Scn1a Seizure Disorders

Clinical characteristics.

SCN1A seizure disorders encompass a spectrum that ranges from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end. Phenotypes with intractable seizures including Dravet syndrome are often associated with cognitive decline. Less commonly observed phenotypes include myoclonic astatic epilepsy (MAE), Lennox-Gastaut syndrome, infantile spasms, epilepsy with focal seizures, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A seizure disorders can vary even within the same family.

Diagnosis/testing.

The diagnosis of an SCN1A seizure disorder is established in a proband by identification of a heterozygous pathogenic variant in SCN1A by molecular genetic testing.

Management.

Treatment of manifestations: Care is best provided by a physician (e.g., pediatric epileptologist) familiar with the pharmacotherapy for this disorder. Seizure control is critical to prevent permanent injury and death. Antiepileptic drugs (AEDs): clobazam (can be used for treatment of seizures in Lennox-Gastaut syndrome); stiripentol, benzodiazepines, cannabidiol, topiramate, levetiracetam, valproic acid, and ethosuximide. Levetiracetam is often effective, but may make seizures worse in some individuals. Phenobarbital is effective but poorly tolerated because of its effects on cognition. Use of the ketogenic diet to decrease seizure frequency has been beneficial in some affected individuals. Parents are advised to take a CPR course. Routine seizure and personal safety education is indicated.

Prevention of secondary complications: Use of protective helmets by individuals with atonic seizures or myoclonic-astatic epilepsy. Good sleep hygiene should be encouraged. Persons with epilepsy should be made aware of motor vehicle driving laws.

Surveillance: Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration; EEG monitoring for new or different seizure types; polysomnography should be considered if obstructive or central sleep apnea is suspected.

Agents/circumstances to avoid: AEDs: carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic seizures; phenytoin, which can induce choreoathetosis; rufinamide may exacerbate seizures as well; acetaminophen, which is hepatotoxic. Activities in which a sudden loss of consciousness could lead to injury or death (e.g., bathing, swimming, driving, or working/playing at heights). Sleep deprivation, which can exacerbate seizures, should be avoided.

Pregnancy management: Pregnant women should receive counseling regarding the risks and benefits of the use of antiepileptic drugs during pregnancy; the advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4,000 µg daily; the effects of pregnancy on anticonvulsant metabolism; and the effect of pregnancy on maternal seizure control.

Genetic counseling.

SCN1A seizure disorders are inherited in an autosomal dominant manner. A proband with an SCN1A seizure disorder may have an inherited or a de novo pathogenic variant. The proportion of cases caused by de novo pathogenic variants varies by phenotype: the percentage of probands with an SCN1A seizure disorder and an affected parent decreases as the severity of the phenotype in the proband increases; thus, most SCN1A-related severe myoclonic epilepsy in infancy (SCN1A-SMEI) and ICE-GTC are the result of a de novo pathogenic variant. Each child of an individual with an SCN1A seizure disorder has a 50% chance of inheriting the pathogenic variant; however, the risk of developing seizures is less than 100% because of reduced penetrance. Prenatal diagnosis for pregnancies at increased risk is possible if the pathogenic variant in the family is known.

Suggestive Findings

SCN1A seizure disorders encompass a spectrum of phenotypes that ranges from mild to severe. When the following suggestive features are present, SCN1A molecular genetic testing should be considered:

• Precipitation of seizure with fever, warmth, or vaccination
• Prolonged or hemiconvulsive seizures
• Seizure provocation with overstimulation or flashing/patterned visual stimulus
• Worsening of seizures with medications that inhibit sodium channel function as the primary mechanism of action (e.g., carbamazepine, oxcarbazepine, phenytoin, lamotrigine)

These features can be seen in any one of several clinical epilepsy syndromes that can occur in individuals with a heterozygous SCN1A pathogenic variant.

Clinical epilepsy syndromes reported in individuals with SCN1A seizure disorders (see Clinical Characteristics):

• Febrile seizures (simple or complex) may be the first and only manifestation of an SCN1A pathogenic variant, although individuals presenting with febrile seizures can also progress to Dravet syndrome. Febrile seizure onset is typically in the first year of life; seizures are prolonged and multiple.
• Febrile seizures plus (FS+) is characterized by seizure onset before age one year, persistence beyond age six years, unusual severity (including status epilepticus), and occurrence of unprovoked (e.g., afebrile) seizures of any kind.
• Generalized epilepsy caused by SCN1A pathogenic variants most often involves tonic, clonic, tonic-clonic, myoclonic, or absence seizures.
• Generalized epilepsy with febrile seizures plus (GEFS+)
• Dravet syndrome
• Severe myoclonic epilepsy, borderline (SMEB)
• Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC)
• Infantile partial seizures with variable foci

Less common presentations of SCN1A seizure disorders

• Epilepsy with focal seizures
• Myoclonic-astatic epilepsy (MAE, Doose syndrome)
• Lennox-Gastaut syndrome
• Infantile spasms
• Vaccine-related encephalopathy and seizures

Establishing the Diagnosis

The diagnosis of an SCN1A seizure disorder is established in a proband by identification of a heterozygous pathogenic variant in SCN1A by molecular genetic testing (see Table 1).

Because the phenotype of SCN1A seizure disorders is indistinguishable from many other inherited disorders with seizures, the recommended molecular genetic testing is an epilepsy multigene panel.

Note: Single-gene testing (sequence analysis of SCN1A, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An epilepsy multigene panel that includes SCN1A 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 this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Single-gene testing. Sequence analysis of SCN1A detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.

Clinical Description

The natural history of SCN1A seizure disorders is strongly influenced by seizure phenotype, which can range from simple febrile seizures and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to Dravet syndrome and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) at the severe end [Kimura et al 2005, Mantegazza et al 2005, Fujiwara 2006, Gennaro et al 2006]. The phenotype varies even among family members with the same pathogenic variant (see Figure 1). As a result of this variable expressivity, long-term prognosis is difficult to determine.

Figure 1.

Findings in a family illustrating variable expressivity among individuals with the same pathogenic variant. The proband, a boy (arrow) with febrile convulsions since age seven months, had frequent, difficult-to-control partial seizures beginning at age (more...)

Features associated with poor cognitive outcome include early myoclonic and absence seizures [Ragona et al 2011].

Phenotypes with intractable seizures (e.g., Dravet syndrome) usually cause epileptic encephalopathy, a form of progressive dementia. The root cause of the encephalopathy is unknown: the effects on cognition of seizures, the most obvious explanation, cannot be separated from the effects of medication or of an SCN1A pathogenic variant [Riva et al 2009].

In addition to having seizures in response to strong environmental stimuli, individuals with SCN1A seizure disorders often have an ADHD-like phenotype characterized by impulsivity, inattentiveness, and distractibility. Possibly related to the inability of the GABA system to provide negative feedback on extraneous sensory input, these symptoms tend to be less responsive to conventional stimulant medications.

The phenotypes in SCN1A seizure disorders include the following (see Table 2).

Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). This phenotype is defined as generalized seizures including absence seizures and generalized tonic-clonic seizures with onset in infancy or childhood. However, partial seizures can occur in up to 13% of affected individuals [Bonanni et al 2004]. Localized epilepsy, either alternating hemiconvulsive or complex partial seizures, may also be seen. Children with frequent generalized tonic-clonic seizures often develop cognitive impairment. The distinction between ICE-GTC and Dravet syndrome is not clear, and the former is not included in the ILAE classification system.

Dravet syndrome. Wirrell et al [2017] published guidelines for the clinical diagnosis of Dravet syndrome. Presentation is between age one and 18 months after a period of normal development. Seizures are often prolonged and include recurrent generalized tonic-clonic or hemiconvulsive seizures. Myoclonic seizures are typically seen by age two years. Obtundation status, focal dyscognitive seizures, and atypical absences are often seen after age two years. The seizures are often triggered by hyperthermia (e.g., a hot bath, physical exertion, fever following vaccination), light stimuli, or sodium channel-blocking antiepileptic medications. Status epilepticus is common, and pharmacologic management is difficult. Seizures tend to lessen in severity after puberty; however, they rarely resolve completely.

The initial EEGs are often normal or show nonspecific changes such as generalized slowing, but over time epileptiform activity appears. Patterns can include generalized spike and wave discharges, multiple spike and wave (also referred to as polyspike and wave) discharges, and multifocal spikes (see Figure 2). Brain MRI is typically normal or may show mild generalized atrophy and/or hippocampal sclerosis.

syndrome often have an unusual seizure type that frequently will manifest as obtundation status epilepticus.">

Figure 2.

Individuals with Dravet syndrome often have an unusual seizure type that frequently will manifest as obtundation status epilepticus. The EEG during these difficult-to-classify seizures shows an alternation of generalized and focal discharges with variable (more...)

The myoclonic seizures that tend to appear later in the course often coincide with the appearance of cognitive dysfunction, ataxia, and psychomotor regression. Some degree of cognitive impairment is always seen, ranging from moderate to severe, often with marked inattention, impulsivity, and distractibility. Anxiety, obsessive personality traits, and autism spectrum disorder are common. Crouched gait, hypotonia, incoordination, and impaired dexterity are typically evident by age three to four years. Parkinsonian features of bradykinesia, tremor, and antecollis have been reported in adults with Dravet syndrome [Rilstone et al 2012, Aljaafari et al 2017].

Individuals with Dravet syndrome often develop a crouched gait. In spite of the gait being commonly described as "ataxic," affected individuals are more mobile than one would expect from how crouched they appear. The gait changes tend to be more prevalent in older children. In one study these changes were absent before age five years, but present in 5/10 children ages 6-12 years and in 8/9 children age 13 years or older [Rodda et al 2012]. In one cohort, 5/10 adults with Dravet syndrome had crouched gait [Rilstone et al 2012]. Decreased passive knee extension, increased external tibial torsion, and pes planovalgus all progressed [Rodda et al 2012]. Hip internal rotation did not show age-related changes. In one study antecollis was present in 9/14 and parkinsonian gait in 8/14 individuals with Dravet syndrome [Aljaafari et al 2017]. The degree of ataxia in affected individuals is greater than would be expected by the use of anticonvulsant medications alone. Pathogenic variants affecting the pore region appear to be more associated with gait changes [Kanai et al 2004, Rilstone et al 2012].

Severe myoclonic epilepsy, borderline (SMEB). This description is sometimes used for children who have some but not all of the features of Dravet syndrome [Fukuma et al 2004].

Generalized epilepsy. This phenotype is otherwise indistinguishable from idiopathic generalized epilepsy with onset in childhood or adolescence. Generalized epilepsies caused by SCN1A pathogenic variants are most often tonic, clonic, tonic-clonic, myoclonic, or absence.

Generalized epilepsy with febrile seizures plus (GEFS+). This term refers to the findings in a family rather than an individual [Arzimanoglou et al 2004]. In a family with GEFS+, epilepsy with variable expressivity and incomplete penetrance is inherited in an autosomal dominant manner. It implies a spectrum from mild (such as febrile seizure alone) to severe (including medically treatable generalized epilepsy, intractable generalized epilepsy, or Dravet syndrome). Intermediate phenotypes with myoclonic epilepsy, absence epilepsy, or focal epilepsy are also included. Individuals with GEFS+ often have febrile seizures (or FS+) in early childhood, followed by occasional tonic, clonic, myoclonic, or absence seizures that respond to medication and remit by late childhood or early adolescence. The proportion of children with GEFS+ whose first seizure occurs in the context of immunization appears to be greater than the proportion of children with febrile seizures unrelated to FS+ and GEFS+.

Febrile seizures plus (FS+). This subset of febrile seizures (simple or complex) is characerized by any of the following features:

• Onset before age one year
• Persistence beyond age six years
• Unusual severity (including status epilepticus)
• Occurrence of unprovoked (i.e., afebrile) seizures of any kind

Febrile seizures. These childhood seizures occur only in association with fever. The epidemiologic definition requires the following:

• Onset on or after age six months
• Resolution by age five years
• Fever higher than 38° C (without other evidence of CNS infection)
• No other identifiable cause

Febrile seizures are divided into simple febrile seizures and complex febrile seizures. Febrile seizures are considered complex if any of the following is present:

• Duration longer than 15 minutes
• Occurrence of more than one seizure within 24 hours
• Presence of any partial (focal) features during the seizure

Febrile seizures with the following criteria are associated with a higher risk for developing Dravet syndrome [Hattori et al 2008]:

• Febrile seizure onset before age seven months
• Five or more febrile seizures
• Prolonged seizure(s) lasting more than ten minutes

The febrile seizure characteristics include hemiconvulsions, partial seizures, myoclonic seizures, and hot water-induced seizures.

Infantile partial seizures with variable foci, also referred to as migrating partial seizures of infancy, cryptogenic focal epilepsy, or severe infantile multifocal epilepsy [Harkin et al 2007]. Multifocal partial seizures are often the first manifestation; however, in some children the first manifestation is febrile seizures. Severity varies and pharmacoresistance is common, but not absolute. Myoclonic seizures are rare but may be precipitated by administration of medications that inactivate the sodium channel, including phenytoin, carbamazepine, or lamotrigine. Cognitive deterioration may occur, especially when seizure control is incomplete. Electroencephalography shows multifocal independent spikes; generalized spike and wave discharges may be seen.

Less common phenotypes associated with SCN1A pathogenic variants include the following:

• Myoclonic-astatic epilepsy (MAE, also called Doose syndrome).This phenotype is defined as the combination of myoclonic, atonic, and atypical absence seizures. Onset is usually after age two years (range: 7 months - 8 years). Although isolated myoclonic seizures as well as tonic seizures can occur, they are not characteristic of this syndrome (which distinguishes them from Lennox-Gastaut syndrome). Development prior to seizure onset is often normal. The course can range from spontaneous seizure resolution without cognitive impairment to intractable seizures with severe intellectual disability [Arzimanoglou et al 2004].
• Lennox-Gastaut syndrome (LGS). This phenotype is defined as slow spike-waves on EEG, developmental delay, and multiple types of generalized seizures (particularly atypical absence, tonic, and atonic seizures). LGS usually begins during childhood (ages 2-14 years). Any type of seizure can be seen in this syndrome; status epilepticus is common [Arzimanoglou et al 2004]. Only a minority of persons with the LGS phenotype have an SCN1A pathogenic variant, usually in the context of a family in which Dravet syndrome occurs [Singh et al 2001]. This subset remains poorly characterized. It is unclear whether SCN1A-associated LGS differs phenotypically from LGS of other etiologies.
• Infantile spasms. This phenotype is defined as clustered seizures that show brief (<1 second) axial contractions associated with a slow-wave transient on EEG, often followed by generalized attenuation of the background. Both findings may be intermixed with fast activity. The resting EEG (between seizures) shows high-voltage slowing and a multifocal spike pattern known as hypsarrhythmia [Arzimanoglou et al 2004]. Association of an SCN1A pathogenic missense variant with infantile spasms has been reported once [Wallace et al 2003]. The single individual represents fewer than 1% of reported cases, although publication bias makes it difficult to estimate the actual proportion.
• Vaccine-related encephalopathy and seizures. This phenotype is defined as sudden onset of seizures and encephalopathy in infants 48 hours after immunization. Berkovic et al [2006] identified an SCN1A pathogenic variant in 11/14 children diagnosed with post-vaccine encephalopathy. Tro-Baumann et al [2011] reported that 19 of 70 individuals with an SCN1A pathogenic variant and the Dravet phenotype had a history of seizures following vaccination.

Imaging. Brain MRI is most often normal early in the course of the disease; however, it often evolves to show cortical atrophy, cerebellar atrophy, white matter hyperintensity, ventricular enlargement, hippocampal sclerosis, or cortical dysplasia [Striano et al 2007]. Individuals with a more severe phenotype early in life often have more atrophic changes seen on MRI later in life.

Genotype-Phenotype Correlations

Given the variable expressivity of SCN1A disorders, consistent genotype-phenotype correlations have been infrequently identified.

Pathogenic nonsense variants and missense variants in the voltage sensor or pore region often lead to a more severe phenotype [Zuberi et al 2011, Meng et al 2015]. A truncation variant, however, does not necessarily result in a severe phenotype [Suls et al 2010, Yu et al 2010].

Affected individuals with missense variants in the pore-forming region and truncations in the SCN1A protein are more likely to have gait changes [Kanai et al 2004, Rilstone et al 2012]. These changes may be due to a direct effect of the SCN1A pathogenic variant in the cerebellar Purkinje cells [Catterall et al 2010].

Variants in SCN9A, CACNA1A, POLG, and CACNB4 have been suggested to play a role in modifying the phenotype of SCN1A seizure disorders [Ohmori et al 2008b, Gaily et al 2013, Ohmori et al 2013, Yang et al 2018]; however, the data are insufficient for use in clinical management or prognosis.

Nomenclature

Generalized epilepsy with febrile seizures plus has been referred to as GEFS+, type 2 related to SCN1A pathogenic variants.

Intractable infantile partial seizures has been referred to as ICE-GTC.

Dravet syndrome is also known as severe myoclonic epilepsy in infancy (SMEI) or polymorphic myoclonic epilepsy in infancy (PMEI). The term "Dravet syndrome" is preferred over the descriptive names because myoclonic seizures can be absent in children whose seizures are otherwise similar.

Penetrance

SCN1A seizure disorders show incomplete penetrance and variable expressivity.

Penetrance varies by phenotype. For example, Bonanni et al [2004] estimated the penetrance to be 70% for the GEFS+ phenotype, whereas Mantegazza et al [2005] reported the penetrance to be 90% for the familial simple febrile seizure phenotype.

Prevalence

Wu et al [2015] reported a population-based estimate of the incidence of Dravet syndrome of 1:15,000. This is supported by similar estimates in Denmark of 1:22,000 [Bayat et al 2015] and a slightly lower number,1:40,900, in the UK [Brunklaus et al 2012]. 2.5% (95%CI:1.3 to 3.6%) of all reported seizures following vaccinations in the first year of life were due to SCN1A Dravet syndrome [Verbeek et al 2013].