Steinlein O. Schizophrenia, psychotic illness and other psychiatric symptoms in families with autosomal dominant nocturnal frontal lobe epilepsy caused by different mutations. Psychiatr Genet. 2003;13:91–5. [PubMed: 12782965]
  • Milligan CJ, Li M, Gazina EV, Heron SE, Nair U, Trager C, Reid CA, Venkat A, Younkin DP, Dlugos DJ, Petrovski S, Goldstein DB, Dibbens LM, Scheffer IE, Berkovic SF, Petrou S. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol. 2014;75:581–90. [PMC free article: PMC4158617] [PubMed: 24591078]
  • Nakken KO, Magnusson A, Steinlein OK. Autosomal dominant nocturnal frontal lobe epilepsy: an electroclinical study of a Norwegian family with ten affected members. Epilepsia. 1999;40:88–92. [PubMed: 9924907]
  • Oldani A, Zucconi M, Ferini-Strambi L, Bizzozero D, Smirne S. Autosomal dominant nocturnal frontal lobe epilepsy: electroclinical picture. Epilepsia. 1996;37:964–76. [PubMed: 8822695]
  • Phillips HA, Favre I, Kirkpatrick M, Zuberi SM, Goudie D, Heron SE, Scheffer IE, Sutherland GR, Berkovic SF, Bertrand D, Mulley JC. CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am J Hum Genet. 2001;68:225–31. [PMC free article: PMC1234917] [PubMed: 11104662]
  • Phillips HA, Marini C, Scheffer IE, Sutherland GR, Mulley JC, Berkovic SF. A de novo mutation in sporadic nocturnal frontal lobe epilepsy. Ann Neurol. 2000;48:264–7. [PubMed: 10939581]
  • Phillips HA, Mulley JC. SSCP variants within the alpha 4 subunit of the neuronal nicotinic acetylcholine receptor gene. Clin Genet. 1997;51:135–6. [PubMed: 9112007]
  • Phillips HA, Scheffer IE, Crossland KM, Bhatia KP, Fish DR, Marsden CD, Howell SJ, Stephenson JB, Tolmie J, Plazzi G, Eeg-Olofsson O, Singh R, Lopes-Cendes I, Andermann E, Andermann F, Berkovic SF, Mulley JC. Autosomal dominant nocturnal frontal-lobe epilepsy: genetic heterogeneity and evidence for a second locus at 15q24. Am J Hum Genet. 1998;63:1108–16. [PMC free article: PMC1377480] [PubMed: 9758605]
  • Picard F, Baulac S, Kahane P, Hirsch E, Sebastianelli R, Thomas P, Vigevano F, Genton P, Guerrini R, Gericke CA, An I, Rudolf G, Herman A, Brice A, Marescaux C, LeGuern E. Dominant partial epilepsies. A clinical, electrophysiological and genetic study of 19 European families. Brain. 2000;123:1247–62. [PubMed: 10825362]
  • Picard F, Bertrand S, Steinlein OK, Bertrand D. Mutated nicotinic receptors responsible for autosomal dominant nocturnal frontal lobe epilepsy are more sensitive to carbamazepine. Epilepsia. 1999;40:1198–209. [PubMed: 10487182]
  • Picard F, Brodtkorb E. Familial frontal lobe epilepsies. In: Engel J, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. 2 ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:2495-502.
  • Picard F, Makrythanasis P, Navarro V, Ishida S, de Bellescize J, Ville D, Weckhuysen S, Fosselle E, Suls A, De Jonghe P, Vasselon Raina M, Lesca G, Depienne C, An-Gourfinkel I, Vlaicu M, Baulac M, Mundwiller E, Couarch P, Combi R, Ferini-Strambi L, Gambardella A, Antonarakis SE, Leguern E, Steinlein O, Baulac S. DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy. Neurology. 2014;82:2101–6. [PubMed: 24814846]
  • Picard F, Pegna AJ, Arntsberg V, Lucas N, Kaczmarek I, Todica O, Chiriaco C, Seeck M, Brodtkorb E. Neuropsychological disturbances in frontal lobe epilepsy due to mutated nicotinic receptors. Epilepsy Behav. 2009;14:354–9. [PubMed: 19059498]
  • Picard F, Scheffer IE. Genetically determined focal epilepsies. In: Bureau M, Genton P, Dravet C, Delgado-Escueta AV, Tassinari CA, Thomas P, Wolf P, eds. Epileptic Syndromes in Infancy, Childhood and Adolescence. 5 ed. Montrouge, France: John Libbey Eurotext; 2012:354-9.
  • Provini F, Plazzi G, Tinuper P, Vandi S, Lugaresi E, Montagna P. Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases. Brain. 1999;122:1017–31. [PubMed: 10356056]
  • Puligheddu M, Melis M, Pillolla G, Milioli G, Parrino L, Terzano GM, Aroni S, Sagheddu C, Marrosu F, Pistis M, Muntoni AL. Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy. Epilepsia. 2017;58:1762–70. [PubMed: 28766701]
  • Rozycka A, Skorupska E, Kostyrko A, Trzeciak WH. Evidence for S284L mutation of the CHRNA4 in a white family with autosomal dominant nocturnal frontal lobe epilepsy. Epilepsia. 2003;44:1113–7. [PubMed: 12887446]
  • Sansoni V, Forcella M, Mozzi A, Fusi P, Ambrosini R, Ferini-Strambi L, Combi R. Functional characterization of a CRH missense mutation identified in an ADNFLE family. PLoS One. 2013;8:e61306. [PMC free article: PMC3623861] [PubMed: 23593457]
  • Scheffer IE, Heron SE, Regan BM, Mandelstam S, Crompton DE, Hodgson BL, Licchetta L, Provini F, Bisulli F, Vadlamudi L, Gecz J, Connelly A, Tinuper P, Ricos MG, Berkovic SF, Dibbens LM. Mutations in mammalian target of rapamycin regulator DEPDC5 cause focal epilepsy with brain malformations. Ann Neurol. 2014;75:782–7. [PubMed: 24585383]
  • Schenck CH, Mahowald MW. Parasomnias. Managing bizarre sleep-related behavior disorders. Postgrad Med. 2000;107:145–56. [PubMed: 10728141]
  • Shimmin LC, Natarajan S, Ibarguen H, Montasser M, Kim DK, Hanis CL, Boerwinkle E, Wadhwa PD, Hixson JE. Corticotropin releasing hormone (CRH) gene variation: comprehensive resequencing for variant and molecular haplotype discovery in monosomic hybrid cell lines. DNA Seq. 2007;18:434–44. [PubMed: 17676473]
  • Steinlein OK. Genetic heterogeneity in familial nocturnal frontal lobe epilepsy. Prog Brain Res. 2014;213:1–15. [PubMed: 25194481]
  • Steinlein OK, Hoda JC, Bertrand S, Bertrand D. Mutations in familial nocturnal frontal lobe epilepsy might be associated with distinct neurological phenotypes. Seizure. 2012;21:118–23. [PubMed: 22036597]
  • Steinlein OK, Magnusson A, Stoodt J, Bertrand S, Weiland S, Berkovic SF, Nakken KO, Propping P, Bertrand D. An insertion mutation of the CHRNA4 gene in a family with autosomal dominant nocturnal frontal lobe epilepsy. Hum Mol Genet. 1997;6:943–7. [PubMed: 9175743]
  • Steinlein OK, Stoodt J, Mulley J, Berkovic S, Scheffer IE, Brodtkorb E. Independent occurrence of the CHRNA4 Ser248Phe mutation in a Norwegian family with nocturnal frontal lobe epilepsy. Epilepsia. 2000;41:529–35. [PubMed: 10802757]
  • Steinlein O, Weiland S, Stoodt J, Propping P. Exon-intron structure of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit (CHRNA4). Genomics. 1996;32:289–94. [PubMed: 8833159]
  • Tassinari CA, Michelucci R. Familial frontal and temporal lobe epilepsy. In: Engel JJ, Pedley TA, eds. Epilepsy: A Comprehensive Textbook. Philadelphia, PA: Lippincott-Raven Publishers; 1997:2427-31.
  • Tenchini ML, Duga S, Bonati MT, Asselta R, Oldani A, Zucconi M, Malcovati M, Dalpra L, Ferini-Strambi L. SER252PHE and 776INS3 mutations in the CHRNA4 gene are rare in the Italian ADNFLE population. Sleep. 1999;22:637–9. [PubMed: 10450598]
  • Trivisano M, Terracciano A, Milano T, Cappelletti S, Pietrafusa Nm Bertini ES, Vigevano F, Specchio N. Mutation of CHRNA2 in a family with benign familial infantile seizures: Potential role of nicotinic acetylcholine receptor in various phenotypes of epilepsy. Epilepsia. 2015;56:e53–7. [PubMed: 25847220]
  • Weiland S, Steinlein O. Dinucleotide polymorphism in the first intron of the human neuronal nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4). Clin Genet. 1996;50:433–4. [PubMed: 9007339]
  • Wood AG, Saling MM, Fedi M, Berkovic SF, Scheffer IE, Benjamin C, Reutens DC. Neuropsychological function in patients with a single gene mutation associated with autosomal dominant nocturnal frontal lobe epilepsy. Epilepsy Behav. 2010;17:531–5. [PubMed: 20189461]

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

  • 15 March 2018 (ma) Comprehensive update posted live
  • 19 February 2015 (me) Comprehensive update posted live
  • 20 September 2012 (me) Comprehensive update posted live
  • 5 April 2010 (me) Comprehensive update posted live
  • 24 June 2004 (me) Comprehensive update posted live
  • 23 January 2004 (cd) Revision: mutation detection rate
  • 16 May 2002 (me) Review posted live
  • 22 January 2002 (ja) Original submission
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