Kcnt1-Related Epilepsy
Summary
Clinical characteristics.
KCNT1-related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal 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 with KCNT1-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 due to other causes.
Less common seizure phenotypes in individuals with KCNT1-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 of KCNT1-related epilepsy is established in a proband with intractable epilepsy and identification of a heterozygous pathogenic variant in KCNT1 by molecular 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 due to 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 antiepileptic drug 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 an autosomal dominant manner. The majority of affected individuals represent simplex cases (i.e., a single occurrence in a family) resulting from a de novo KCNT1 pathogenic variant. The proportion of cases caused by a de novo pathogenic variant varies by phenotype. All individuals diagnosed with KCNT1-related epilepsy of infancy with migrating focal seizures (EIMFS) have the disorder as the result of a de novo pathogenic variant or an inherited variant from an unaffected parent with somatic and/or germline mosaicism. Some individuals diagnosed with KCNT1-related autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have an affected parent. Each child of an individual with KCNT1-related epilepsy has a 50% chance of inheriting the pathogenic variant, and intrafamilial clinical variability and reduced penetrance have been reported. Prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if the pathogenic variant in the family is known.
Diagnosis
No formal diagnostic criteria for KCNT1-related epilepsy have been published to date.
KCNT1-related epilepsy is most often associated with two phenotypes: epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Less often, KCNT1 pathogenic variants are associated with epilepsy with variable presentation.
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-related autosomal 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 of KCNT1-related epilepsy is established in a proband with intractable epilepsy and identification of a heterozygous pathogenic variant in KCNT1 by molecular genetic testing (see Table 1).
Because the phenotype of KCNT1-related epilepsy is indistinguishable from many other inherited disorders with epilepsy, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.
Note: (1) Single-gene testing (sequence analysis of KCNT1) is rarely useful and typically NOT recommended. (2) KCNT1-related epilepsy is postulated to occur through a gain-of-abnormal-function mechanism. Large intragenic deletions and duplication have not been reported; testing for intragenic deletions or duplication is not indicated.
A seizure multigene panel that includes KCNT1 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.
Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. 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 KCNT1-Related Epilepsy
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| KCNT1 | Sequence analysis 3 | 100% 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported 4, 6 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
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.
- 4.
Lim et al [2016]
- 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.
McTague et al [2018]
Clinical Characteristics
Clinical Description
KCNT1-related epilepsy encompasses a range of epilepsy syndromes. The most common phenotypes reported in individuals with KCNT1-related epilepsy are epilepsy of infancy with migrating focal seizures (EIMFS) and autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).
Epilepsy Phenotype
EIMFS is an early infantile epileptic encephalopathy characterized by seizures beginning in the first six months of life with associated developmental plateau or regression. The seizures are primarily focal motor, variably with secondary generalization, but also include tonic, clonic, tonic-clonic, myoclonic, and epileptic spasms [McTague et al 2013]. Autonomic manifestations (e.g., perioral cyanosis, flushing, apnea) are common. Seizures progress to become nearly continuous by age six to nine months. Seizures are intractable to multiple anticonvulsants. Rarely, status epilepticus at onset has been described [Zamponi et al 2008]. The characteristic feature on EEG is focal ictal discharges that migrate across contiguous cortical regions and arise independently at multiple foci. An increase in amplitude and frontal predominance over time with post-ictal and interictal suppression has been noted [McTague et al 2018].
Additional neurologic features reported in individuals with KCNT1-related EIMFS include hypotonia (axial>appendicular), decreased head growth with microcephaly developing by age 12 months, strabismus, and profound developmental delay with rare ability to ambulate or verbalize. Additional reported movement disorders include choreoathetosis, dyskinesias, and focal and generalized dystonia.
Prognosis for individuals with KCNT1-related EIMFS is currently unknown.
ADNFLE is characterized by clusters of nocturnal motor seizures that vary from simple arousals to hyperkinetic events with tonic or dystonic features (see Autosomal Dominant Nocturnal Frontal Lobe Epilepsy). Individuals with KCNT1-related ADNFLE are more likely to develop seizures before adolescence, have cognitive comorbidity, and display psychiatric and behavioral problems than are individuals with ADNFLE due to other causes.
Less common epilepsy phenotypes in individuals with a KCNT1 pathogenic variant include:
- West syndrome
- Ohtahara syndrome (early infantile epileptic encephalopathy)
- Early myoclonic encephalopathy
- Leukodystrophy/leukoencephalopathy
- Focal or multifocal epilepsy
Brain MRI and/or CT examination is often normal prior to seizure onset, though recent studies have noted variable delayed myelination, hippocampal volume loss, and cerebellar atrophy [McTague et al 2018]. Temporal lobe pathology as a cause versus consequence has been noted in two individuals with KCNT1-related temporal lobe epilepsy [Hansen et al 2017].
Other. Prenatal history, birth, and neonatal history prior to seizure onset are normal, with no notable dysmorphic features.
Pulmonary Hemorrhage
Three individuals with KCNT1-related EIMFS were reported to have prominent systemic-to-pulmonary collateral artery formation and subsequent pulmonary hemorrhage that developed between age four and 19 months [Kawasaki et al 2017]. Evaluation for pulmonary hemorrhage should be considered if an individual develops acute respiratory failure, heart failure, or hemoptysis.
Cardiac Arrhythmia
Brugada syndrome was reported in one individual with a de novo KCNT1 variant [Juang et al 2014]. An individual with confirmed familial KCNT1-related epilepsy and an unspecified cardiac arrhythmia was reported by Møller et al [2015].
Genotype-Phenotype Correlations
There is some evidence for a genotype-phenotype correlation. However, disparate phenotypes (e.g., ADNFLE, EIMFS) have been identified in family members with the same pathogenic variant.
EIMFS. The majority of pathogenic variants associated with EIMFS occur in either the S5 transmembrane domain or the regulator of potassium conductance domains within the C-terminus.
ADNFLE-related pathogenic variants are concentrated in the NAD+ binding domain 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% for KCNT1-related EIMFS [Barcia et al 2012, Heron et al 2012] but is reported as reduced in KCNT1-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 of KCNT1-related epilepsy is unknown. To date, 88 probands with KCNT1-related epilepsy have been reported in the literature.
Differential Diagnosis
Phenotypic and EEG features associated with KCNT1 pathogenic variants are not sufficient to diagnose KCNT1-related epilepsy. All genes known to be associated with early-infantile epileptic encephalopathy (>30 have been identified; see OMIM Phenotypic Series) should be included in the differential diagnosis of KCNT1-related epilepsy including other genes less commonly associated with epilepsy of infancy with migrating focal seizures (SCN1A, SCN2A, SLC12A5, SLC25A22, TBC1D4, PLCB1) and autosomal dominant nocturnal frontal lobe epilepsy (CHRNA4, CHRNB2, DEPDC5, CRH).
Note: At seizure onset, it is most important to distinguish KCNT1-related epilepsy from potentially treatable causes of early infantile-onset epileptic encephalopathy, such as neurometabolic disorders, CNS infection, structural brain lesions, and other syndromes (see Table 2).
Table 2.
Treatable Disorders Associated with Early Infantile-Onset Epileptic Encephalopathy
| Conditions | Gene(s) | MOI | Clinical Findings | Treatment | |
|---|---|---|---|---|---|
| Neuro- metabolic disorders | Pyridoxine-dependent epilepsy | ALDH7A1 | AR |
| Seizures/encephalopathy responsive to pyridoxine |
| Pyridoxamine 5'-phosphate oxidase deficiency (OMIM 610090) | PNPO | AR |
| Seizures/encephalopathy responsive to pyridoxal 5-prime phosphate | |
| Biotinidase deficiency | BTD | AR |
| Lifelong biotin supplementation | |
| Glucose transporter 1 deficiency syndrome | SLC2A1 | AD AR |
| Ketogenic diet | |
| Creatine deficiency syndromes | GAMT GATM SCL6A8 | AR XL |
| Creatine monohydrate supplementation | |
| Holocarboxylase synthetase deficiency (OMIM 253270) | HLCS | AR |
| Responsive to biotin | |
| Serine biosynthesis disorders (OMIM 601815, 610992, 614023) | PHGDG PSAT1 PSPH | AR |
| L-serine & glycine supplementation can reduce seizures, improve psychomotor symptoms, & prevent progression depending on subtype | |
| Other | Infection of the CNS | n/a | MRI, blood culture &/or lumbar puncture suggestive of infection | Antibiotic, antiviral, or antifungal therapy | |
| Structural brain lesions | n/a | (Multi)focal lesions on brain MRI | |||
| Tuberous sclerosis complex | TSC1 TCS2 |
| Consideration of mTOR inhibitor for astrocytoma, additional seizure reduction | ||
| ARX-associated encephalopathy (OMIM 308350) | ARX | Enlarged ventricles & T2-weighted signals in basal ganglia on brain MRI | |||
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with KCNT1-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 a benzodiazepine (commonly clonazepam or clobazam), levetiracetam, and the ketogenic 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 with KCNT1 pathogenic 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 of KCNT1 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 of KCNT1-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 due to 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, see Epilepsy & My Child Toolkit.
Pulmonary collaterals and pulmonary hemorrhage. Embolization of systemic pulmonary collateral arteries has been used with limited success [Kawasaki et al 2017].
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. In the US, early intervention is a federally funded program available in all states.
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.
Ages 5-21 years
- In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21.
- Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life.
Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
In the US:
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a 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.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility.
- Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction. Assuming that the individual is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended for affected individuals who have difficulty feeding due to poor oral motor control.
Communication issues. Consider evaluation for alternative means of communication (e.g., Augmentative and Alternative Communication [AAC]) for individuals who have expressive language difficulties.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications (e.g., to treat attention deficit hyperactivity disorder) when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
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 exacerbate KCNT1-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 by molecular genetic testing for the KCNT1 pathogenic variant in the family. Family members who are found to have a heterozygous KCNT1 pathogenic variant are at risk for seizures and cardiac arrhythmias, and thus appropriate screening should be performed.
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 (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 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.