GeneReviews^® [Internet].

Clinical characteristics.

KCNT1-related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) andautosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

• EIMFS is characterized by seizures, typically focal and asynchronous, beginning in the first six months of life with associated developmental plateau or regression. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures are intractable to multiple anticonvulsants and progress to become nearly continuous by age six to nine months.
• ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features. Individuals withKCNT1-related ADNFLE are more likely to develop seizures at a younger age, have cognitive comorbidity, and display psychiatric and behavioral problems than individuals with ADNFLE resulting from other causes.

Less common seizure phenotypes in individuals withKCNT1-related epilepsy include West syndrome, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy and/or leukoencephalopathy, focal epilepsy, and multifocal epilepsy. Additional neurologic features include hypotonia, microcephaly developing by age 12 months, strabismus, profound developmental delay, and additional movement disorders. Other systemic manifestations including pulmonary hemorrhage caused by prominent systemic-to-pulmonary collateral arteries or cardiac arrhythmia have been reported.

Diagnosis/testing.

The diagnosis ofKCNT1-related epilepsy is established in aproband with intractable epilepsy and aheterozygouspathogenic variant inKCNT1 identified bymolecular genetic testing.

Management.

Treatment of manifestations: KCNT1-related epilepsy is often refractory to conventional anticonvulsants; stiripentol, benzodiazepines, levetiracetam, and the ketogenic diet have all been well tolerated with limited success; quinidine has been used as an off-label anticonvulsant with success in some individuals; in rare cases of pulmonary hemorrhage as a result of systemic pulmonary collaterals, embolization has been recommended; developmental support is appropriate.

Surveillance: EEG at intervals determined by seizure frequency and progression, for evaluation of new involuntary movements or unexplained, paroxysmal changes in vital signs, or following adjustments to an anticonvulsant regimen; monitoring of development.

Agents/circumstances to avoid: For individuals with ADNFLE, activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights).

Pregnancy management: For women with ADNFLE, a discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

Genetic counseling.

KCNT1-related epilepsy is inherited in anautosomal dominant manner. The majority of affected individuals representsimplex cases (i.e., a single occurrence in a family) resulting from ade novo KCNT1pathogenic variant. The proportion of cases caused by ade novo pathogenic variant varies byphenotype. All individuals diagnosed withKCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) have the disorder as the result of ade novo pathogenic variant or an inherited variant from an unaffected parent with somatic and/orgermline mosaicism. Some individuals diagnosed withKCNT1-related autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have an affected parent. Each child of an individual withKCNT1-related epilepsy has a 50% chance of inheriting the pathogenic variant, and intrafamilial clinical variability and reducedpenetrance have been reported. Prenatal testing for a pregnancy at increased risk andpreimplantation genetic testing are possible if the pathogenic variant in the family is known.

Suggestive Findings

KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS)should be suspected in individuals with the following history and findings:

• Normal prenatal course and birth without history, clinical features, or imaging suggestive of traumatic, anoxic, vascular, or infectious injury
• Sporadic, asynchronous focal seizures arising independently from either hemisphere with patterns of intracortical "migration" occurring by age six months, with subsequent escalation of seizure frequency
• Developmental plateau or regression following the onset of seizures
• Intractability to anticonvulsant medication

KCNT1-relatedautosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)should be suspected in individuals with the following history and findings:

• Frequent brief, nocturnal seizures
• Mild-to-moderate intellectual disability
• Psychiatric disease (e.g., depression, anxiety, suicidality, attention-deficit/hyperactivity disorder)
• Family history of ADNFLE or EIMFS

KCNT1-related epilepsy has been less frequently identified in individuals with the following phenotypes:

• West syndrome
• Ohtahara syndrome (early-infantile epileptic encephalopathy)
• Early myoclonic encephalopathy
• Leukodystrophy/leukoencephalopathy
• Focal epilepsy
• Multifocal epilepsy

Establishing the Diagnosis

The diagnosis ofKCNT1-related epilepsyis established in aproband with intractable epilepsy and aheterozygous pathogenic (orlikely pathogenic) variant inKCNT1 identified bymolecular genetic testing (seeTable 1).

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 can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in thisGeneReview is understood to include likely pathogenic variants. (2) Identification of aheterozygousKCNT1 variant ofuncertain significance does not establish or rule out the diagnosis.

Because thephenotype ofKCNT1-related epilepsy is indistinguishable from many other inherited disorders with epilepsy, recommendedmolecular genetic testing approaches include use of amultigene panel orcomprehensivegenomic testing.

Note: (1) Single-gene testing (sequence analysis ofKCNT1) is rarely useful and typically NOT recommended. (2)KCNT1-related epilepsy is postulated to occur through again-of-function mechanism. Large intragenic deletions andduplication have not been reported; testing for intragenic deletions or duplication is not indicated.

A seizuremultigene panel that includesKCNT1 and other genes of interest (seeDifferential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of pathogenic variants and variants ofuncertain significance in genes that do not explain the underlyingphenotype. Note: (1) The genes included in the panel and the diagnosticsensitivity of the testing used for eachgene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in thisGeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focusedexome analysis that includes genes specified by the clinician. (4) Methods used in a panel may includesequence analysis,deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels clickhere. More detailed information for clinicians ordering genetic tests can be foundhere.

Comprehensivegenomic testing (which does not require the clinician to determine whichgene[s] are likely involved) is another good option.Exome sequencing is most commonly used;genome sequencing is also possible.

For an introduction to comprehensivegenomic testing clickhere. More detailed information for clinicians ordering genomic testing can be foundhere.

Clinical Description

KCNT1-related epilepsy encompasses a range of epilepsy syndromes. The most common phenotypes reported in individuals withKCNT1-related epilepsy are epilepsy of infancy with migrating focal seizures (EIMFS) andautosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

Genotype-Phenotype Correlations

There is some evidence for agenotype-phenotype correlation. However, disparate phenotypes (e.g., ADNFLE, EIMFS) have been identified in family members with the samepathogenic variant.

EIMFS. The majority of pathogenic variants associated with EIMFS occur in either the S5 transmembranedomain or the regulator of potassium conductance domains within the C-terminus.

ADNFLE-related pathogenic variants are concentrated in the NAD+ bindingdomain or more distal C-terminus.

Specific correlations between genetic variant and seizure burden, developmental impairment, or medication responsiveness have not yet been elucidated.

Penetrance

Penetrance is reported to be 100% forKCNT1-related EIMFS [Barcia et al 2012,Heron et al 2012] but is reported as reduced inKCNT1-related epilepsy with other seizure phenotypes [Møller et al 2015].

Nomenclature

In the initial description of EIMFS,Coppola et al [1995] described his cohort of globally arrested infants with frequent focal, "migrating" seizures that were medically intractable as malignant migrating partial seizures of infancy (MMPSI); it has also been variably referred to as migrating partial epilepsy of infancy (MPEI). In 2010, the International League Against Epilepsy reclassified this epilepsy syndrome as EIMFS [Berg et al 2010].

Prevalence

The prevalence ofKCNT1-related epilepsy is unknown. To date, 88 probands withKCNT1-related epilepsy have been reported in the literature.

Table 2.

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Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed withKCNT1-related epilepsy, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Prolonged video EEG monitoring to evaluate electroclinical and electrographic seizure burden in consultation with a pediatric epileptologist
• Evaluation by a movement disorder specialist if dictated by clinical presentation
• Consideration of echocardiogram to evaluate for pulmonary collaterals
• Electrocardiogram (EKG) to evaluate for cardiac rhythm abnormalities
• Cognitive and behavioral assessment
• Physical, occupational, and speech therapy evaluation
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Seizures.KCNT1-related epilepsy is often refractory to conventional anticonvulsants.

• Stiripentol in combination with abenzodiazepine (commonly clonazepam or clobazam), levetiracetam, and theketogenic diet have all been well tolerated with limited success [Hmaimess et al 2006,Caraballo et al 2008,Cilio et al 2009,McTague et al 2018].
• Vagal nerve stimulator (VNS) has not been shown to be effective [Zamponi et al 2008].
• Quinidine. Seizure control and developmental progression with off-label use of quinidine was reported in an individual withKCNT1pathogenic variant p.Arg428Gln [Bearden et al 2014], prompting subsequent treatment trials in individuals with the same and other pathogenic variants with negative results [Mullen et al 2018] and pro-arrhythmic cardiotoxicity. Potential explanations for this variable responsiveness include genetic/epigenetic modifiers ofKCNT1 as well as polymorphisms in P-glycoprotein transporters, which actively shuttle quinidine across the blood-brain barrier [Liu et al 2015]. The limited efficacy may also be narrowed by epilepsy type, as a small, randomized, placebo-controlled, crossover clinical trial ofKCNT1-related ADNFLE showed no efficacy [Mullen et al 2018]. It has also been suggested that quinidine administered after age four years may be less effective [Abdelnour et al 2018]. In addition, given the increased risk for arrhythmia associated with quinidine treatment, some individuals are not able to achieve adequate serum levels because of the development of life-threating cardiac rhythm abnormalities, thus limiting its utility.
• Caregivers. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, seeEpilepsy Foundation Toolbox.

Pulmonary collaterals and pulmonary hemorrhage. Embolization of systemic pulmonary collateral arteries has been used with limited success [Kawasaki et al 2017].

Surveillance

EEG is recommended at intervals determined by seizure frequency and progression, for evaluation of new involuntary movements or unexplained, paroxysmal changes in vital signs, or following adjustments to an anticonvulsant regimen.

Developmental evaluation and initiation of therapies is recommended at time of diagnosis if not already begun.

Following initial EKG and echocardiogram, there is no indication to repeat cardiac monitoring or cardiopulmonary imaging unless clinically indicated or following initiation of quinidine therapy.

Agents/Circumstances to Avoid

No anticonvulsants have been noted to exacerbateKCNT1-related epilepsy.

For individuals with ADNFLE, activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights).

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual bymolecular genetic testing for theKCNT1pathogenic variant in the family. Family members who are found to have aheterozygousKCNT1 pathogenic variant are at risk for seizures and cardiac arrhythmias, and thus appropriate screening should be performed.

SeeGenetic Counseling for issues related to testing of at-risk relatives forgenetic 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 during pregnancy reduces this risk. However, exposure to anti-seizure medication (e.g., valproate, phenobarbital, topiramate) 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 anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure medication 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].

SeeMotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

SearchClinicalTrials.gov in the US andEU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

KCNT1-related epilepsy is inherited in anautosomal dominant manner.

Risk to Family Members

Parents of aproband

• Most individuals diagnosed withKCNT1-related epilepsy have the disorder as the result of ade novopathogenic variant.
  • All individuals diagnosed withKCNT1-related epilepsy of infancy with migrating focal seizures [EIMFS] representsimplex cases (i.e., a single occurrence of EIMFS in the family) and have the disorder as the result of ade novopathogenic variant or an inherited variant from either aheterozygous parent with a less severephenotype (e.g.,autosomal dominant nocturnal frontal lobe epilepsy) or an unaffected parent with somatic and/orgermline mosaicism [Møller et al 2015,Ohba et al 2015].
  • Some individuals diagnosed withKCNT1-relatedautosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have an affected parent.
• Molecular genetic testing is recommended for the parents of aproband with an apparentde novopathogenic variant.
• If thepathogenic variant found in theproband cannot be detected in the leukocyte DNA of either parent, possible explanations include ade novo pathogenic variant in the proband orgermline mosaicism in an unaffected parent. Somatic and germline mosaicism have been reported [Ohba et al 2015].
• The family history of some individuals diagnosed withKCNT1-related epilepsy may appear to be negative because of failure to recognize the disorder in family members or reducedpenetrance. Therefore, an apparently negative family history cannot be confirmed unlessmolecular genetic testing has been performed on the parents of theproband.
• Note: If the parent is the individual in whom thepathogenic variant first occurred, the parent may havesomatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of aproband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

• If a parent of theproband is known to be affected and/or isheterozygous for theKCNT1pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Note: Intrafamilial clinical variability and reducedpenetrance in someKCNT1 seizure phenotypes has been observed (seeGenotype-Phenotype Correlations andPenetrance) [Møller et al 2015].
• If theKCNT1pathogenic variant found in theproband cannot be detected in the leukocyte DNA of either parent, therecurrence risk to sibs is slightly greater than that of the general population because of the possibility of parentalgermline orsomatic mosaicism [Møller et al 2015,Ohba et al 2015].
• If the parents have not been tested for theKCNT1pathogenic variant but are clinically unaffected, sibs of aproband are still at increased risk forKCNT1-related epilepsy because of the possibility of reducedpenetrance in aheterozygous parent or parentalgermline mosaicism. (Note: Reduced penetrance has not been reported inKCNT1-related EIMFS.)

Offspring of aproband. Each child of an individual withKCNT1-related epilepsy has a 50% chance of inheriting theKCNT1pathogenic variant.

Other family members. The risk to other family members depends on the status of theproband's parents: if a parent has theKCNT1pathogenic 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.

Considerations in families with an apparentde novopathogenic variant. When neither parent of aproband with anautosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likelyde novo. However, non-medical explanations includingalternate 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/preimplantation genetic testing is before pregnancy.
• It is appropriate to offergenetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

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, seeHuang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once theKCNT1pathogenic variant has been identified in an affected family member, prenatal andpreimplantation genetic testing are possible.

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

Table A.

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Table B.

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Table 3.

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Author Notes

TheKCNT1 Registry includes individuals with epilepsy and known or suspected pathogenic variants inKCNT1. The registry is an ongoing natural history study ofKCNT1-related epilepsy. Individuals interested in participating in theKCNT1 Registry should contact Dr David Bearden at david_bearden@urmc.rochester.edu.

Revision History

• 20 September 2018 (tg) Review posted live
• 28 February 2018 (jlr) Original submission

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