Clinical characteristics.

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

Diagnosis/testing.

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

Management.

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

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

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

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

Genetic counseling.

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

Suggestive Findings

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

Clinical features

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

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

EEG findings

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

Neuroimaging. Normal findings

Family history

• Consistent with autosomal dominant inheritance [Tassinari & Michelucci 1997, Provini et al 1999, Combi et al 2004]
• Note: Absence of a known family history of ADNFLE does not preclude the diagnosis.

Establishing the Diagnosis

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

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

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

Clinical Description

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

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

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

The seizures are often stereotyped and brief (5 seconds to 5 minutes); they vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling movements, ballism (flinging or throwing arm movements), and pelvic thrusting movements.

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

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

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

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

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

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

EEG findings

• Ictal EEG recordings may be normal or may be obscured by movement artifact. Ictal rhythms, if present, are usually sharp waves or repetitive 8- to 11-Hz spikes. Recruiting patterns and rhythmic theta (bifrontal, unilateral frontal, or with diffuse desynchronization) are occasionally seen [Picard & Scheffer 2012]. El Helou et al [2008] suggest that seizures may be initiated by K-complexes.
• Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals.
• Interictal sleep EEG may show infrequent epileptiform discharges.

Cognitive findings. Clinical neurologic examination is normal and intellect is usually preserved [Oldani et al 1996, Nakken et al 1999]; however, in some individuals neuropsychological assessment reveals reduced intellect, cognitive deficits, or psychiatric comorbidity [Khatami et al 1998, Provini et al 1999, Picard et al 2000, Cho et al 2003, Wood et al 2010].

Picard et al [2009] found below-normal general intellect in five (45%) of 11 subjects with special difficulty in executive tasks and concluded that cognitive dysfunction is an integral part of ADNFLE caused by a heterozygous pathogenic variant in the nicotinic receptor (see Phenotype Correlations by Gene).

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

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

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

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

Phenotype Correlations by Gene

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

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

Genotype-Phenotype Correlations

Steinlein et al [2012] suggested that certain nAchR pathogenic variants may be associated with an increased risk for cognitive dysfunction. Marked intrafamilial variation in severity is seen, the reasons for which are unknown.

Penetrance

Penetrance is estimated at 70%. KCNT1-related ADNFLE demonstrates complete penetrance compared to 60%-80% in nAChR-related ADNFLE.

Prevalence

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

Families with the disorder have been identified worldwide [Steinlein 2014].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) the following evaluations are recommended if they have not already been completed:

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

Treatment of Manifestations

In about 70% of individuals with ADNFLE, carbamazepine is associated with remission of seizures, often with relatively low doses. However, individuals with ADNFLE associated with the CHRNA4 pathogenic variant p.Ser284Leu respond only partially to carbamazepine and are more responsive to zonisamide [Provini et al 1999, Ito et al 2000, Combi et al 2004].

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

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

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

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

Prevention of Secondary Complications

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

Surveillance

Serial evaluation of EEGs to monitor disease progression is appropriate.

Evaluation of Relatives at Risk

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

• 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.

Pregnancy Management

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

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

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

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• Most individuals diagnosed with ADNFLE have an affected parent.
• A proband with ADNFLE may have the disorder as the result of a de novo CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, or CRH pathogenic variant. The proportion of cases caused by a de novo pathogenic variant is unknown, as the frequency of subtle signs of the disorder in parents has not been thoroughly evaluated and molecular genetic data are insufficient. In one report a mother with a de novo pathogenic variant passed the condition on to her son [Phillips et al 2000].
• Recommendations for the evaluation of parents of a child with nocturnal frontal lobe epilepsy and no known family history of NFLE include a detailed clinical and family history and molecular genetic testing (if the pathogenic variant in the proband has been identified).
• If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent (though theoretically possible, no instances of germline mosaicism have been reported).
• The family history of some individuals diagnosed with ADNFLE may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.

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

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

Offspring of a proband

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

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

Related Genetic Counseling Issues

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

Other genetic counseling issues. Individuals may not be aware of the significance of their attacks; in some families, individuals may be reluctant to reveal their symptoms [Picard & Scheffer 2012].

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

Family planning

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

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

Prenatal Testing and Preimplantation Genetic Diagnosis

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

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Molecular Genetic Pathogenesis

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

• Genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR):
  • CHRNA4, encoding the α4 subunit of the neuronal nicotinic acetylcholine receptor (nAChR); associated with type 1 ADNFLE
  • CHRNB2, encoding the β2 subunit of the nAChR; associated with type 3 ADNFLE
  • CHRNA2, encoding α2 subunit of the nAChR; associated with type 4 ADNFLE
  The neuronal nicotinic acetylcholine receptor is a heterologous pentamer comprising various combinations of alpha and beta subunits, encoded by CHRNA2-CHRNA7 and CHRNB2-CHRNB4, respectively. The most common configuration in thalamus and isocortex is (α4)₂(β2)₃ subunits (i.e., 2 α4 and 3 β2 subunits).
  The receptor is widely distributed in the brain, including the frontal lobes. It is thought that the receptor is a presynaptic modulator of other neurotransmitter systems including gamma-amino butyric acid (GABA), glutamate, and dopamine, and therefore may have variable effects on excitatory and inhibitory pathways [Kuryatov et al 1997, Bertrand 1999, Buisson et al 1999, Picard et al 1999].
  The second transmembrane domain of the receptor forms the ion channel pore and is the site of most of the pathogenic variants implicated in ADNFLE. Pathogenic variants in CHRNA4 and CHRNB2 associated with ADNFLE occur in highly conserved amino acids and alter the function of the resulting receptors.
  Functional studies of different pathogenic variants provide conflicting results, although an increase in acetylcholine (Ach) sensitivity in vitro is typical for known ADNFLE-associated pathogenic variants [Kuryatov et al 1997, Steinlein et al 1997, Bertrand et al 1998, Bertrand 1999, De Fusco et al 2000, Phillips et al 2001, di Corcia et al 2005]; thus, the mechanism whereby the pathogenic variants cause ADNFLE is poorly understood.
• KCNT1, encoding a sodium-activated potassium channel; associated with type 5 ADNFLE. Sodium-activated potassium channel encoded by KCNT1 is widely distributed in many regions of the mammalian brain, including the frontal cortex. Its activity contributes to the slow hyperpolarization that follows repetitive firing.
  Mutated channels with pathogenic variants identified in ADNFLE produce voltage-activated currents with higher magnitude compared to wild type, leading to gain of function.
• DEPDC5, encoding dishevelled, egl-10, and pleckstrin (DEP) domain-containing protein 5. DEPDC5 is a component of GATOR1 (GTPase-activating protein [GAP] activity toward RAGs complex 1), which negatively regulates mTORC1 (mammalian target of rapamycin complex 1) and is expressed ubiquitously in human tissues. Most pathogenic variants are truncating variants that can be expected to result in nonsense-mediated mRNA degradation.
• CRH, encoding corticotropin-releasing hormone (CRH). CRH is widely distributed throughout the central nervous system; it acts as a neurotransmitter or neuromodulator in extrahypothalamic circuits to integrate a multisystem response to stress that controls numerous behaviors including sleep and arousal. Variations in the promotor [Combi et al 2005] or in the pro-sequence region [Sansoni et al 2013] have been reported. The variant identified in one family with ADNFLE decreases peptide secretion in vitro [Sansoni et al 2013].

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Author History

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

Revision History

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