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SCN1A-Related Seizure Disorders

, MD and , MD.

Author Information
, MD
Director, Clinical Neuroinformatics
Miami Children's Hospital
Miami, Florida
, MD
Director of Pediatric Epilepsy/Neurology and Genetic Epilepsy Clinic
Pediatric Neuroscience Center
Swedish Neuroscience Institute
Clinical Associate Professor in Neurology
University of Washington
Seattle Children's Hospital
Seattle, Washington

Initial Posting: ; Last Update: May 15, 2014.

Summary

Disease characteristics. SCN1A-related seizure disorders encompass a spectrum that ranges from simple febrile seizures (FS) 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 (also known as severe myoclonic epilepsy in infancy [SMEI] or polymorphic myoclonic epilepsy in infancy [PMEI]) are usually associated with progressive dementia. Less commonly observed phenotypes include myoclonic-astatic epilepsy (MAE or Doose syndrome), Lennox-Gastaut syndrome (LGS), infantile spasms, and vaccine-related encephalopathy and seizures. The phenotype of SCN1A-related seizure disorders can vary even within the same family.

Diagnosis/testing. The diagnosis of SCN1A-related seizure disorders relies on detection of a heterozygous pathogenic variant in SCN1A.

Management. Treatment of manifestations: Antiepileptic drugs (AEDs) include benzodiazepines (diazepam and clonazepam), stiripentol (used in Europe; not currently FDA approved for use in the US), topiramate, and valproic acid. Clobazam can be used for the treatment of seizures in Lennox-Gastaus syndrome. 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.

Prevention of secondary complications: Use of protective helmets by individuals with atonic seizures or myoclonic-astatic epilepsy.

Surveillance: Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration; EEG monitoring for new or different seizure types.

Agents/circumstances to avoid: AEDs: carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic seizures; phenytoin, which can induce choreoathetosis. Activities in which a sudden loss of consciousness could lead to injury or death (e.g., bathing, swimming, driving, or working/playing at heights).

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 4000 µg daily; the effects of pregnancy on anticonvulsant metabolism; and the effect of pregnancy on maternal seizure control.

Other: The AEDs clobazam and stiripentol, used in treatment of SMEI, are not FDA-approved for this use in the US. Sleep deprivation and illness can exacerbate seizures. Persons with epilepsy should be made aware of motor vehicle driving laws.

Genetic counseling. SCN1A-related seizure disorders are inherited in an autosomal dominant manner. A proband with an SCN1A-related seizure disorder may have an inherited or de novo mutation. The proportion of cases caused by de novo mutation varies by phenotype: the percentage of probands with an SCN1A-related seizure disorder and an affected parent decreases as the severity of the phenotype in the proband increases; thus, most SCN1A-related SMEI and ICE-GTC are the result of de novo mutation. Each child of an individual with an SCN1A-related 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.

GeneReview Scope

SCN1A-Related Seizure Disorders: Included Disorders 1
  • Generalized epilepsy with febrile seizures plus
  • Intractable childhood epilepsy with generalized tonic-clonic seizures
  • Intractable infantile partial seizures
  • Myoclonic-astatic epilepsy
  • Severe myoclonic epilepsy in infancy
  • Simple febrile seizures

For synonyms and outdated names see Nomenclature.

1. Disorders included in the GeneReview are those caused by mutation of SCN1A. Forms of the disorder associated with other genes are not addressed in this GeneReview.

Diagnosis

SCN1A-related seizure disorders encompass a spectrum of phenotypes that ranges from mild to severe. Because clinical findings alone cannot establish the diagnosis, detection of a heterozygous pathogenic SCN1A variant is necessary. Identification of an SCN1A pathogenic variant may also have implications for medical management of the affected individual’s seizure disorder (see Treatment of Manifestations and Agents/Circumstances to Avoid).

The phenotypes seen in SCN1A-related seizure disorders include the following*:

  • Febrile seizures (FS), which may or may not have features suggestive of an SCN1A-related condition
  • Generalized epilepsy with febrile seizures plus (GEFS+)
  • Dravet syndrome, also known as severe myoclonic epilepsy in infancy (SMEI) or polymorphic myoclonic epilepsy in infancy (PMEI)
    Note: The term "Dravet syndrome" is preferred because the myoclonic seizures implied by the descriptive name(s) can be absent in children whose seizures are otherwise similar.
  • Severe myoclonic epilepsy, borderline (SMEB)
  • Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC), which does not represent an epilepsy defined by ILAE, and is most similar to late-onset Dravet syndrome in the ILAE classification system
    Note: This classification is widely used in the SCN1A literature and is thus included for completeness.
  • Infantile partial seizures with variable foci, also referred to as migrating partial seizures of infancy, cryptogenic focal epilepsy, or severe infantile multifocal epilepsy per Harkin et al [2007]

*Note: Terms used in the literature to describe the phenotypes sometimes differ from the standard epilepsy syndrome terminology as defined by the International League Against Epilepsy (ILAE).

Less commonly associated phenotypes

  • Myoclonic-astatic epilepsy (MAE, Doose syndrome), initially defined conceptually as a group of individuals with a genetic predisposition to generalized epilepsies. In the ILAE classification system it is a superset including Dravet syndrome, benign myoclonic epilepsy, and childhood-onset epilepsies with primarily generalized seizures.
  • Lennox-Gastaut syndrome (LGS), associated with slow-spike wave on EEG, generalized seizures, and intellectual disability. Selmer et al [2009] reported finding one adult with LGS in a cohort of 22 who had an SCN1A pathogenic variant.
  • Infantile spasms
  • Vaccine-related encephalopathy and seizures

The clinical suspicion of SCN1A-related seizure disorders is complicated by the following three issues:

  • The phenotypes cover a broad spectrum of severity, even within the same family.
  • The epilepsy phenotypes are incompletely specific (i.e., they are seen in other conditions as well).
  • Some epilepsy phenotypes refer to features observed in the family, rather than in a particular individual in the family.

Familial features that have some specificity for SCN1A-related seizure disorders include the following.

  • One or more family members with epilepsy, especially of more than one type
  • Febrile seizures:
  • A history of seizures following vaccination
  • Hemiconvulsive seizures
  • Seizures triggered by environmental stimuli, including heat, temperature changes, bright lights, or busy, noisy environments

Note: Because the suggestive features may occur in some members of the family and not others, a complete family history must be taken.

The diagnosis of an SCN1A-related seizure disorder requires detection of a heterozygous pathogenic SCN1A variant. See Table 1.

Table 1. Summary of Molecular Genetic Testing Used in SCN1A-Related Seizure Disorders

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
SCN1ASequence analysis 273%-92% 3
Deletion/duplication analysis 48%-27% 5, 6, 7, 8

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. Estimated value based on subtracting experimental values of deletion frequencies of 8%-27% from 100% (see footnote 5).

4. Testing that identifies exonic or whole-gene deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Using a variety of methods to identify deletions encompassing the SCN1A locus in individuals with SMEI who did not have an SCN1A pathogenic variant identified on sequence analysis, Madia et al [2006] found deletions in three of 39 (8%), Mulley et al [2006] found deletions in two of 13 (15%), and Suls et al [2006] found deletions in three of 11 (27%). In these three studies a total of eight of 63 (12%) individuals with SMEI who did not have a sequence variant identified on sequence analysis had an identifiable SCN1A deletion.

6. Marini et al [2009] found that 12.5% of individuals with Dravet syndrome who did not have a pathogenic variant identified on sequence analysis had copy number variations that were detectable by MLPA.

7. It is not known if the percent of exonic and whole-gene deletions is the same for the other phenotypes in the spectrum of SCN1A-related seizure disorders.

8. A contiguous gene deletion syndrome of severe epilepsy, intellectual disability, and dysmorphic features that includes the genes SCN1A and SCN2A at chromosomal locus 2q23-q24. One affected individual has been described [Pereira et al 2004].

Secondary or modulatory genes in individuals with SCN1A pathogenic variants

  • SCN9A. Pathogenic variants in SCN9A are thought to have a role in modulating disease resulting from SCN1A variants; in some cases isolated SCN9A variants (without SCN1A alterations) have been associated with Dravet Syndrome [Singh et al 2009, Mulley et al 2013] (see Differential Diagnosis).
  • CACNB4. An individual with a missense mutation (Arg468Gln) of CACNB4 in addition to a de novo SCN1A nonsense mutation (Arg568Ter) showed a Dravet phenotype. The phenotype of Dravet syndrome was thought to be due at least in part to the augmentation of the excitatory neurotransmitter release mediated by the increased Ca(v)2.1 currents [Ohmori et al 2008b].
  • CACNA1A. A larger study of 48 people with Dravet syndrome with SCN1A pathogenic variants found that 21/48 had alterations of CACNA1A that appeared to be common variants (polymorphisms). The authors then compared the clinical features of affected individuals with documented SCN1A pathogenic variants who had a CACNA1A polymorphism to those affected individuals who did not have a CACNA1A polymorphism. Forty individuals in the study had documented SCN1A pathogenic variants and Dravet syndrome; of these 40 individuals, the clinical features of 20 individuals with a CACNA1A polymorphism were compared to the phenotypes of 20 without a CACNA1A polymorphism [Ohmori et al 2013]. Affected individuals with a CACNA1A polymorphism had earlier onset of seizures, more frequent prolonged seizures before age one year, and more frequent absence seizures [Ohmori et al 2013].
  • POLG. Gaily et al [2013] reported two individuals with the combination of a heterozygous POLG variant (p.Trp748Ser or p.Gly517Val) and a heterozygous SCN1A pathogenic variant. The affected individuals had prolonged seizures with acute encephalopathy and persistent neurologic deficits postictally. The observation requires further confirmation because heterozygous POLG variants have not generally been associated with seizures and deterioration, which are more typically present in those with compound heterozygous or homozygous POLG pathogenic variants.

Note: The role of the so-called modulatory genes must be interpreted with caution given the phenotypic variability in Dravet syndrome associated with a given pathogenic variant. That said, the phenotypic variability in Dravet syndrome will be only explained when a comprehensive list of possible modifier factors has been compiled.

Clinical Description

Natural History

The natural history of SCN1A-related seizure disorders is strongly influenced by seizure phenotype, which can range from simple febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+) at the mild end to severe myoclonic epilepsy of infancy (SMEI) 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. Figure 1 shows a pedigree that demonstrates variable expressivity. As a result of this variable expressivity, long-term prognosis is difficult to predict.

Figure 1

Figure

Figure 1. Findings in a family illustrating variable expressivity among individuals with the same mutation. 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].

Seizures tend to lessen in severity after puberty; however, they rarely resolve completely. Only approximately 16% of individuals with Dravet syndrome had complete resolution of their seizures, meaning that anticonvulsant treatment is usually lifelong. Complete resolution tended to occur in individuals with less severe seizures earlier in life. Akiyama et al [2010] found that resolution of seizures correlated with having less than three lifetime episodes of convulsive status epilepticus.

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 of seizures, the most obvious explanation, cannot be separated from the effects of medication or the effects of mutation of SCN1A on cognition [Riva et al 2009].

In addition to having seizures in response to strong environmental stimuli, individuals with mutation of SCN1A often have an ADHD-like phenotype characterized by impulsivity, inattentiveness, and distractibility. Possibly related to the inability of the GABA system to “filter out” unimportant sensory input, these symptoms tend to be fairly unresponsive to conventional stimulant medications.

Individuals with severe epilepsy phenotypes often develop the locomotor findings of postural change (flexion at the hips, knees, and trunk, giving a “hunched over” appearance) and ataxia. In spite of the gait being commonly described as “ataxic”, affected individuals seem to be quite a bit more skilled 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 5 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]. The patterns that worsened with increasing age were: decreased passive knee extension and hip extension; increased external tibial torsion; and pes planovalgus [Rodda et al 2012]. The hip internal rotation did not show age-related changes. The gait changes usually begin in childhood, but often develop after the onset of epilepsy. The degree of ataxia in affected individuals is greater than would be expected by the use of anticonvulsant medications alone.

The phenotypes in SCN1A-related seizure disorders, summarized in Table 2, include the following:

Febrile seizures (FS). 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 greater than 15 minutes
  • Occurrence of more than one seizure within 24 hours
  • Presence of any partial (focal) features during the seizure

Febrile seizures plus (FS+). This subset of febrile seizures (simple or complex) has 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

Generalized epilepsy. This phenotype is otherwise indistinguishable from idiopathic generalized epilepsy with onset in childhood or adolescence. Generalized epilepsies caused by mutation of SCN1A 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. Although the complete range of associated phenotypes can be seen within any family, the seizure phenotypes tend toward the mild end of the spectrum [Scheffer & Berkovic 1997] because the more severe seizure types have a reproductive disadvantage and, thus, are less likely to be familial [Claes et al 2001].

Affected individuals within a family with GEFS+ often have febrile seizures (or FS+) in early childhood, followed by occasional tonic, clonic, myoclonic, or absence seizures which 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+.

Dravet syndrome. This phenotype is defined as seizures with onset during the first year of life (usually around age six months; in some cases before age three months) that do not remit, and usually evolve to include myoclonic seizures.

  • Early seizures are often prolonged febrile seizures. Seizures can sometimes be provoked by modest hyperthermia (e.g., a hot bath, physical exertion).
  • Any seizure type is possible; generalized tonic-clonic, myoclonic, and hemiconvulsive seizures are most common.
  • Myoclonic seizures tend to appear later in the course, often coinciding with the appearance of cognitive dysfunction, ataxia, and psychomotor regression.
  • Status epilepticus is common, and pharmacologic management is difficult.
  • The initial EEGs are often normal, 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.

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

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.

Infantile partial seizures with variable foci. This phenotype is defined as focal seizures beginning in infancy with multiple independent zones of seizure onset involving both hemispheres. 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.

Table 2. Distribution of Seizure Phenotypes in SCN1A-Related Seizure Disorders

DisorderDistribution
Simple febrile seizures (FS)Unknown
Febrile seizures plus (FS+)Unknown
Generalized epilepsy with febrile seizures plus (GEFS+)5%-10% 1
Severe myoclonic epilepsy in infancy (SMEI)33%-90% 2
Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC)70% 3

The features and course for the less common phenotypes associated with mutation of SCN1A 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].

Ebach et al [2005] compared two cohorts in order to determine if the MAE phenotype was more specific for the presence of an SCN1A mutation than the severe idiopathic generalized epilepsy of infancy (SIGEI) phenotype. They found one mutation in 20 children with MAE and two mutations in 18 children with SIGEI; the small sample size precluded a statistically significant result.

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 missense mutation with infantile spasms has been reported once [Wallace et al 2003]. The single case 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.

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

Mulley et al [2005] found that most SCN1A pathogenic variants cluster in the C-terminus and in the pore loops connecting S5 and S6 especially in the first three domains of the protein (Figure 2).

Figure 2

Figure

Figure 2. Topologic diagram of Nav1.1, the alpha subunit of the neuronal voltage-gated sodium channel encoded by SCN1A. Nav1.1 is 2,000 amino acids in size and has four homologous domains (D1-D4) that fold around a central pore and are connected by cytoplasmic (more...)

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

Affected individuals with missense mutations of the pore-forming region and truncations of the SCN1A protein are more prone 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].

An estimated 5% of individuals with mutation-positive SMEI have a familial missense SCN1A pathogenic variant that is associated with a milder phenotype (i.e., GEFS+) in other family members [Mulley et al 2005].

Nomenclature

Generalized epilepsy with febrile seizures plus has been referred to as GEFS+ type 2.

Intractable infantile partial seizures has been referred to as ICEGTC.

Penetrance

SCN1A-related 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.

Anticipation

Anticipation is not observed in SCN1A-related seizure disorders.

Prevalence

The prevalence of SCN1A-related seizure disorders is unknown.

Differential Diagnosis

The phenotypes typically seen with mutation of SCN1A are neither necessary nor sufficient to diagnose an SCN1A-related seizure disorder. Other conditions (including those caused by mutation of other genes) may be associated with the same phenotypes.

It is most important to distinguish SCN1A-related seizure disorders from potentially treatable conditions, including the following [Arzimanoglou et al 2004, Roger et al 2006]:

If the family history is negative or unavailable, sporadic epilepsies (i.e., those without a genetic cause) need to be included in the differential diagnosis, as does any cause of epilepsy with nonspecific imaging findings. Some general categories of injury to consider include the following [Arzimanoglou et al 2004, Roger et al 2006]:

  • Trauma
  • Hypoxia
  • Sequelae of meningitis or hemorrhage
  • Infectious or autoimmune cerebritis
  • Vasculitis
  • Paraneoplastic syndrome
  • Toxins (including drug withdrawal)
  • Endocrinopathy

If the family history is positive for other individuals with epilepsy, the differential diagnosis includes the following inherited epilepsy syndromes [Arzimanoglou et al 2004, Roger et al 2006]:

To date, at least 12 loci associated with familial febrile seizures and at least eight loci associated with generalized epilepsy febrile seizures plus (GEFS+) have been identified. The phenotype in simple febrile seizures is usually less severe than that of febrile seizures associated with GEFS+ (see Natural History) [Nakayama & Arinami 2006].

See OMIM Phenotypic Series: Seizures, familial febrile and Epilepsy, generalized, with febrile seizures plus to view genes associated with this phenotype in OMIM.

Genetic loci known to be associated with GEFS+ include the following:

Persons with seizures who have a 2q24.2 deletion may have a deletion of SCN1A or the candidate gene SLC4A10 [Krepischi et al 2010].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an SCN1A-related seizure disorder, the following evaluations are recommended:

  • Neurologic examination
  • Cognitive neuropsychological evaluation
  • Behavioral neuropsychological evaluation
  • Electroencephalogram (EEG), including video EEG telemetry where ictal onset or semiology is unclear
  • Medical genetics evaluation [Pal et al 2010]

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 because children with SCN1A-related seizure disorder are at high risk for sudden unexplained death in epilepsy (SUDEP). In addition, prolonged acute seizures may cause permanent injury [Chipaux et al 2010, Takayanagi et al 2010].

Pharmacologic treatment focuses on the observations that abnormal SCN1A channels disproportionately affect GABA neurons [Yu et al 2006] and that the associated seizures respond optimally to antiepileptic drugs (AEDs) that bind to the GABA receptor:

  • Clobazam (0.2-1 mg mg/kg/day), part of the standard of care in Europe, is now approved by the FDA in the US. Clobazam is FDA approved for the treatment of seizures in Lennox-Gastaut syndrome [Selmer et al 2009].
  • Stiripentol (30-100 mg/kg/day) is accepted by epileptologists as an effective therapeutic agent in SCN1A-related seizure disorders. It is part of the early standard of care in Europe, and is used in the US after other conventional anticonvulsants have failed. It is not approved by the FDA for use in the US, but the evidence of effectiveness in SCN1A-related epilepsy is more specific than for any other agent (based on double-blind evaluation of seizure reduction in severe myoclonic epilepsy in infancy (SMEI) [Chiron et al 2000]). As a result, stiripentol is not considered an “investigational” therapy.

    Thanh et al [2002] demonstrated efficacy of the drug when compared with placebo; only moderate side effects including drowsiness, loss of appetite, and occasional neutropenia in infants and young children were observed. In a recent US survey of 82 children with Dravet syndrome, stiripentol was found to be effective in reducing prolonged seizures [Wirrell et al 2013].

    Stiripentol, which acts directly on GABAA receptors [Quilichini et al 2006], is also a potent inhibitor of the hepatic enzymes CYP3A4, CYP1A2, and CYP2C19. As a result, it increases the serum concentration of several common AEDs, including valproic acid, clobazam, and its metabolite nor-clobazam [Thanh et al 2002]. Doses above 50 mg/kg/day are usually not tolerated when used in conjunction with valproic acid and clobazam.

    Children older than age 12 years may not tolerate stiripentol because of digestive tract side effects and nausea [Thanh et al 2002].
  • Benzodiazepines. Individuals taking stiripentol must exercise caution in the use of benzodiazepines [Thanh et al 2002]. A single infusion of diazepam and clonazepam appears to be safe [Thanh et al 2002].
  • Topiramate [Coppola et al 2002]
  • Valproic acid (10-30 mg/kg/day) [Thanh et al 2002]
  • Ethosuximide. Can be effective for absence seizures. The dose is usually limited by gastrointestinal side effects, which can be minimized by more frequent dosing.
  • Levetiracetam (20-80 mg/kg/day). Often effective, but may make seizures worse in some individuals [Caraballo et al 2010].
  • Potassium bromide. Not FDA-approved in the US, but widely used in Japan with reasonable effectiveness [Tanabe et al 2008].
  • Phenobarbital. Although effective, phenobarbital is poorly tolerated because of its effects on cognition. When it is taken in combination with stiripentol, the serum concentration of phenobarbital is increased because stiripentol slows the metabolism and excretion of barbiturates.
  • Ketogenic diet. Dressler et al [2010] report that seizures were reduced by more than 50% in 62.5% of persons with Dravet syndrome who stayed on the diet for six months. The findings of Nabbout et al [2011] in 15 individuals also support the use of the ketogenic diet in Dravet syndrome.

Sleep deprivation and illness can exacerbate SCN1A-related seizures; thus, good sleep hygiene should be encouraged. Comorbidity with sleep apnea can also occur frequently in individuals with epilepsy [Malow et al 2000], and can influence seizure control, behavior, and cognition. Polysomnography should be considered if obstructive or central sleep apnea is suspected.

Due to the sedating effects of seizure medications and the possibility of respiratory depression (especially with benzodiazepines and barbiturates), parents are advised to take a CPR course. Routine seizure and personal safety counseling is indicated.

Seizures are not always responsive to conventional AEDs. Anecdotal evidence suggests that the following drugs/treatment modalities may be effective for SCN1A-related SMEI seizures [Dravet et al 2002]:

  • Ethosuximide and high-dose piracetam for myoclonic seizures
  • Corticosteroids
  • Immunoglobulins

Non-medical interventions that families have reported to be helpful include the following [Nolan et al 2008]:

  • Placement of an indwelling venous access device
  • Creating a portable microenvironment
  • Having a written emergency department protocol
  • Establishing emergency routines for the family
  • Assigning a parent on call to lessen the effect on the siblings
  • Creating personal time to decrease parent stress
  • Finding respite care
  • Contacting an internet support group

Prevention of Secondary Complications

Individuals experiencing atonic seizures or myoclonic-astatic epilepsy should be advised to wear a protective helmet.

Although immunization may trigger a seizure, it does not affect the natural course of the disorder. McIntosh et al [2010] looked retrospectively at a cohort of 14 individuals with Dravet syndrome, and found no effect of immunization on cognitive outcome. These authors suggest that the immunization schedule not be altered and that the risk for fever following immunization could be reduced by providing a scheduled, long-acting NSAID (e.g., naproxen). The treating neurologist may also consider increasing the anticonvulsant dose(s) temporarily around the time of the immunization.

Surveillance

Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration is appropriate.

EEG monitoring is appropriate when new or different seizure types are suspected.

Agents/Circumstances to Avoid

Several antiepileptic drugs (AEDs) which are effective for most forms of epilepsy can make seizures due to heterozygous SCN1A pathogenic variants worse:

  • Carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic seizures [Horn et al 1986, Guerrini et al 1998, Ceulemans et al 2004a]
  • Phenytoin, which may worsen seizures and can induce choreoathetosis [Saito et al 2001]
  • Rufinamide, which has a pharmacologic mechanism similar to carbamazepine and phenytoin and may exacerbate seizures as well
  • Acetaminophen, which is hepatotoxic in overdose. Given the possibility of interaction with anticonvulsant medications, especially valproate and topiramate [Nicolai et al 2008], acetaminophen should be avoided. Any of the NSAIDs are effective as antipyretics, and represent much lower risk.

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

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In addition to the considerations described in Genetic Counseling, other pregnancy-related considerations include the following:

  • Risk of major malformations (especially due to valproic acid exposure in utero [Samrén et al 1997]) and minor anomalies
  • Advantages and disadvantages of increasing maternal periconceptional folic acid supplementation to 4000 µg daily, particularly when women are taking valproic acid or carbamazepine during pregnancy
  • Effect of in utero exposure to anticonvulsants on future cognitive development [Meador et al 2009]
  • Effect of anticonvulsants on hormonal methods of birth control
  • Effects of anticonvulsants on conception; the risk for complications in mothers who are on anticonvulsants
  • Effect of pregnancy on anticonvulsant metabolism
  • Effect of pregnancy on maternal seizure control

Pregnancy, family planning, and contraception are issues that should be raised with every female near childbearing age who has epilepsy. These considerations are not unique to or (aside from medication selection) significantly influenced by the presence of an SCN1A-related seizure disorder.

Therapies Under Investigation

Cannabis-derived compounds (including cannabidiol [CBD], tetrahydrocannabinol [THC], and marijuana oils), collectively called “cannabinoids,” have received much attention from the media based on anecdotal experiences; however, there is currently no scientific evidence that they are effective. As a result, they should never be used in place of treatments that are known to be effective. A randomized clinical trial is required to determine whether cannabinoid treatment is effective. There has been rapid progress in starting such a trial, and it is expected to begin in 2014. Cannabinoids are bioactive and may have psychotropic and/or systemic side effects; they also may act as an immunosuppressant and an anti-inflammatory in animal models and thus should be studied carefully in immature humans before widespread use is considered [Rieder et al 2010, Bergamaschi et al 2011].

Thalamic deep brain stimulation (DBS) was reported by Andrade et al [2010] in two children with Dravet syndrome with ten-year follow up. One showed “marked improvement” after implantation, whereas the other received no benefit.

Lacosamide has not been studied in SCN1A-related seizure disorders; however, there are theoretic reasons why it may be effective [Curia et al 2009].

Verapamil was reported to help two girls with severe epilepsy resulting from mutation of SCN1A [Iannetti et al 2009]; however, it has not been formally studied.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Persons with epilepsy should be made aware of local motor vehicle driving laws and physician reporting laws.

Hippocampal sclerosis can occur as a secondary feature of SCN1A-related seizure disorders [Livingston et al 2009], but there is no proven role for surgery given the widespread epileptogenic potential in this disorder. Of note, Scheffer et al [2007] reported good outcomes after temporal lobe surgery in two persons with mutation of SCN1B.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SCN1A-related seizure disorders are inherited in an autosomal dominant manner.

Note: Most SCN1A-related severe myoclonic epilepsy in infancy (SMEI) and intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC) are the result of de novo heterozygous mutation.

Risk to Family Members

Parents of a proband

  • A parent of the proband is presumed to have an SCN1A pathogenic variant if he/she has additional family members who have seizures.
  • A proband with an SCN1A-related seizure disorder may have the disorder as the result of de novo mutation. The proportion of cases caused by de novo mutation varies by phenotype. The percentage of probands with an SCN1A-related seizure disorder and an affected parent decreases as the severity of the phenotype in the proband increases.
    • More than 95% of individuals with GEFS+ have a parent with the same SCN1A pathogenic variant.
    • Only approximately 5% of probands with SMEI have a parent with the same SCN1A pathogenic variant [Wallace et al 2003, Ceulemans et al 2004b, Fukuma et al 2004].
    • Testing of parents of children who had SMEI and a confirmed SCN1A pathogenic variant showed that in 95% (76/80) of the children the pathogenic variant was de novo in the proband. Of the four children who had a parent with the pathogenic variant, two had a missense variant and two had a truncation variant; the parents were either asymptomatic or had mild epilepsy [Gennaro et al 2003, Nabbout et al 2003].
    • Berkovic et al [2006] found an SCN1A pathogenic variant in 11/14 children diagnosed with post-vaccine encephalopathy; in nine the variant was de novo in the proband.
  • If a pathogenic variant found in the proband cannot be detected in DNA extracted from the leukocytes of either parent, the risk to either parent of having the pathogenic variant is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has been documented [Gennaro et al 2006, Selmer et al 2009, Azmanov et al 2010], and may occur in up to 7% of families with Dravet syndrome [Depienne et al 2010].
  • In one series, 75% of de novo pathogenic variants originated on the paternally inherited chromosome [Heron et al 2010].
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing.
  • An apparently negative family history cannot be confirmed until appropriate evaluations have been performed. Although 95% of individuals with SCN1A-related GEFS+ have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or because of early death before the onset of symptoms. If the parent is the individual in whom the pathogenic variant first occurred, s/he may have somatic mosaicism for the pathogenic variant and may be only mildly or minimally affected [Gennaro et al 2006].

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected (i.e., has the pathogenic variant documented by molecular genetic testing) or is presumed to have a pathogenic variant (based on family history), the risk to the sibs of inheriting the pathogenic variant is 50%.
  • If a sib has epilepsy, he/she is presumed to be affected (and therefore to have a pathogenic variant).
  • If a sib does not have epilepsy, the prior probability of the sib having inherited the pathogenic variant is 50%; however, the probability of the sib developing symptoms depends on the penetrance, which can only be estimated. For example, for an estimated penetrance of 70% for the GEFS+ phenotype, the probability of the asymptomatic sib having inherited the pathogenic variant is 23%.
  • If a pathogenic variant is found in the proband but cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism [Gennaro et al 2006].

Offspring of a proband

  • Each child of an individual with an SCN1A-related seizure disorder has a 50% chance of inheriting the pathogenic variant.
  • Penetrance is incomplete (see Penetrance) and varies by phenotype.
  • The likelihood that the child of an individual with an SCN1A-related seizure disorder will develop the same phenotype is the probability of inheriting the pathogenic variant (50%) times the penetrance for that particular phenotype.
  • Individuals with GEFS+ may have offspring who are more severely affected than they are. For example, they may have a child with Dravet syndrome.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or has a pathogenic variant, the other family members are at greater risk than the general population.

Related Genetic Counseling Issues

Interpreting test results in at-risk asymptomatic relatives. Counseling asymptomatic family members who are identified to have the family-specific pathogenic variant should include information on reduced penetrance and the limited ability to predict phenotype based on molecular genetic testing alone.

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

If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Dravet Syndrome Foundation, Inc.
    11 Nancy Drive
    Monroe CT 06468
    Phone: 203-880-9456
    Email: info@dravetfoundation.org
  • American Epilepsy Society (AES)
    342 North Main Street
    West Hartford CT 06117-2507
    Phone: 860-586-7505
    Fax: 860-586-7550
    Email: info@aesnet.org
  • Epilepsy Canada
    2255B Queen Street East
    Suite 336
    Toronto Ontario M4E 1G3
    Canada
    Phone: 877-734-0873
  • Epilepsy Foundation
    8301 Professional Place
    Landover MD 20785-7223
    Phone: 800-332-1000 (toll-free)
    Fax: 301-577-2684
    Email: info@efa.org
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • National Institute of Neurological Disorders and Stroke (NINDS)
    PO Box 5801
    Bethesda MD 20824
    Phone: 800-352-9424 (toll-free); 301-496-5751; 301-468-5981 (TTY)
  • International Ion Channel Epilepsy Patient Registry

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. SCN1A-Related Seizure Disorders: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for SCN1A-Related Seizure Disorders (View All in OMIM)

182389SODIUM CHANNEL, NEURONAL TYPE I, ALPHA SUBUNIT; SCN1A
604233GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 1; GEFSP1
604403GENERALIZED EPILEPSY WITH FEBRILE SEIZURES PLUS, TYPE 2; GEFSP2
607208EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 6; EIEE6

Molecular Genetic Pathogenesis

SCN1A encodes the alpha subunit (also known as Nav1.1) of the neuronal voltage-gated sodium channel. SCN1A-related seizure disorders are therefore best conceptualized as a "channelopathy" with seizures (and their sequelae) as their primary manifestation. The molecular abnormality causes neuronal dysfunction, and ultimately hyperexcitability at the level of the cortical network: the sine qua non of epilepsy.

SCN1A is part of a cluster of sodium channel genes encoded on chromosome 2q24 that includes SCN2A and SCN3A [Mulley et al 2005]. The alpha subunit of sodium channels forms the membrane pore. Each alpha subunit protein has four domains with six transmembrane segments connected by loops (Figure 2). Pore-lining residues are found in S5, S6, and the P-loop, the latter connecting S5 with S6. The voltage sensor is in S4, where positively charged residues allow for the sensing of membrane potential changes [Catterall 2000]. Although epilepsy-associated pathogenic variants are found in all parts of Nav1.1, they occur more frequently in the C-terminus, to some extent in the N-terminus, in the P-loops of D1-D5, and in the voltage sensor [Ceulemans et al 2004b, Mulley et al 2006].

Gene structure. SCN1A spans approximately 84 Mb of genomic DNA and has a transcript of 8,100 bp (reference sequence NM_006920.4). The gene comprises 26 exons that encode a protein of 1,998 amino acid residues (reference sequence NP_008851.3). Splicing variability has been reported [Wallace et al 2001b]. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants

  • Generalized epilepsy with febrile seizures plus (GEFS+). SCN1A pathogenic variants associated with GEFS+ are mostly missense and familial (i.e., inherited) [Mulley et al 2005].
  • Dravet syndrome. Almost half the pathogenic variants associated with the severe myoclonic epilepsy in infancy (SMEI) phenotype are truncating variants [Mulley et al 2006]. The remainder includes missense variants (39%-43%; fewer than the GEFS+ phenotype, but with a similar topologic distribution within Nav1.1), splice site variants (7%), and deletions (3%) [adapted from Mulley et al 2005].
  • Intractable childhood epilepsy with generalized tonic-clonic seizures (ICE-GTC). Seven out of ten individuals with ICE-GTC had an SCN1A missense pathogenic variant [Mulley et al 2005]. In the two cases with an inherited pathogenic variant, the parents had GEFS+.
  • Infantile partial seizures with variable foci. In the authors' experience, such cases often have missense pathogenic variants affecting the pore region or the carboxy-terminus of Nav1.1.
  • Infantile spasms. The literature cites an isolated case of infantile spasms and an SCN1A missense pathogenic variant [Wallace et al 2003].
  • Vaccine-related encephalopathy and seizures. There are five reports of pathogenic variants causing Nav1.1 truncation and six reports of missense pathogenic variants in conserved regions of Nav1.1 [Berkovic et al 2006].

Normal gene product. See Molecular Genetic Pathogenesis.

Abnormal gene product. The molecular pathogenesis of SCN1A-related seizure disorders may vary depending on the specific pathogenic variant type (loss of function vs. alteration in activity). The pathophysiology is an active area of investigation; it appears likely that the predominant effect is the loss of excitability in inhibitory GABAergic neurons [Escayg & Goldin 2010].

References

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Chapter Notes

Revision History

  • 15 May 2014 (me) Comprehensive update posted live
  • 10 November 2011 (me) Comprehensive update posted live
  • 29 November 2007 (me) Review posted to live Web site
  • 13 October 2006 (msm) Original submission
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