Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

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2021-01-18

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Genes

CHRNA4, CHRNB2, CHRNA2, KCNT1, CRH, DEPDC5, CABP4, ENFL2, IGBP1, FGFR3, KCNQ2, KCNQ3, SCN1A, CHRNA3, CHRNA7, CHRNA5, CHRFAM7A

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Summary

Clinical characteristics.

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

Diagnosis/testing.

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

Management.

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

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

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

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

Genetic counseling.

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

Diagnosis

Suggestive Findings

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

Clinical features

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

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

EEG findings

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

Neuroimaging. Normal findings

Family history

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 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.
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Table 1.

Molecular Genetic Testing Used in Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

Gene ^1, 2	Proportion of ADNFLE Attributed to Pathogenic Variants in Gene	Proportion of Pathogenic Variants ³ Detectable by Method
Gene ^1, 2		Sequence analysis ⁴	Gene-targeted deletion/duplication analysis ⁵
CHRNA2	Rare ⁶	Rare ⁶	None reported ⁷
CHRNA4	10%-15% ⁸	10%-15% ⁸
CHRNB2	Lower than in CHRNA4 ⁸	Lower than in CHRNA4 ⁸
CRH	Rare ⁹	Rare ⁹
DEPDC5	10% ¹⁰	10% ¹⁰
KCNT1	<5% ¹¹	<5% ¹¹

1.: Genes are listed in alphabetic order.
2.: See Table A. Genes and Databases for chromosome locus and protein.
3.: See Molecular Genetics for information on allelic variants detected in this gene.
4.: Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
5.: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
6.: Reported in two families [Aridon et al 2006, Conti et al 2015]
7.: To date, exon or whole-gene deletions/duplications have not been detected in ADNFLE.
8.: 10%-15% of individuals with a family history have pathogenic variants in subunits of nicotinic acetylcholine receptor [Ferini-Strambi et al 2012].
9.: Combi et al [2005], Sansoni et al [2013]
10.: Picard et al [2014]
11.: Heron et al [2012]

Clinical Characteristics

Clinical Description

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

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

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

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

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

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

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

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

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

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

EEG findings

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

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

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

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

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

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

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

Phenotype Correlations by Gene

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

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

Genotype-Phenotype Correlations

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

Penetrance

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

Prevalence

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

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

Differential Diagnosis

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

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

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

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

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

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

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

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

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

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

Management

Evaluations Following Initial Diagnosis

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

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

Treatment of Manifestations

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

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

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

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

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

Caregivers

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

Prevention of Secondary Complications

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

Surveillance

Serial evaluation of EEGs to monitor disease progression is appropriate.

Evaluation of Relatives at Risk

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

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 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.