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Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Synonym: ADNFLE

, MD, PhD and , MD, PhD.

Author Information
, MD, PhD
Aichi Medical University
Nagakute, Japan
, MD, PhD
Fukuoka University
Fukuoka, Japan

Initial Posting: ; Last Update: February 19, 2015.

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 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 pathogenic variants in CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH 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 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. 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 mutation 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

Diagnosis of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) should be suspected in individuals with

  • Clusters of seizures with a frontal semiology (see Note 1)
  • Occurrence of seizures predominantly during sleep (see Note 1)
  • 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]

Note: (1) 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. (2) 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].

Establishing the Diagnosis

The diagnosis of ADNFLE is established in a proband who has the clinical characteristics detailed above combined with a family history that is positive for other affected individuals and/or molecular genetic testing that detects a pathogenic variant in one of the six genes known to be associated with ADNFLE (see Table 1).

One genetic testing strategy is serial single-gene molecular genetic testing 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 could be considered.

An alternative genetic testing strategy is use of a multi-gene panel that includes CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, CRH and other genes of interest (see Differential Diagnosis). Note: The genes included and the methods used in multi-gene panels vary by laboratory and over time.

Genomic testing. If serial single-gene testing (and/or use of a multi-gene panel) has not confirmed a diagnosis in an individual with features of ADNFLE, genomic testing may be considered. Such testing may include whole-exome sequencing (WES) or whole-genome sequencing (WGS).

Notes regarding WES and WGS. (1) False negative rates vary by genomic region; therefore, genomic testing may not be as accurate as targeted single-gene testing or multi-gene molecular genetic testing panels; (2) most laboratories confirm positive results using a second, well-established method; (3) nucleotide repeat expansions and epigenetic alterations cannot be detected; (4) deletions/duplications larger than 8-10 nucleotides are not detected effectively [Biesecker & Green 2014]

Table 1.

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

ADNFLE TypeGene 1 Proportion of ADNFLE Attributed to Mutation of This GeneTest Method
Family History
PositiveNegative 2
1CHRNA410%-20% 3RareSequence analysis 4
Deletion/duplication analysis 5, 6
3CHRNB2Lower than in CHRNA4 3Rare 7Sequence analysis 4
Deletion/duplication analysis 5, 6
4CHRNA2Rare 8 UnknownSequence analysis 4
Deletion/duplication analysis 5, 6
5KCNT1<5% 9UnknownSequence analysis 4
Deletion/duplication analysis 5, 6
UnknownDEPDC510% 10UnknownSequence analysis 4
Deletion/duplication analysis 5, 6
UnknownCRHRare 11UnknownSequence analysis 4
Deletion/duplication analysis 5, 6
1.

See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2.

The affected individual is a simplex case (i.e., a single occurrence in a family)

3.

Approximately 20% of individuals with a family history have pathogenic variants in subunits of nicotinic acetylcholine receptor [Ottman et al 2010].

4.

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

5.

Testing that identifies exonic or whole-gene deletions/duplications not 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.

6.

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

7.

Reported in one individual [Liu et al 2011]

8.

Reported in one family [Aridon et al 2006]

9.

[Heron et al 2012]

10.

[Picard et al 2014]

11.

Reported by one group [Combi et al 2005, Sansoni et al 2013]

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. 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 (NREM) sleep, most commonly in stage 2 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.

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 [Oldani et al 1998, Provini et al 1999] 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 means 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 patients reported more than 15 seizures per month [Oldani et al 1996, Thomas et al 1998, Nakken et al 1999, Provini et al 1999, Ito et al 2000, Picard et al 2000].

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 [Oldani et al 1998, Provini et al 1999, Picard et al 2014].

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 8-11 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.

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 45% of 11 subjects with special difficulty in executive tasks and concluded that cognitive dysfunction is an integral part of ADNFLE with nicotinic receptor mutation. It is suggested that certain neuronal nicotinic acetylcholine receptor (nAChR) pathogenic variants could be associated with an increased risk for such symptoms [Steinlein et al 2012].

Magnusson et al [2003] reported an increase in psychiatric symptoms in families with ADNFLE. Psychiatric and behavioral problems as well as intellectual disability are more common in the individuals with KCNT1 mutation than in those with nAChR mutations [Heron et al 2012].

Familial variation. 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.

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]. 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 patient. 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 [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.

Genotype-Phenotype Correlations

Steinlein et al [2012] suggested that certain nAchR pathogenic variants may be associated with an increased risk for cognitive dysfunction. Individuals with KCNT1 pathogenic variants present a more severe phenotype than those with nAChR mutations, with lower age of onset, complete penetrance, and cognitive comorbidities [Heron et al 2012]. 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.

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 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 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.

Pathogenic variants 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.

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

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 SimulConsult®, 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 to help determine the extent of disease
  • Medical genetics consultation

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.

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

Prevention of Secondary Complications

Daytime complaints such as morning tiredness and somnolence may be caused by sleep fragmentation due to seizure-related arousals. To prevent this, it is important to provide diagnosis and treatment for ADNFLE appropriately.

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.

  • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives.
  • If the pathogenic variant in the family is not known, a medical history to seek evidence of affected status should be elicited from relatives at risk.

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. 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 mutation. The proportion of cases caused by de novo mutation 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].
  • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • 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).

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 pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%. The chance that the sib will manifest ADNFLE is (50% x70% =) 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 low but greater than that of the general population because of the 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 [Thomas et al 1998].

Considerations in families with apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant 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, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing of this gene or custom prenatal testing.

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 CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH pathogenic variant 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)
  • Epilepsy Canada
    2255B Queen Street East
    Suite 336
    Toronto Ontario M4E 1G3
    Canada
    Phone: 877-734-0873
  • 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 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
608167POTASSIUM CHANNEL, SUBFAMILY T, MEMBER 1; KCNT1
610353EPILEPSY, NOCTURNAL FRONTAL LOBE, 4; ENFL4
614191DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5
615005EPILEPSY, NOCTURNAL FRONTAL LOBE, 5; ENFL5

Molecular Genetic Pathogenesis

The genes in which mutations are known to cause ADNFLE:

  • 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
  • KCNT1, encoding a sodium-activated potassium channel; associated with type 5 ADNFLE
  • DEPDC5, encoding Dishevelled, Egl-10 and Pleckstrin (DEP) domain–containing protein 5
  • CRH, encoding corticotropin-releasing hormone

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 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.

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.

Mutant channels with pathogenic variants identified in ADNFLE produces voltage-activated currents with higher magnitude compared to wild type, leading to gain of function.

DEPDC5 is a component of GATOR1 (GTPase-actibating protein (GAP) activity toward RAGs complex 1) which negatively regulates mTORC1 (mammalian target of rapamycin complex 1), and expressed ubiquitously in human tissues. Most of pathogenic variants are truncating mutations that can be expected to result in nonsense-mediated mRNA degradation.

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

Gene structure. 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]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Benign 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 pathogenic variants have been observed in many different countries; these pathogenic variants 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 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Four families [Sáenz 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 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 of developing ADNFLE. Studies on mutated nAchR demonstrated an increased sensitivity to carbamazepine [Picard et al 1999].

CHRNB2

Gene structure. CHRNB2 has six exons distributed over approximately 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 Symbol.

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

Pathogenic allelic variants. Various pathogenic variants 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 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

De Fusco et al [2000]

2.

Kurahashi et al [unpublished observation]

3.

Phillips et al [2001], Díaz-Otero et al [2008]

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 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 of developing ADNFLE.

CHRNA2

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

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

Pathogenic allelic variants. One pathogenic variant 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 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 (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 pathogenic variant 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

Benign allelic variants. Benign variants of CRH have been described [Shimmin et al 2007]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Two variants in the promotor region and one missense mutation were reported [Combi et al 2005, Sansoni et al 2013]. See Table 5.

Table 5.

Selected CRH Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

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

2.

Combi et al [2005]

3.

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

4.

Sansoni et al [2013]

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 c.-669C>A variation, whereas reduction of the promotor activity was detected for the c.-365G>C pathogenic variant [Combi et al 2005].

KCNT1

Gene structure. KCNT1 has 31 exons distributed over approximately 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 Symbol.

Pathogenic allelic 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 6.

Table 6.

Selected KCNT1 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid 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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Heron et al [2012]

Normal gene product. KCNT1 (previously known as SLACK, SLO2.2 and KCa4.1) encodes a sodium-activated potassium channel, and is composed of 1235 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), which is 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 (p.Met896Ile, p.Arg398Gln, p.Tyr796His, and p.Arg928Cys) 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.

DEPDC5

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

Pathogenic allelic variants. The majority of the DEPDC5 pathogenic variants detected resulted in premature termination, suggesting haploinsufficiency as the disease mechanism. A certain DEPDC5 mutation (p.Trp1369Ter) was also found in a family with and familial focal epilepsy with variable foci (FFEVF) [Dibbens et al 2013]. See Table 7.

Table 7.

Selected DEPDC5 Pathogenic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.2355-2A>G p.Arg785_Gly839del 1 NM_001242896​.1
NP_001229825​.1
c.1459C>Tp.Arg487Ter 1, 2
c.3259C>Tp.Arg1087Ter 1
c.4107G>Ap.Trp1369Ter 1, 2, 3
c.4567C>Tp.Gln1523Ter 4

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 (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Only pathogenic variants reported as a cause of ADNFLE are listed. Other pathogenic variants related to familial focal epilepsies could be also detected in ADNFLE.

1.

Picard et al [2014]

2.

Dibbens et al [2013]

3.

See Genetically Related Disorders.

4.

Ishida et al [2013]

Normal gene product. DEPDC5 is composed of 1603 amino acids and expressed ubiquitously in human tissues [Dibbens et al 2013]. It contains a DEP homology domain which is present in many proteins of G-protein signaling pathways. DEPDC5 is a component of GATOR1 (GTPase-actibating 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 of pathogenic variants are truncating mutations that can be expected to result in nonsense-mediated mRNA degradation. Aberrant mTORC1 signaling is known to cause disturbances 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 develop 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].

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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

  • 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 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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