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SCN8A-Related Epilepsy with Encephalopathy

Synonym: Early-Infantile Epileptic Encephalopathy 13 (EIEE13)

, PhD, , PhD, , MD, PhD, and , PhD.

Author Information and Affiliations

Initial Posting: .

Estimated reading time: 23 minutes


Clinical characteristics.

SCN8A-related epilepsy with encephalopathy is characterized by developmental delay, seizure onset in the first 18 months of life (mean 4 months), and intractable epilepsy characterized by multiple seizure types (generalized tonic-clonic seizures, infantile spasms, and absence and focal seizures). Epilepsy syndromes can include Lennox-Gastaut syndrome, West syndrome, and epileptic encephalopathies (e.g., Dravet syndrome). Hypotonia and movement disorders including dystonia, ataxia, and choreoathetosis are common. Psychomotor development varies from normal prior to seizure onset (with subsequent slowing or regression after seizure onset) to abnormal from birth. Intellectual disability, present in all, ranges from mild to severe (in ~50% of affected individuals). Autistic features are noted in some. Sudden unexpected death in epilepsy (SUDEP) of unknown cause has been reported in approximately 10% of published cases. To date SCN8A-related epilepsy with encephalopathy has been reported in the literature in about 50 individuals.


The diagnosis is established in a proband with encephalopathy and epilepsy and identification of a de novo pathogenic variant in SCN8A on molecular genetic testing.


Treatment of manifestations: Seizure control should be managed by a pediatric neurologist with expertise in epilepsy management who is familiar with the pharmacotherapy for SCN8A-related epilepsy with encephalopathy and aware of how it differs from treatment of similar disorders. Vigorous attempts to control seizures are warranted. Several studies suggest a favorable response to sodium channel blockers.

Surveillance: Periodic evaluation for neurologic, cognitive, and/or behavioral deterioration; monitoring with EEG and other modalities such as video EEG telemetry or ambulatory EEG when new or different seizure types are suspected. Because of the increased risk of SUDEP, some families use oxygen monitoring during sleep.

Agents/circumstances to avoid: Several families of affected individuals report worsening of seizures with levetiracetam.

Genetic counseling.

SCN8A-related epilepsy with encephalopathy is expressed in an autosomal dominant manner. Most affected individuals have a de novo pathogenic variant and typically do not reproduce. While the risk to future pregnancies is presumed to be low, some parents of an affected child may wish to consider prenatal testing or preimplantation genetic testing in future pregnancies as the risk may be slightly greater than in the general population because of the possibility of parental germline mosaicism.


Suggestive Findings

SCN8A-related epilepsy with encephalopathy should be suspected in individuals with early-onset epileptic encephalopathy (i.e., refractory seizures and cognitive slowing or regression associated with ongoing epileptiform activity), particularly those with the following epilepsy features, seizure types, and/or epilepsy syndromes.

Epilepsy features

  • Seizure onset in the first 18 months of life (mean age 4 months)
  • Focal clonic seizures evolving into bilateral convulsive seizures
  • Development of multiple seizure types
  • Motor abnormalities including hypotonia
  • Movement disorders including dystonia, ataxia, choreoathetosis

Seizure types

  • Intractable childhood epilepsy with generalized tonic-clonic seizures
  • Infantile spasms
  • Absence and focal seizures

Epilepsy syndromes

  • Lennox-Gastaut syndrome
  • West syndrome
  • Early-onset epilepsy with hypotonia, movement disorders, and/or intellectual disability (e.g., Dravet syndrome)

Establishing the Diagnosis

The diagnosis of SCN8A-related epilepsy with encephalopathy is established in a proband with encephalopathy and epilepsy by identification of a de novo pathogenic (or likely pathogenic) variant in SCN8A through molecular genetic testing (see Table 1).

Note: Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants.

Molecular genetic testing approaches can include targeted gene testing (multigene panel) or genomic testing (comprehensive genomic sequencing).

Targeted gene testing requires the clinician to develop a hypothesis about which specific gene(s) are likely to be involved, whereas genomic testing may not. Because the phenotypes of many genetic epileptic encephalopathies overlap, most children with SCN8A encephalopathy with epilepsy are diagnosed by following recommended testing (multigene panel) or testing to consider (comprehensive genomic sequencing). Note that testing of SCN8A alone (i.e., single-gene testing) is rarely used.

Recommended Testing

A multigene panel that includes SCN8A and other genes of interest (see Differential Diagnosis) is the recommended approach. 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; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (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.

Testing to Consider

Comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered if the phenotype is indistinguishable from other inherited disorders (or the phenotype alone is insufficient to support focused gene testing).

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 SCN8A-Related Encephalopathy with Epilepsy

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
SCN8A Sequence analysis 3100% 4
Gene-targeted deletion/duplication analysis 5Unknown, none reported to date 4

See Molecular Genetics for information on allelic variants detected in this gene.


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.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Clinical Characteristics

Clinical Description

SCN8A pathogenic variants have been associated with developmental delay prior to and/or after onset of seizures, intellectual disability without seizures, and epileptic encephalopathy.

SCN8A-related epilepsy with encephalopathy is an early-onset, intractable epilepsy characterized by multiple seizure types and developmental delay. To date 50 individuals with a de novo SCN8A pathogenic variant have been reported [Rauch et al 2012, Veeramah et al 2012, Allen et al 2013, Carvill et al 2013, de Kovel et al 2014, Estacion et al 2014, Ohba et al 2014, Vaher et al 2014, Blanchard et al 2015, Dyment et al 2015, Fitzgerald et al 2015, Fung et al 2015, Kong et al 2015a, Larsen et al 2015, Mercimek-Mahmutoglu et al 2015, Olson et al 2015, Singh et al 2015, Takahashi et al 2015, Wagnon et al 2015a, Boerma et al 2016].

The most common clinical features of SCN8A-related epilepsy with encephalopathy are described below. Of note, sudden setbacks of unknown cause are common.

Seizures. In 48 of the 50 affected individuals reported to date age of onset of seizures ranged from the first day of life to age 22 months (median age: 4 months; mean age: 4.7 months). Of note, prenatal onset of seizures may occur as some mothers reported unusual "drumming" movements in the later stages of pregnancy [Singh et al 2015].

Initial seizure type varies, and most affected individuals develop additional seizure types, including the following:

  • Focal clonic seizures evolving to a bilateral convulsive seizure
  • Afebrile generalized tonic clonic seizures
  • Tonic seizures
  • Infantile spasms
  • Myoclonic seizures

Although both convulsive and nonconvulsive status epilepticus appear to be common [Larsen et al 2015], they are not as common as in Dravet syndrome.

Seizure frequencies range from hundreds per day to fewer than one per month.

Most affected individuals have refractory seizures and require polytherapy (see Treatment of Manifestations).

Psychomotor development varies from normal prior to seizure onset (with subsequent slowing or regression after seizure onset) to abnormal from birth [Larsen et al 2015]. Many affected individuals experience marked slowing or arrest in development either for no apparent reason or after an event that occurred before the developmental decline, such as a change in seizure type or change in medication.

Approximately half of affected children learn to sit and walk unassisted; the remainder are nonambulatory. Ataxia and sudden loss of mobility are common in those who are ambulatory.

The oldest patient of whom the authors are aware is 47 years old; the majority of diagnosed individuals are younger than age 20 years. For the several who are in their teens, cognitive and motor disabilities persist.

Language is frequently affected. The majority of affected individuals speak few or no words.

Intellectual disability ranges from mild to severe, with about half of affected individuals having severe intellectual disability. Autistic features are noted in some [Larsen et al 2015].

Movement abnormalities including hypotonia, dystonia, choreoathetosis, ataxia, spasticity, and increased startle have been described in some affected individuals.

Startle and sleep problems. Many children are hyper-alert as infants (i.e., more awake and aware of their surroundings than typical infants) and are easily startled. For example, Singh et al [2015] reported a newborn with jittery movements shortly after birth and a pathologically exaggerated startle response to tactile and acoustic stimuli, findings that prompted a suspicion of hyperekplexia. The hyper-alert sleep appears to make it difficult for the infant to settle into a deep, healthy sleep. These findings have been anecdotally reported in several other individuals with SCN8A-related encephalopathy with epilepsy.

Associated medical problems, reported in some affected individuals, can include the following:

  • Autonomic nervous system dysfunction, including difficulty with temperature regulation and tachypnea
  • Hearing problems
  • Bone fractures, often associated with prolonged seizures
  • Laryngomalacia
  • Scoliosis
  • Microcephaly
  • Cortical visual impairment
  • Gum hyperplasia secondary to anti-seizure medication

Sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of published cases [Veeramah et al 2012, Estacion et al 2014, Kong et al 2015a, Larsen et al 2015]. The cause of SUDEP is unknown, but may be related to prolonged seizures, cardiac abnormalities, or brain stem dysfunction. SUDEP can occur at any age.

EEG. Early on the EEG may be normal or exhibit focal or multifocal epileptiform activity. The EEG tends to evolve over time, often showing moderate to severe background slowing and focal or multifocal sharp waves or spikes, most often in the temporal regions. Some show almost continuous delta slowing in the temporo-parietal-occipital regions, with superimposed beta frequencies and bilateral asynchronous spikes or sharp waves [Larsen et al 2015].

Brain MRI is usually normal at the onset of seizures; however, abnormal findings may include cerebral atrophy and hypoplasia of the corpus callosum. Some affected individuals have been shown to have developed cerebral or cerebellar atrophy in follow-up studies [Larsen et al 2015, Singh et al 2015].

Genotype-Phenotype Correlations

There is no obvious correlation between the position of an SCN8A pathogenic variant and the seizure onset, seizure type, or clinical severity. Most pathogenic variants are located in the transmembrane segments of the channel.

Notable similarities in age of onset and movement impairment were reported in two severely affected, unrelated individuals with the same de novo pathogenic variant p.Ile1327Val [Vaher et al 2014, Singh et al 2015]; in contrast, however, multiple individuals with the pathogenic variant p.Arg1617Gln had different ages of onset and disease severity [Wagnon & Meisler 2015].


Penetrance for SCN8A-related epilepsy with encephalopathy is unknown but assumed to be complete.

  • All SCN8A pathogenic variants identified to date have been de novo or inherited from a parent with a somatic mosaic pathogenic variant that included the germline.
  • None of the SCN8A pathogenic variants have been seen in unaffected individuals, including controls in various studies and the ExAC database of ~60,000 genomes (exac.broadinstitute.org).


The prevalence of SCN8A-related epilepsy with encephalopathy is not known.

The frequency of SCN8A pathogenic variants among individuals with epileptic encephalopathy was 13/1557 (close to 1%) in four independent studies, each of which included several hundred individuals [Allen et al 2013, Carvill et al 2013, Larsen et al 2015, Mercimek-Mahmutoglu et al 2015].

Differential Diagnosis

The clinical features associated with a SCN8A pathogenic variant overlap significantly with other genetic (and non-genetic) epileptic encephalopathies. The differential diagnosis should include all genes known to be associated with early infantile epileptic encephalopathy (>30 have been identified; see OMIM Phenotypic Series).

Structural abnormalities of the brain that cause epileptic encephalopathy should be included in the differential diagnosis and can be identified by brain MRI.

Treatable neurometabolic disorders causing early infantile-onset epileptic encephalopathy that should be considered in the differential diagnosis include:

Dravet syndrome is an infantile epileptic encephalopathy characterized by hemiclonic or generalized seizures that are often triggered by fever. More than 80% of individuals with Dravet syndrome have a de novo pathogenic variant in SCN1A (a related sodium channel gene) that results in loss of function due to protein truncation (60%) or pathogenic missense variants that inactivate the channel [Marini et al 2011]. The distinction between epilepsy caused by mutation of SCN1A and epilepsy caused by mutation of SCN8A is important because sodium channel blockers should be avoided in Dravet syndrome whereas they may be beneficial in SCN8A-related epilepsy with encephalopathy (see Treatment of Manifestations).

Distinctions between SCN8A-related epilepsy with encephalopathy and Dravet syndrome include:

  • Age of onset. The mean age of onset is similar but the range of 0 days to 22 months in SCN8A-related epilepsy with encephalopathy is broader than that seen in Dravet syndrome.
  • Febrile seizures. Susceptibility to seizures with fever is common in Dravet syndrome, but rare in SCN8A-related encephalopathy with epilepsy.
  • Infantile spasms. Many patients with SCN8A-related epilepsy with encephalopathy present with spasms, which are not a feature of Dravet syndrome.
  • Myoclonic seizures. Patients with SCN8A-related epilepsy with encephalopathy rarely have myoclonic seizures, which are common in Dravet syndrome.
  • Hypotonia and movement disorders are common in patients with SCN8A-related encephalopathy with epilepsy, but are not typical of Dravet syndrome.
  • EEG findings. Generalized spike wave, a hallmark of Dravet syndrome after age one to two years, is not typical in SCN8A-related encephalopathy with epilepsy.
  • Medications. Sodium channel blockers such as carbamazepine, oxcarbazepine, and phenytoin appear to be the most efficacious anti-seizure medication for SCN8A-related epilepsy with encephalopathy [Larsen et al 2015, Boerma et al 2016], while many patients with Dravet syndrome do worse on sodium channel blockers.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with a SCN8A-related encephalopathy with epilepsy, the following evaluations are recommended:

  • Neurologic examination including:
    • EEG, which may provide an assessment of the overall degree of epileptic encephalopathy and seizure type
    • Brain MRI if not previously performed
  • Cognitive and behavioral neuropsychological evaluation
  • EKG to assess for cardiac arrhythmias, which have been identified in some affected individuals with mutation of genes encoding other sodium channel subunits and may increase the risk of sudden unexpected death in epilepsy (SUDEP)
  • Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

No published treatment guidelines exist.

Seizure control should be managed by a pediatric neurologist with expertise in epilepsy management who is familiar with the pharmacotherapy for SCN8A-related epilepsy with encephalopathy and how it differs from treatment of similar disorders (e.g., Dravet syndrome; see SCN1A-Related Seizure Disorders and Differential Diagnosis).

Vigorous attempts to control seizures with drug polytherapy are warranted because children with SCN8A-related epilepsy with encephalopathy are at risk for sudden unexplained death in epilepsy (SUDEP) as well as prolonged acute seizures that may cause permanent injury [Chipaux et al 2010, Takayanagi et al 2010].

Sodium channel blockers. Several studies suggest that patients with SCN8A-related epilepsy with encephalopathy respond favorably to the class of anti-seizure medication (ASM) that blocks sodium channels; this includes phenytoin, valproate, carbamazepine, lacosamide, lamotrigine, rufinamide, and oxcarbazepine [Kong et al 2015b, Larsen et al 2015, Boerma et al 2016]. The effectiveness of sodium channel blockers is consistent with the activating effects of most SCN8A pathogenic variants [Wagnon & Meisler 2015, Wagnon et al 2015a, Wagnon et al 2015b]. Most patients are maintained on multiple medications with incomplete seizure control. One study of four patients reported a positive response to high doses of phenytoin [Boerma et al 2016].

Other ASMs

  • Clobazam, part of the standard of care for epilepsy in Europe, is now FDA-approved for the treatment of seizures in Lennox-Gastaut syndrome [Selmer et al 2009].
  • Phenobarbital, while effective for seizure control, is poorly tolerated because of its effects on cognition.
  • Levetiracetam (Keppra®) has been reported by several families to be ineffective or occasionally associated with an increase in seizure frequency [M Hammer, unpublished data].

Other. When seizures are not responsive to conventional ASMs, the following drugs/treatment modalities may be effective based on anecdotal information:

  • Corticosteroids
  • Immunoglobulins
  • Vagus nerve stimulator
  • Ketogenic diet
  • Cannabinoids

Sleep hygiene. As described for Dravet syndrome, sleep deprivation and illness can exacerbate SCN8A-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.

Caregivers. For information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see Epilepsy Foundation Toolbox.


Evaluate periodically for neurologic, cognitive, and/or behavioral deterioration.

Monitor with EEG and other modalities (e.g., video EEG telemetry or ambulatory EEG) when new or different seizure types are suspected.

Because of the increased risk of SUDEP, some families use oxygen monitoring during sleep.

Agents/Circumstances to Avoid

Several families of affected individuals report worsening of seizures with levetiracetam (Keppra®) [M Hammer, unpublished data].

Evaluation of Relatives at Risk

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

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of 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; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SCN8A-related epilepsy with encephalopathy is expressed in an autosomal dominant manner (i.e., heterozygous mutation of SCN8A results in the disorder).

Risk to Family Members

Parents of a proband

  • Most probands with SCN8A-related epilepsy with encephalopathy reported to date have the disorder as a result of a de novo pathogenic variant.
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo pathogenic variant. If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the most likely explanation is a de novo pathogenic variant in the proband; another possible explanation is germline mosaicism in a parent. Molecular genetic tests sensitive enough to detect low-level germline mosaicism, such as allele-specific PCR or high-coverage next-generation sequencing methods, should be considered.

Sibs of a proband. The risk to the sibs of the proband depends on the genetic status of the proband's parents: if the SCN8A pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but slightly greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with SCN8A-related epilepsy with encephalopathy has a 50% chance of inheriting the pathogenic variant. However, individuals with SCN8A-related epilepsy with encephalopathy typically do not reproduce.

Other family members. The risk to other family members depends on the genetic status of the proband's parents but appears to be low given that most probands with SCN8A-related epilepsy with encephalopathy reported to date have the disorder as a result of a de novo pathogenic variant.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Risk to future pregnancies is presumed to be low as the proband most likely has a de novo SCN8A pathogenic variant. However, couples with an affected child may wish to consider prenatal or preimplantation genetic testing in future pregnancies as the risk for SCN8A-related epilepsy with encephalopathy may be greater than in the general population because of the possibility of parental germline mosaicism.


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
    Phone: 203-392-1950
    Fax: 203-907-1940
    Email: info@dravetfoundation.org
  • American Epilepsy Society
  • Canadian Epilepsy Alliance
    Phone: 1-866-EPILEPSY (1-866-374-5377)
  • Epilepsy Canada
    Phone: 877-734-0873
    Email: epilepsy@epilepsy.ca
  • Epilepsy Foundation
    Phone: 800-332-1000; 301-459-3700
    Email: ContactUs@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)

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.

SCN8A-Related Epilepsy with Encephalopathy: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
SCN8A 12q13​.13 Sodium channel protein type 8 subunit alpha SCN8A @ LOVD SCN8A SCN8A

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for SCN8A-Related Epilepsy with Encephalopathy (View All in OMIM)


Gene structure. SCN8A comprises 27 exons. Exon 1 encodes the noncoding 5' UTR. The 26 protein-coding exons encode a protein of 1980 amino acids (NP_055006.1). The approximate position of each exon is indicated in Figure 1.

Figure 1. . Intron-exon organization of SCN8A.

Figure 1.

Intron-exon organization of SCN8A. Horizontal bars mark the positions of the introns of the sodium channel protein type 1.6 subunit alpha (Nav1.6) superimposed on the secondary structure of the sodium channel [Plummer et al 1998].

It is important to recognize that the structure of SCN8A includes the alternatively spliced exons 6A (adult) and 6N (neonatal) that encode segment 3/4 of domain I, as well as the alternatively spliced exons 21A (adult) and 21N (neonatal) that encode segment 3/4 of domain 3. Note: Exon 21N is a "poison" exon that contains an in-frame stop codon and encodes a truncated protein terminating in domain 3 that does not have channel activity.

  • During the first year of postnatal life, the "neonatal" and the "adult" exons are expressed in roughly equal proportions [O'Brien et al 2012].
  • Exon 21N is expressed at a low level in non-neuronal cells including glia.

The most complete full-length reference transcript contains exon 6N and exon 21A: NM_014191.3 (ENST00000354534).

Note that the reference sequence missing exon 21 should not be used for sequence comparisons: NM_001177984.2 (ENST00000545061).

Benign variants. See Table 2.

Variants of uncertain significance. A SCN8A 2-bp deletion protein truncation variant was identified in a child with intellectual disability, pan cerebellar atrophy, and ataxia but no seizures [Trudeau et al 2006]. It is unknown if the findings in the proband result from the predicted loss of channel function resulting from this SCN8A variant or from an unrelated developmental disorder. Three additional heterozygous family members with the SCN8A variant had a history of cognitive impairment; however, the clinical information available for heterozygous relatives was incomplete.

An individual with intellectual disability, severe speech delay, absence seizures, and QRS-fragmentation on EKG had a rare SCN8A missense variant of uncertain significance (NM_014191.3:c.4748T>C, p.Ile1583Thr) inherited on the maternal allele along with a de novo multiexon SCN8A deletion on the paternal allele [Berghuis et al 2015]. The deletion involving exons 2-14 was mosaic in the child and estimated to occur in 50% of peripheral blood cells. This case suggests that complex alterations in SCN8A may underlie at least some instances of epilepsy and cognitive impairment. Interestingly, this individual also had a heterozygous SCN5A missense variant (rs41313691) of uncertain significance.

The heterozygous SCN8A missense variant (c.4447G>A; p.Glu1483Lys) was found in six individuals with benign infantile seizures (afebrile focal or generalized tonic-clonic) and paroxysmal dyskinesia from three unrelated families [Gardella et al 2016]. The onset of clinical manifestations occurred during the first to second years of life. Some heterozygotes for the SCN8A variant were unaffected, implying reduced penetrance.

Pathogenic variants. The SCN8A pathogenic variants identified in the first 100 individuals with epileptic encephalopathy were missense variants with the exception of one splice site variant predicted to cause an in-frame deletion [Rauch et al 2012; Veeramah et al 2012; Allen et al 2013; Carvill et al 2013; de Kovel et al 2014; Estacion et al 2014; Ohba et al 2014; Vaher et al 2014; Blanchard et al 2015; Dyment et al 2015; Fitzgerald et al 2015; Fung et al 2015; Kong et al 2015a; Larsen et al 2015; Mercimek-Mahmutoglu et al 2015; Olson et al 2015; Singh et al 2015; Takahashi et al 2015; Wagnon et al 2015a; Boerma et al 2016; M Hammer, unpublished data]. All variants were de novo, except two that were inherited from a parent mosaic for the variant.

Approximately one third of the 100 individuals with an SCN8A pathogenic variant have a recurrent pathogenic variant that has been observed in up to ten unrelated individuals [Wagnon & Meisler 2015, Wagnon et al 2015a]. Many of the recurrent pathogenic variants arise due to deamination of CpG dinucleotides, often in arginine codons. The locations of recurrent pathogenic variants are shown in Figure 2 and several examples are listed in Table 3 (pdf).

Figure 2. . Positions of SCN8A missense pathogenic variants in the sodium channel protein type 1.

Figure 2.

Positions of SCN8A missense pathogenic variants in the sodium channel protein type 1.6 subunit alpha (Nav1.6). The protein has four homologous domains (D1 to D4), each containing six transmembrane segments (S1-S6) [Wagnon & Meisler 2015].

The clinical variation among individuals with identical pathogenic variants may be as great as that among individuals with different pathogenic variants, indicating the important roles of background genetic and developmental variation on clinical outcome [Wagnon & Meisler 2015]. The locations of known pathogenic variants in the Nav1.6 channel protein are indicated in Figure 2.

It is important to note that some de novo missense variants may not be pathogenic (e.g., Blanchard et al [2015]).

Table 2.

SCN8A Variants Discussed in This GeneReview

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.3979A>Gp.Ile1327Val NM_014191​.3

Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

See Table 3 (pdf) for additional SCN8A variants.

Normal gene product. SCN8A encodes the sodium channel protein type 1.6 subunit alpha (isoform Nav1.6) that contains 1980 amino acids. The protein includes four homologous domains with six transmembrane segments each, as well as two large cytoplasmic loops, a short cytoplasmic inactivation gate, and cytoplasmic N-terminal and C-terminal domains (Figure 1, with exon designations and functional domains marked). The amino acids forming the sodium- specific pore are located in segments S5 and S6 of each domain.

The protein is highly conserved through evolution, and the human sequence can be aligned with the bacterial sodium channel, whose crystal structure has been determined.

Abnormal gene product. Most pathogenic variants result in substitution of a single amino acid. Of the nine pathogenic variants tested functionally, seven resulted in elevated channel activity due to premature channel opening or impaired channel closing. Elevated activity of Nav1.6 leads to neuronal hyperexcitability and seizures in a mouse model of SCN8A-related epilepsy with encephalopathy [Wagnon et al 2015b]. Nav1.6 is expressed at a low level in cardiac ventricular myocytes, and cardiac arrhythmia is seen in the mouse model, suggesting that sudden unexplained death in epilepsy (SUDEP) may have a cardiac component [Frasier et al 2016].

Chapter Notes

Author Notes

The Meisler laboratory carried out the first studies of SCN8A structure and expression and currently studies the function of pathogenic alleles in mouse models and transfected cells.

The Hammer lab identified the first case of SCN8A epilepsy and is establishing a registry and an online database of the clinical features of patients with pathogenic variants in SCN8A (www.scn8a.net). The Hammer and Meisler labs are collaborating on experiments using mouse models of SCN8A epilepsy.


We thank Wishes for Elliott (www.wishesforelliott.org) for funding the first SCN8A workshop in association with the American Epilepsy Society conference in Washington DC (April 20, 2015) and for initiating the process to make this GeneReview possible.

Revision History

  • 25 August 2016 (bp) Review posted live
  • 29 September 2015 (mfh) Original submission


Literature Cited

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