U.S. flag

An official website of the United States government

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy

Synonym: Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), ADSHE

, MD, PhD and , MD, PhD.

Author Information and Affiliations

Initial Posting: ; Last Update: March 23, 2023.

Estimated reading time: 35 minutes


Clinical characteristics.

Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is a seizure disorder characterized by clusters of nocturnal motor seizures that are often stereotyped and brief (<2 minutes). They vary from simple arousals from sleep to dramatic, often hyperkinetic events with tonic or dystonic features. Affected individuals may experience an aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Age of onset ranges from infancy to adulthood. About 80% of individuals develop ADSHE 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 comorbidities, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent.


The diagnosis of ADSHE is established in a proband who has suggestive clinical findings and a family history consistent with autosomal dominant inheritance and/or a heterozygous pathogenic variant in CABP4, CHRNA4, CHRNA2, CHRNB2, CRH, DEPDC5, KCNT1, NPRL2, NPRL3, or STX1B identified by molecular genetic testing.


Treatment of manifestations: Many anti-seizure medications (ASM) may be effective. Carbamazepine is associated with remission in about 70% of individuals, often in relatively low doses. Individuals with ADSHE associated with the CHRNA4 pathogenic variant p.Ser284Leu are more responsive to zonisamide than carbamazepine. KCNT1-related ADSHE is difficult to treat but may be treatable using quinidine based on limited data. Resistance to ASM is present in about 30% of affected individuals and typically requires a trial of all appropriate ASM. Adjunctive fenofibrate therapy or vagal nerve stimulation may be considered in individuals resistant to standard ASM.

Surveillance: Reevaluation of EEGs at regular intervals to monitor disease progression, as well as assessment for changes in seizure semiology, changes in tone, and movement disorders; monitoring of developmental progress and educational needs.

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

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

Genetic counseling.

ADSHE, by definition, is inherited in an autosomal dominant manner. Most individuals diagnosed with ADSHE have an affected parent. Each child of an individual with ADSHE has a 50% chance of inheriting the ADSHE-related pathogenic variant; the chance that the offspring will manifest ADSHE is (50% x 70% =) 35%, assuming penetrance of 70%. If the ADSHE-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.


The International League Against Epilepsy (ILAE) has proposed diagnostic criteria for sleep-related hypermotor (hyperkinetic) epilepsy (SHE) [Riney et al 2022], which consist of three groups of criteria.

Mandatory feature. Brief focal motor seizure with hyperkinetic or asymmetric tonic/dystonic features occurring predominantly during sleep

Alerts. Features that are absent in most cases but rarely can be seen. Their presence should result in caution in diagnosing the syndrome and consideration of other conditions. They include the following:

  • Seizures predominantly from the awake state
  • Frequent epileptiform abnormality outside of the frontal regions
  • Generalized epileptiform abnormality by EEG
  • Age at onset younger than ten or older than 20 years
  • Moderate-to-severe intellectual disability, or focal neurologic abnormalities on examination

Exclusionary features

  • Seizures occur only during wakefulness
  • Generalized-onset seizures
  • Age at onset younger than two months or older than 64 years

Suggestive Findings

Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) should be suspected in individuals with the following clinical and neuroimaging findings, EEG findings, and family history.

Clinical findings

  • Clusters of brief (<2 minutes) motor seizures during sleep that are often stereotyped with abrupt onset and offset. Seizures may include the following:
    • Nightmares
    • Verbalizations
    • Sudden limb movements
  • Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidities may occur
  • Normal clinical neurologic examination

Note: The clinical features of ADSHE are indistinguishable from those of nonfamilial SHE (i.e., SHE diagnosed in an individual with a negative family history), the causes of which are unknown but may include de novo variants of relevant genes [Hayman et al 1997, Tenchini et al 1999, Steinlein et al 2000, Tinuper et al 2016].

EEG findings

  • Interictal EEG may be normal or show infrequent epileptiform discharges.
  • Ictal scalp EEG may be normal or obscured by movement artifact.
  • Intracranial recordings demonstrate that ictal discharge may arise from various frontal as well as extrafrontal areas.

Neuroimaging findings

  • Usually normal in individuals with ADSHE
  • Focal cortical dysplasia may be present in some individuals with drug-resistant SHE, especially in individuals with pathogenic variants in GATOR complex genes (e.g., DEPDC5, NPRL2, NRPL3).

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

A clinical diagnosis of ADSHE is established in a proband based on the presence of clinical features, EEG findings and family history detailed in Suggestive Findings. A molecular diagnosis of ADSHE is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in in one of the genes listed in Table 1. A pathogenic variant is identified in 19% of individuals with a family history of SHE and 7% of individuals with a negative family history [Licchetta et al 2020].

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a heterozygous variant of uncertain significance in any of the genes in Table 1 does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the clinical findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those with a phenotype indistinguishable from many other epilepsy phenotypes are more likely to be diagnosed using genomic testing (see Option 2).

Option 1

When the phenotypic and EEG findings suggest the diagnosis of ADSHE, molecular genetic testing approaches can include use of a multigene panel.

An epilepsy multigene panel that includes CABP4, CHRNA2, CHRNA4, CHRNB2, CRH, DEPDC5, KCNT1, NPRL2, NPRL3, and STX1B (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Notes: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change 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.

Option 2

When the phenotype is indistinguishable from many other epilepsy phenotypes, comprehensive genomic testing does not require the clinician to determine which gene is likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.

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 Sleep-Related Hypermotor (Hyperkinetic) Epilepsy

Gene 1, 2Proportion of ADSHE Attributed to Pathogenic Variants in GeneProportion of Probands with a Pathogenic Variant 3 Detectable by Method
Sequence analysis 4Gene-targeted deletion/duplication analysis 5
CABP4 Rare (only 1 pedigree reported) 6, 7Rare (only 1 pedigree reported) 6
CHRNA2 Rare 6, 8Rare 6, 8
CHRNA4 2.9% of sporadic cases 6, 8, 9
6.3% of familial cases 6, 9
2.9% of sporadic cases 6, 8, 9
6.3% of familial cases 6, 9
CHRNB2 Rare 6, 10Rare 6, 10
CRH Rare 6, 11Rare 6, 11
DEPDC5 3.9% of sporadic cases 6, 9,12
6.3% of familial cases 6, 9
2.9% of sporadic cases 6, 8, 9
6.3% of familial cases 6, 9
1 person w/intragenic deletion in DEPDC5 13
KCNT1 1.0% 6, 9, 141.0% 6, 9, 14
NRPL2 1.0% of sporadic cases 6, 9, 12
6.3% of familial cases 6, 9
1.0% of sporadic cases 6, 9, 12
6.3% of familial cases 6, 9
NRPL3 RareRare
STX1B Rare (only 1 pedigree reported)Rare (only 1 pedigree reported)
Unknown 14~90%

Genes are listed in alphabetic order.


See Molecular Genetics for information on variants detected in these genes.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or 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.


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


Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]


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


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


Clinical Characteristics

Clinical Description

Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is characterized by clusters of nocturnal motor seizures with a range of manifestations.

Table 2.

Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Frequency of Select Features

Feature% of Persons w/FeatureComment
Sleep-related seizures100%
  • Focal motor seizures w/vigorous hyperkinetic or asymmetric tonic/dystonic features 1
  • May occur at any stage during sleep, but typically cluster in non-REM sleep
  • Some persons experience daytime seizures.
EEG abnormalities
  • 10%-50% while awake 1, 2
  • 50% during sleep 1, 2
  • Interictal epileptiform abnormalities over the frontal areas during sleep.
  • Ictal EEG may show evolving sharp- or spike-and-wave, rhythmic slow activity, or diffuse flattening.
Cognitive issues53% 3Some persons have reduced intellect, cognitive deficits, or psychiatric issues.

Sleep-related seizures. History may be obtained from the affected individual and witnesses, supplemented if necessary by video EEG monitoring.

Seizures may occur during any stage of sleep, although typically they cluster 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.

Seizures in ADSHE are often stereotyped and brief (<2 minutes); they vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. Subtle and stereotypic motor seizures are accompanied by abrupt recurrent arousals from NREM sleep ("paroxysmal arousals"). The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling, and a wide range of movements including flinging, throwing the arms, jumping, and pelvic thrusting. Seizures may have greater complexities ("epileptic wandering"). Reported seizure frequency ranges from one to 20 attacks each night, with a mean of 20 seizures per month; about 60% of affected individuals reported more than 15 seizures per month.

Retained awareness during seizures is common and may cause affected individuals to fear falling asleep. Autonomic signs such as tachycardia, tachypnea, and irregular respiratory rhythm are also seen. Focal aware sensory or cognitive seizures, for example, or a sense of difficulty breathing and hyperventilation may precede the motor signs. Focal seizures evolving to bilateral tonic-clonic seizures can also occur.

Some individuals experience an aura preceding the seizure during sleep and are aware of the onset of a seizure. Auras 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 reported seizures are paroxysmal dystonia similar to those during sleep, and others are generalized tonic-clonic seizures, generalized atonic seizures, and focal impaired awareness seizures.

EEG findings

  • Ictal EEG recordings may not show definitive ictal patterns, or ictal patterns may be obscured by movement artifact. If present, ictal rhythms may show evolving sharp waves or a spike-and-wave pattern, rhythmic slow activity, or diffuse flattening [Riney et al 2022].
  • Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals.
  • Interictal sleep EEG shows epileptiform abnormalities over the frontal areas in approximately 50% of affected individuals [Provini et al 1999].

Cognitive findings. Clinical neurologic examination is typically normal and intellect is usually preserved [Oldani et al 1996, Nakken et al 1999]. Several studies have reported that some individuals with SHE have reduced intellect, cognitive deficits, or psychiatric comorbidities [Provini et al 1999, Picard et al 2000, Wood et al 2010, Licchetta et al 2018]. 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 ADSHE caused by heterozygous pathogenic variants in the nicotinic acetylcholine receptor (see Phenotype Correlations by Gene).

Licchetta et al [2018] reported 60 individuals with SHE. Of these, 15% had intellectual disability and 53.3% had neuropsychologic deficits. The profile of impairment showed worse verbal IQ, as well as deficits in extrafrontal and selective frontal functions. In addition, individuals with pathogenic variants in ADSHE genes had lower IQ than individuals without pathogenic variants, irrespective of the specific 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 individuals with ADSHE [Provini et al 1999]. True parasomnias were distinguished from true seizures based on their age-dependent course, rarity, and nature of the episodes (episodes typically not violent and often not disturbing for the affected individual). They often ended well before the onset of clear-cut seizures.

Onset and prognosis. ADSHE is lifelong but not progressive. Onset ranges from infancy to adulthood. Most affected individuals develop ADSHE in the first two decades of life, typically in adolescence (age 11-14 years), but age of onset ranges from two months to 64 years [Scheffer et al 1995, Oldani et al 1996, Provini et al 1999, Licchetta et al 2017]. 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

Table 3.

Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Phenotype Correlations by Gene

Gene 1Phenotypic Feature
EpilepsyCognitive issuesOther psychiatric & behavioral issuesPenetrance
DEPDC5 2Higher rate of drug resistance, daytime seizures
KCNT1 3More severe, earlier age of onsetMore severeMore commonMore complete penetrance
STX1B Peri-ictal hypotension

There are no known phenotype correlations for the other ADSHE-associated genes: CABP4, CHRNA2, CHRNA4, CHRNB2, CRH, NPRL2, and NPRL3.


Individuals with heterozygous pathogenic variants in KCNT1 may have these features in comparison to individuals with pathogenic variants in neuronal nicotinic acetylcholine receptor (nAChR) genes (CHRNA2, CHRNA4, CHRNB2) [Heron et al 2012].

Genotype-Phenotype Correlations

Steinlein et al [2012] suggested that certain pathogenic variants in nicotinic acetylcholine receptor (nAChR) genes (CHRNA2, CHRNA4, CHRNB2) may be associated with an increased risk of unfavorable outcomes.

Individuals with the CHRNA4 pathogenic variant p.Ser284Leu tend to have early onset of epilepsy and less favorable cognitive function. They respond only partially to carbamazepine and are more responsive to zonisamide [Provini et al 1999, Ito et al 2000, Combi et al 2004].

The CHRNB2 pathogenic variant p.Ile312Met was associated with clinically relevant deficits in cognitive function. Affected members from two unrelated families with the variant show normal or low-average intellect with moderate-to-significant verbal memory deficits [Bertrand et al 2005, Cho et al 2008].

Marked intrafamilial variation in severity is seen in ADSHE; the reasons for this are not well understood.


The penetrance of ADSHE is estimated to be 70%. KCNT1-related ADSHE demonstrates complete penetrance compared to 60%-80% in nAChR-related ADSHE.


Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is now referred to as autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) [Tinuper et al 2016, Riney et al 2022].

The term "nocturnal" implies a chronobiological pattern of seizure occurrence, whereas occurrence in sleep (rather than at night) is the most important characteristic of the epilepsy in ADSHE. The characteristic seizures that consist of hypermotor manifestations can arise from other cerebral regions in addition to the frontal lobe [Tinuper et al 2016]. The ILAE task force notes that "hyperkinetic" rather than "hypermotor" is the currently accepted term for the focal motor seizures with vigorous movements that can be seen in this syndrome [Riney et al 2022].


The number of families with ADSHE reported to date exceeds 100 [Picard & Brodtkorb 2007]. The estimated prevalence of SHE in the adult population is estimated to be 1.8-1.9 in 100,000 [Vignatelli et al 2017].

Differential Diagnosis

The differential diagnosis of autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) includes autosomal recessive SHE caused by biallelic pathogenic variants in PRIMA1 (reported in only one family to date [Hildebrand et al 2015]) and other conditions of varied etiology, including the following:

  • Other focal seizures occurring predominantly from sleep but not having the hyperkinetic or asymmetric tonic/dystonic features, which are characteristics of ADSHE
  • Normal sleep is characterized by periodic arousals, and occasionally other sleep-related movements or phenomena including nightmares.
  • Parasomnias (disorders in which undesirable physical and mental phenomena occur mainly or exclusively during sleep [American Academy of Sleep Medicine 2014]) 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 (sleepwalking) 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 in the differential diagnosis 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 (i.e., 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.


No clinical practice guidelines regarding the management for autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) have been published.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ADSHE, the evaluations summarized in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 5.

Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy

Neurologic Assessment by neurologist w/eval of suspected seizures as indicatedTo incl EEG & high-resolution brain MRI to evaluate for focal brain malformations, if suspected based on seizure semiology
Development Assessment by developmental specialist
  • To incl motor, adaptive, cognitive, & speech-language eval
  • Eval for early intervention / special education
Psychiatric Assessment by psychiatristFor any psychiatric comorbidities or complications
Genetic counseling By genetics professionals 1To inform affected persons & their families re nature, MOI, & implications of ADSHE to facilitate medical & personal decision making
Family support
& resources
Assess need for:

ADSHE = autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy; MOI = mode of inheritance


Medical geneticist, certified genetic counselor, certified advanced genetic nurse

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 6).

Table 6.

Treatment of Manifestations in Individuals with Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy

Epilepsy Standardized treatment w/ASM by epileptologist or experienced neurologist
  • Many ASM may be effective; In about 70% of persons w/ADSHE, carbamazepine is assoc w/remission of seizures, often w/relatively low doses. However, persons w/ADSHE assoc w/CHRNA4 pathogenic variant p.Ser284Leu respond only partially to carbamazepine & are more responsive to zonisamide. 1
  • KCNT1-related ADSHE is difficult to treat. Some persons w/EIMFS caused by pathogenic variants in KCNT1 & treated w/quinidine were noted to have marked reduction in seizure frequency. 2 Therefore, quinidine may be considered for treatment of KCNT1-related ADSHE, though data regarding its efficacy are limited.
  • Resistance to ASM occurs in ~30% of affected persons. Intrafamilial variation in pharmacoresponsiveness occurs; therefore, all appropriate ASMs should be tried.
  • Adjunctive therapy w/fenofibrate ↓ seizure frequency in persons w/pharmacoresistant ADSHE in 1 study. 3
  • Surgical treatment is effective in persons w/FCD-assoc SHE.
  • Education of parents/caregivers is recommended. 4
Vagal nerve stimulationMay be considered in persons w/epilepsy who are resistant to ASM. 5
Developmental delay / Intellectual disability See Developmental Delay / Intellectual Disability Management Issues.
Psychiatric issues Standardized treatment by psychiatrist
  • Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
  • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
  • Ongoing assessment of need for support

ADSHE = autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy; ASM = anti-seizure medication; EIMFS = epilepsy of infancy with migrating focal seizures; FCD = focal cortical dysplasia


Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.


Developmental Delay / Intellectual Disability Management Issues

The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.

Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.

All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:

  • IEP services:
    • An IEP provides specially designed instruction and related services to children who qualify.
    • IEP services will be reviewed annually to determine whether any changes are needed.
    • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
    • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
    • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
  • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
  • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.


For information on nonmedical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.


To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 7 are recommended.

Table 7.

Recommended Surveillance for Individuals with Autosomal Dominant Sleep-related Hypermotor Epilepsy (ADSHE)

  • Monitor those w/seizures as clinically indicated.
  • Assess for new manifestations such as new seizure types, changes in tone, & movement disorders.
At each visit
Development Monitor developmental progress & educational needs.If applicable
Eval by developmental pediatrician or developmental specialistAnnually &/or as needed
Psychiatric Eval by psychiatrist for any psychiatric comorbiditiesIf applicable
Family/Community Assess family need for social work support (e.g., palliative/respite care, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).At each visit

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. Evaluations can include one of the following:

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 anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy during which the medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended.

Discussion of the risks and benefits of using a given ASM 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 EU Clinical Trials Register 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, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

By definition, autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is inherited in an autosomal dominant manner.

PRIMA1-related SHE, which is inherited in an autosomal recessive manner, was reported in only one family [Hildebrand et al 2015].

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with ADSHE have an affected parent.
  • A proband may have the disorder as the result of a de novo ADSHE-related pathogenic variant.
  • Recommendations for the evaluation of parents of a child with SHE and no known family history of SHE include:
    • A detailed clinical and family history;
    • Molecular genetic testing (if a molecular diagnosis has been established in the proband).
  • If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The family history of some individuals diagnosed with ADSHE 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 without appropriate clinical evaluations of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the ADSHE-related pathogenic variant identified in the proband).

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

  • If one parent has phenotypic features of ADSHE and/or is known to have an ADSHE-related pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%. The chance that the sib will manifest ADSHE is (50% x 70% =) 35%, assuming an estimated penetrance of 70%. (Note: KCNT1-related ADSHE demonstrates complete penetrance.)
    Within a family, the manifestations of ADSHE in affected individuals may vary considerably.
  • If the proband has a known ADSHE-related pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016].
  • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband

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

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent is affected with ADSHE or has an ADSHE-related pathogenic variant, the parent's 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].

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.
  • Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before pregnancy (see Pregnancy Management).

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

If the ADSHE-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Because ADSHE is associated with intrafamilial clinical variability and reduced penetrance, the prenatal identification of an ADSHE-related pathogenic variant cannot be used to reliably predict future clinical manifestations.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.


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.

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 B.

OMIM Entries for Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy (View All in OMIM)


Molecular Pathogenesis

Pathogenic variants in (1) genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR) (CHRNA4, CHRNB2, CHRNA2); (2) genes encoding components of GATOR1 (DEPDC5, NPRL2, NPRL3); and (3) KCNT1, CRH, CABP4, and STX1B are known to cause autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE).

Genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR)

  • CHRNA4, encoding the alpha-4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR)
  • CHRNB2, encoding the beta-2 subunit of the nAChR
  • CHRNA2, encoding the alpha-2 subunit of the nAChR

The nAChR 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 the thalamus and the cortex is (α-4)2(β-2)3 subunits (i.e., 2 α-4 and 3 β-2 subunits). The nicotinic acetylcholine 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].

Each nAChR 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) presumed to function as part of the acetylcholine binding site when the α-4 subunits are complexed as a heterologous pentamer with the β subunits [Figl et al 1998]. 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]. The second transmembrane domain of the receptor forms the ion channel pore and is the site of most of the pathogenic variants implicated in ADSHE.

Pathogenic variants in CHRNA4, CHRNA2, and CHRNB2 associated with ADSHE 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 in vitro acetylcholine sensitivity is typical for known ADSHE-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 pathogenic variants cause ADSHE is poorly understood, though increased receptor sensitivity to acetylcholine and gain of function of nAChR may be a contributing mechanism [Aridon et al 2006, Hoda et al 2009]. Carbamazepine and oxcarbazepine produce a noncompetitive channel inhibition in heteromeric neuronal nicotinic receptors including mutated α-2 subunits as well as wild type α-2 subunits, but the different heteromeric nicotinic receptors exhibit distinct pharmacologic properties [Di Resta et al 2010].

Genes encoding components of GATOR1

  • DEPDC5, encoding dishevelled, egl-10, and pleckstrin (DEP) domain-containing protein 5
  • NPRL2, nitrogen permease regulator-like 2
  • NPRL3, nitrogen permease regulator-like 3

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] and is expressed ubiquitously in human tissues. The mTOR pathway plays a role in many activities including cell growth, cell proliferation, and metabolism. Most pathogenic variants in DEPDC5 are truncating variants that can be expected to result in nonsense-mediated mRNA degradation. 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 has expanded 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]. NPRL2 and NPLR3 are also components of GATOR1, and pathogenic variants in these genes have been reported in ADSHE and sporadic SHE, as well as other focal epilepsies [Ricos et al 2016].

KCNT1. KCNT1 (previously known as SLACK, SLO2.2, and KCa4.1) encodes a sodium-activated potassium channel [Joiner et al 1998]. The 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. The KCNT1 channel contains six putative membrane-spanning regions and an 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]. All identified pathogenic variants to date are located within the intracellular region, and most alter amino acids within or immediately adjacent to a nicotinamide adenine dinucleotide (NAD+)-binding site. Mutated channels with pathogenic variants identified in ADSHE produce voltage-activated currents with higher magnitude compared to wild type, leading to gain of function. However, the mechanisms underlying increased neuronal excitability due to a gain of function of KCNT1 channels are not known.

CRH. CRH encodes corticotropin-releasing hormone (CRH), which 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 promoter [Combi et al 2005] or in the pro-sequence region [Sansoni et al 2013] have been reported. The variant identified in one family with ADSHE decreases peptide secretion in vitro [Sansoni et al 2013].

CABP4. CABP4 encodes the calcium-binding protein 4 (CABP4), which belongs to the family of neuronal Ca2+-binding proteins and shares structural homology with calmodulin. It has been shown to modulate voltage-dependent Ca2+ channels. Pathogenic variants in CABP4 have been identified in individuals with retinal diseases. Missense variant c.464G>A (p.Gly155Asp) was identified in seven affected individuals from a four-generation ADSHE pedigree [Chen et al 2017]. The mechanisms by which pathogenic variants in this gene cause ADSHE are still unclear; the missense variant noted above was associated with reduced expression of CABP4 proteins in vitro [Guo et al 2022].

STX1B. STX1B, encoding syntaxin-1B, is involved in the release of glutamate and GABA and plays a role in the regulation of fast synaptic vesicle exocytosis [Mishima et al 2014]. STX1B pathogenic variants have been identified in individuals with fever-associated epilepsy syndromes [Schubert et al 2014]. In one study, multigene panel testing revealed a likely pathogenic variant c.106-2A>G in an individual with SHE [Peres et al 2018]. Seizures in this individual were accompanied by autonomic features evidenced by significant peri-ictal hypotension. This splice site variant is predicted to abolish the native splicer acceptor site, leading to aberrant splicing resulting in abnormal protein or nonsense-mediated mRNA decay.

Mechanism of disease causation

  • CHRNA2, CHRNA4, CHRNB2, KCNT1. Likely gain of function
  • DEPDC5, NPRL2, NPRL3, STX1B. Loss of function (haploinsufficiency)
  • CRH. The direct role in the pathogenesis of SHE is still unclear, but alteration of hormone levels may be associated.
  • CABP4. The direct role in the pathogenesis of SHE is still unclear, but reduction of the expression of CABP4 may be associated.
  • STX1B. The direct role in the pathogenesis of SHE is still unclear; loss of function of STX1B leads to impairment of regulation of synaptic vesicle exocytosis, which may cause SHE.

Table 8.

Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Gene-Specific Laboratory Considerations

Gene 1Special Consideration
CABP4 Only 1 variant, c.464G>A, has been reported.
CHRNA2 2Located w/in transmembrane 1 & 2
CHRNA4 2Mainly located w/in transmembrane 2
CRHNB2 2Mainly located w/in transmembrane 2 & 3
CRH Only has 2 exons, & the 1st is noncoding. Variants in promotor region (e.g., c.-365G>C, c.-669C>A 3) have been identified in ADSHE that may not be detected by standard exome sequencing.
DEPDC5 4Pathogenic variants are located in protein-coding region.
KCNT1 5Variants identified in persons w/ADSHE cluster in regulators of potassium (RCK) domains of channel protein.
NPRL2 4Pathogenic variants are located throughout protein-coding region.
NPRL3 4Pathogenic variants are located throughout protein-coding region.

Table 9.

Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Notable Pathogenic Variants by Gene

Gene 1Reference SequencesDNA Nucleotide ChangePredicted Protein ChangeComment [Reference]
CABP4 NM_145200​.5
c.464G>Ap.Gly155AspVariant specifically assoc w/ADSHE [Chen et al 2017]
CHRNA4 NM_000744​.7
c.851C>Tp.Ser284LeuAssoc w/early-onset epilepsy & less favorable cognitive function. Persons respond only partially to carbamazepine & are more responsive to zonisamide. 2
CHRNB2 NM_000748​.3
c.936C>Gp.Ile312MetClinically relevant deficits in cognitive functions, esp in verbal memory 3
STX1B NM_052874​.5
c.106-2A>Gp.?Reported in 1 person w/sleep-related epilepsy. Seizures accompanied by autonomic features. Variant is predicted to abolish native splicer acceptor site, leading to aberrant splicing resulting in abnormal protein or nonsense-mediated mRNA decay. 4

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

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


Genes from Table 1 are in alphabetic order.


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

  • 23 March 2023 (gm) Comprehensive update posted live
  • 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


Literature Cited

  • American Academy of Sleep Medicine. International Classification of Sleep Disorders 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014. Available online. Accessed 3-15-23.
  • 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]
  • Baldassari S, Picard F, Verbeek NE, van Kempen M, Brilstra EH, Lesca G, Conti V, Guerrini R, Bisulli F, Licchetta L, Pippucci T, Tinuper P, Hirsch E, de Saint Martin A, Chelly J, Rudolf G, Chipaux M, Ferrand-Sorbets S, Dorfmüller G, Sisodiya S, Balestrini S, Schoeler N, Hernandez-Hernandez L, Krithika S, Oegema R, Hagebeuk E, Gunning B, Deckers C, Berghuis B, Wegner I, Niks E, Jansen FE, Braun K, de Jong D, Rubboli G, Talvik I, Sander V, Uldall P, Jacquemont ML, Nava C, Leguern E, Julia S, Gambardella A, d'Orsi G, Crichiutti G, Faivre L, Darmency V, Benova B, Krsek P, Biraben A, Lebre AS, Jennesson M, Sattar S, Marchal C, Nordli DR Jr, Lindstrom K, Striano P, Lomax LB, Kiss C, Bartolomei F, Lepine AF, Schoonjans AS, Stouffs K, Jansen A, Panagiotakaki E, Ricard-Mousnier B, Thevenon J, de Bellescize J, Catenoix H, Dorn T, Zenker M, Müller-Schlüter K, Brandt C, Krey I, Polster T, Wolff M, Balci M, Rostasy K, Achaz G, Zacher P, Becher T, Cloppenborg T, Yuskaitis CJ, Weckhuysen S, Poduri A, Lemke JR, Møller RS, Baulac S. The landscape of epilepsy-related GATOR1 variants. Genet Med. 2019;21:398–408. [PMC free article: PMC6292495] [PubMed: 30093711]
  • Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, 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 D, Elmslie F, Hughes E, Trounce J, Sander T, Bertrand S, Steinlein OK. The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits. Neurobiol Dis. 2005;20:799–804. [PubMed: 15964197]
  • 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]
  • Bisulli F, Licchetta L, Tinuper P. Sleep related hyper motor epilepsy (SHE): a unique syndrome with heterogeneous genetic etiologies. Sleep Sci Practice. 2019:3.
  • 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 ZH, Wang C, Zhuo MQ, Zhai QX, Chen Q, Guo YX, Zhang YX, Gui J, Tang ZH, Zeng XL. Exome sequencing identified a novel missense mutation c.464G>A (p.G155D) in Ca2+-binding protein 4 (CABP4) in a Chinese pedigree with autosomal dominant nocturnal frontal lobe epilepsy. Oncotarget. 2017;8:78940–7. [PMC free article: PMC5668010] [PubMed: 29108277]
  • Cho YW, Yi SD, Lim JG, Kim DK, Motamedi GK. Autosomal dominant nocturnal frontal lobe epilepsy and mild memory impairment associated with CHRNB2 mutation I312M in the neuronal nicotinic acetylcholine receptor. Epilepsy Behav. 2008;13:361–5. [PubMed: 18534914]
  • 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]
  • 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]
  • 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]
  • Guo Y, Miao Q, Zhang Y, Wang C, Liang M, Li X, Qiu W, Shi G, Zhai Q, Chen Z. A novel missense creatine mutant of CaBP4, c.464G>A (p.G155D), associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), reduces the expression of CaBP4. Transl Pediatr. 2022;11:396–402. [PMC free article: PMC8976675] [PubMed: 35378956]
  • 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]
  • Hildebrand MS, Tankard R, Gazina EV, Damiano JA, Lawrence KM, Dahl HH, Regan BM, Shearer AE, Smith RJ, Marini C, Guerrini R, Labate A, Gambardella A, Tinuper P, Lichetta L, Baldassari S, Bisulli F, Pippucci T, Scheffer IE, Reid CA, Petrou S, Bahlo M, Berkovic SF. PRIMA1 mutation: a new cause of nocturnal frontal lobe epilepsy. Ann Clin Transl Neurol. 2015;2:821–30. [PMC free article: PMC4554443] [PubMed: 26339676]
  • 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]
  • Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389–97. [PMC free article: PMC9314484] [PubMed: 35834113]
  • 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]
  • Khan AO, Alrashed M, Alkuraya FS. Clinical characterisation of the CABP4-related retinal phenotype. Br J Ophthalmol. 2013;97:262–5. [PubMed: 23099293]
  • 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. [PMC free article: PMC6573611] [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]
  • Licchetta L, Bisulli F, Vignatelli L, Zenesini C, Di Vito L, Mostacci B, Rinaldi C, Trippi I, Naldi I, Plazzi G, Provini F, Tinuper P. Sleep-related hypermotor epilepsy: Long-term outcome in a large cohort. Neurology. 2017;88:70–7. [PMC free article: PMC5200852] [PubMed: 27881627]
  • Licchetta L, Pippucci T, Baldassari S, Minardi R, Provini F, Mostacci B, Plazzi G, Tinuper P, Bisulli F, et al. Sleep-related hypermotor epilepsy (SHE): Contribution of known genes in 103 patients. Seizure. 2020;74:60–4. [PubMed: 31835056]
  • Licchetta L, Poda R, Vignatelli L, Pippucci T, Zenesini C, Menghi V, Mostacci B, Baldassari S, Provini F, Tinuper P, Bisulli F. Profile of neuropsychological impairment in Sleep-related Hypermotor Epilepsy. Sleep Med. 2018;48:8–15. [PubMed: 29843024]
  • Mishima T, Fujiwara T, Sanada M, et al. Syntaxin 1B, but not syntaxin 1A, is necessary for the regulation of synaptic vesicle exocytosis and of the readily releasable pool at central synapses. PLoS One. 2014;9:e90004. [PMC free article: PMC3938564] [PubMed: 24587181]
  • 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]
  • Peres J, Antunes F, Zonjy B, et al. Sleep-related hypermotor epilepsy and peri-ictal hypotension in a patient with syntaxin-1B mutation. Epileptic Disorders. 2018;20:413–7. [PubMed: 30378543]
  • 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]
  • 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]
  • Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, Turki SA, Dominiczak A, Morris A, Porteous D, Smith B, Stratton MR, Hurles ME, et al. Timing, rates and spectra of human germline mutation. Nat Genet. 2016;48:126–33. [PMC free article: PMC4731925] [PubMed: 26656846]
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24. [PMC free article: PMC4544753] [PubMed: 25741868]
  • Ricos MG, Hodgson BL, Pippucci T, Saidin A, Ong YS, Heron SE, Licchetta L, Bisulli F, Bayly MA, Hughes J, Baldassari S, Palombo F., Epilepsy Electroclinical Study Group. Santucci M, Meletti S, Berkovic SF, Rubboli G, Thomas PQ, Scheffer IE, Tinuper P, Geoghegan J, Schreiber AW, Dibbens LM. Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol. 2016;79:120–31. [PubMed: 26505888]
  • Riney K, Bogacz A, Somerville E, Hirsch E, Nabbout R, Scheffer IE, Zuberi SM, Alsaadi T, Jain S, French J, Specchio N, Trinka E, Wiebe S, Auvin S, Cabral-Lim L, Naidoo A, Perucca E, Moshé SL, Wirrell EC, Tinuper P. International League Against Epilepsy classification and definition of epilepsy syndromes with onset at a variable age: position statement by the ILAE Task Force on Nosology and Definitions. Epilepsia. 2022;63:1443–74. [PubMed: 35503725]
  • 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]
  • Sarma AK, Khandker N, Kurczewski L, Brophy GM. Medical management of epileptic seizures: challenges and solutions. Neuropsychiatr Dis Treat. 2016;12:467–85. [PMC free article: PMC4771397] [PubMed: 26966367]
  • Scheffer IE, Bhatia KP, Lopes-Cendes I, Fish DR, Marsden CD, Andermann E, Andermann F, Desbiens R, Keene D, Cendes F, et al. Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder. Brain. 1995;118:61–73. [PubMed: 7895015]
  • 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]
  • Schubert J, Siekierska A, Langlois M, May P, Huneau C, Becker F, Muhle H, Suls A, Lemke JR, de Kovel CG, Thiele H, Konrad K, Kawalia A, Toliat MR, Sander T, Rüschendorf F, Caliebe A, Nagel I, Kohl B, Kecskés A, Jacmin M, Hardies K, Weckhuysen S, Riesch E, Dorn T, Brilstra EH, Baulac S, Møller RS, Hjalgrim H, Koeleman BP. EuroEPINOMICS RES Consortium; Jurkat-Rott K, Lehman-Horn F, Roach JC, Glusman G, Hood L, Galas DJ, Martin B, de Witte PA, Biskup S, De Jonghe P, Helbig I, Balling R, Nürnberg P, Crawford AD, Esguerra CV, Weber YG, Lerche H. Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet. 2014;46:1327–32. [PubMed: 25362483]
  • 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]
  • Stenson PD, Mort M, Ball EV, Chapman M, Evans K, Azevedo L, Hayden M, Heywood S, Millar DS, Phillips AD, Cooper DN. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting. Hum Genet. 2020;139:1197–207. [PMC free article: PMC7497289] [PubMed: 32596782]
  • 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]
  • Tinuper P, Bisulli F, Cross JH, Hesdorffer D, Kahane P, Nobili L, Provini F, Scheffer IE, Tassi L, Vignatelli L, Bassetti C, Cirignotta F, Derry C, Gambardella A, Guerrini R, Halasz P, Licchetta L, Mahowald M, Manni R, Marini C, Mostacci B, Naldi I, Parrino L, Picard F, Pugliatti M, Ryvlin P, Vigevano F, Zucconi M, Berkovic S, Ottman R. Definition and diagnostic criteria of sleep-related hypermotor epilepsy. Neurology. 2016;86:1834–42. [PMC free article: PMC4862248] [PubMed: 27164717]
  • 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]
  • Vignatelli L, Bisulli F, Giovannini G, Licchetta L, Naldi I, Mostacci B, Rubboli G, Provini F, Tinuper P, Meletti S. Prevalence of sleep-related hypermotor epilepsy-formerly named nocturnal frontal lobe epilepsy-in the adult population of the Emilia-Romagna region, Italy. Sleep. 2017:40. [PubMed: 28364515]
  • 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]
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2024 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK1169PMID: 20301348


Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed
  • Gene
    Locus Links

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...