Clinical characteristics.

SCN8A-related epilepsy and/or neurodevelopmental disorders encompasses a spectrum of phenotypes. Epilepsy phenotypes include developmental and epileptic encephalopathy (DEE) associated with severe developmental delays and usually pharmacoresistant epilepsy with multiple seizure types; mild-to-moderate developmental and epileptic encephalopathy (mild/modDEE, or intermediate epilepsy) with partially treatable epilepsy; self-limited familial infantile epilepsy (SeLFIE, also known as benign familial infantile epilepsy or BFIE) with normal cognition and medically treatable seizures; neurodevelopmental delays with generalized epilepsy (NDDwGE); and neurodevelopmental disorder without epilepsy (NDDwoE) with mild-to-moderate intellectual disability (though it can be severe in ~10% of affected individuals). Hypotonia and movement disorders including dystonia, ataxia, and choreoathetosis are common in some phenotypes. Sudden unexpected death in epilepsy (SUDEP) has been reported in some affected individuals.

Diagnosis/testing.

The diagnosis of SCN8A-related epilepsy and/or neurodevelopmental disorders is established in a proband with suggestive findings and a heterozygous pathogenic variant in SCN8A identified by molecular genetic testing.

Management.

Treatment – targeted therapy: Several studies suggest a favorable response to sodium channel blockers in the SCN8A-related epilepsy phenotypes of SCN8A-DEE, SCN8A-mild/modDEE, and SCN8A-SeLFIE.

Treatment – supportive care: Seizure control should be managed by a pediatric neurologist with expertise in epilepsy management who is familiar with the pharmacotherapy for SCN8A-related epilepsy and aware of how it differs from treatment of similar disorders. Vigorous attempts to control seizures are warranted. Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields.

Surveillance: Periodic evaluations 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, monitoring seizures in individuals at higher risk, including those with generalized tonic-clonic seizures and/or nighttime seizures, is warranted.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify those who are at risk for developing seizures. This typically entails targeted molecular genetic testing for the known pathogenic variant(s) in the family.

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

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

Genetic counseling.

SCN8A-related epilepsy and/or neurodevelopmental disorders are inherited in an autosomal dominant manner. Individuals with more severe SCN8A-related phenotypes are more likely to have the disorder as the result of a de novo pathogenic variant than individuals with milder SCN8A-related phenotypes. Each child of an individual with SCN8A-related epilepsy and/or neurodevelopmental disorders has a 50% chance of inheriting the SCN8A pathogenic variant. Once the SCN8A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Suggestive Findings

SCN8A-related epilepsy and/or neurodevelopmental disorders encompass a spectrum of phenotypes that range from mild to severe and should be considered in probands with the following clinical findings and family history.

Establishing the Diagnosis

The diagnosis of SCN8A-related epilepsy and/or neurodevelopmental disorders is established in a proband with suggestive clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in SCN8A identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and 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. (2) Identification of a heterozygous SCN8A variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing in a child with epilepsy and/or developmental delay or an older individual with epilepsy and/or intellectual disability may begin with a multigene panel or exome sequencing. Subsequent testing may involve chromosomal microarray analysis (CMA); however, to date, there are very few reported copy number variants in this spectrum. Note: Single-gene testing (sequence analysis of SCN8A, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• An epilepsy or intellectual disability multigene panel that includes SCN8A and other genes of interest (see Differential Diagnosis) 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. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used and yields results similar to an epilepsy or intellectual disability multigene panel, with the additional advantage that exome sequencing includes genes recently identified as causing epilepsy or intellectual disability, whereas some multigene panels may not. To date, the majority of reported SCN8A pathogenic variants are within the coding region and are therefore likely to be identified on exome sequencing. Genome sequencing is also possible.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Five different clinical phenotypes have been identified in association with pathogenic SCN8A variants. Most individuals have features that fit into one of these five phenotypes:

• Developmental and epileptic encephalopathy (DEE)
• Mild-to-moderate developmental and epileptic encephalopathy (mild/modDEE, also referred to as intermediate epilepsy or IE)
• Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE)
• Neurodevelopmental disorder with generalized epilepsy (NDDwGE)
• Neurodevelopmental disorder without epilepsy (NDDwoE)

To date, more than 500 individuals have been identified with a pathogenic variant in SCN8A [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, Berghuis et al 2015, 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, Anand et al 2016, Boerma et al 2016, Gardella et al 2016, Lelieveld et al 2016, Malcolmson et al 2016, McNally et al 2016, Møller et al 2016, Trump et al 2016, Arafat et al 2017, Braakman et al 2017, Butler et al 2017, Han et al 2017, Jain 2017, Parrini et al 2017, Rolvien et al 2017, Wagnon et al 2017, Wang et al 2017, Atanasoska et al 2018, Bagnasco et al 2018, Epilepsy Genetics Initiative 2018, Gardella et al 2018, Ko et al 2018, Kothur et al 2018, Lindy et al 2018, Liu et al 2018, Oates et al 2018, Pons et al 2018, Rim et al 2018, Tsang et al 2018, Wagnon et al 2018, Xiao et al 2018, Balciuniene et al 2019, Costain et al 2019, Denis et al 2019, Encinas et al 2019, Epifanio et al 2019, Jain et al 2019, Jang et al 2019, Johannesen et al 2019, Kim et al 2019, Liao et al 2019, Lin et al 2019, Liu et al 2019, Trivisano et al 2019, Wengert et al 2019, Xie et al 2019, Zaman et al 2019, Canafoglia et al 2020, Fatema et al 2020, Lee et al 2020, Mitta et al 2020, Pergande et al 2020, Ranza et al 2020, Schreiber et al 2020, Alagia et al 2021, Fan et al 2021, Negishi et al 2021, Solazzi et al 2021, Stringer et al 2021, Hu et al 2022, Johannesen et al 2022, Keshri et al 2022, Medlin et al 2022, Peng et al 2022].

The following description of the phenotypic features associated with this condition is based on these reports.

Genotype-Phenotype Correlations

SCN8A pathogenic variants can be either gain-of-function (GoF) or loss-of-function (LoF) variants. Several genotype-phenotype correlations have been observed:

• Affected individuals with LoF variants mostly have SCN8A-NDDwGE or SCN8A-NDDwoE, whereas affected individuals with GoF have SCN8A-DEE, SCN8A-SeLFIE, or SCN8A-mild/modDEE [Hack et al 2023]. The effectiveness of sodium channel blockers for treating epilepsy in these phenotypes is believed to be consistent with the activating effects of the SCN8A pathogenic GoF variant [Wagnon & Meisler 2015, Wagnon et al 2015a, Wagnon et al 2015b].
• Several recurrent variants are associated with specific phenotypes (see Table 6):
  • The variants c.2549G>A (p.Arg850Gln) and c.5614C>T (p.Arg1872Trp) are associated with SCN8A-DEE.
  • The variants c.4423G>A (p.Gly1475Arg), c.4850G>A (p.Arg1617Gln), c.5615G>A (p.Arg1872Gln), and c.5630G>T (p.Asn1877Ser) are associated with SCN8A-mild/modDEE.
  • The variant c.4447G>A (p.Glu1483Lys) is associated with SCN8A-SeLFIE.
• All individuals with GoF variants have epilepsy, whereas 50%-70% of individuals with LoF variants have epilepsy [Johannesen et al 2022, Hack et al 2023]. Based on these differences, early mortality has not been observed in individuals with LoF variants to date.

Penetrance

Penetrance for SCN8A-related epilepsy and/or neurodevelopmental disorders is unknown but is assumed to be complete.

Nomenclature

Alternate naming conventions for SCN8A-related phenotypes have been used in the literature [Johannesen et al 2022]:

• SCN8A-related mild-to-moderate developmental and epileptic encephalopathy (SCN8A-mild/modDEE) may also be described as SCN8A-related intermediate epilepsy (SCN8A-IE).
• SCN8A-related self-limited familial infantile epilepsy (SCN8A-SeLFIE) may also be referred to as SCN8A-related benign familial infantile epilepsy (SCN8A-BFIE).

Prevalence

The prevalence of SCN8A-related epilepsy and/or neurodevelopmental disorders is not known.

The frequency of SCN8A pathogenic variants among individuals with DEE was around 1% (51 of 3,489) across multiple independent studies, most of which included several hundred individuals [Allen et al 2013, Carvill et al 2013, Larsen et al 2015, Mercimek-Mahmutoglu et al 2015, Møller et al 2016, Trump et al 2016, Butler et al 2017, Ko et al 2018, Kothur et al 2018, Lindy et al 2018, Balciuniene et al 2019, Costain et al 2019, Heyne et al 2019, Jang et al 2019, Lee et al 2020, Mitta et al 2020].

A study evaluating the incidence of SCN8A-related disorders in the Danish population found an estimated incidence of one in 56,247 [Johannesen et al 2022].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SCN8A-related epilepsy and/or neurodevelopmental disorders, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to diagnosis) are recommended.

Treatment – Targeted Therapy

Sodium channel blockers represent a targeted treatment option for SCN8A-related focal epilepsy phenotypes (SCN8A-related developmental and epileptic encephalopathy [SCN8A-DEE], SCN8A-related mild-to-moderate developmental and epileptic encephalopathy [SCN8A-mild/modDEE], and SCN8A-related self-limited familial infantile epilepsy [SCN8A-SeLFIE]) with onset in the first year of life. See Table 4.

Treatment – Supportive Care

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Agents/Circumstances to Avoid

Several families of affected individuals report worsening of seizures, encephalopathy, and/or developmental regression with levetiracetam (Keppra^®) [Schreiber et al 2020]. However, some may respond favorably to levetiracetam, regardless of the phenotype. Therefore, careful evaluation and follow up by a neurologist is recommended.

Evaluation of Relatives at Risk

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

Therapies Under Investigation

NBI-921352, an Na_v1.6 selective sodium channel inhibitor, is currently in Phase II clinical trials for individuals with SCN8A-related developmental and epileptic encephalopathy (SCN8A-DEE) (NCT04873869) [Johnson et al 2022].

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.

Mode of Inheritance

SCN8A-related epilepsy and/or neurodevelopmental disorders are inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Some individuals diagnosed with an SCN8A-related phenotype have the disorder as the result of a de novo SCN8A pathogenic variant. Individuals with more severe SCN8A-related phenotypes are more likely to have the disorder as the result of a de novo pathogenic variant than individuals with milder SCN8A-related phenotypes.
• Some individuals diagnosed with an SCN8A-related phenotype have the disorder as the result of a pathogenic variant inherited from an affected and/or mosaic parent. Of families in which parental testing was performed, the percentage of individuals with a pathogenic variant inherited from a mosaic and/or affected parent varied by phenotype [Johannesen et al 2022]:
  • 2% (3/166) of individuals with SCN8A-related developmental and epileptic encephalopathy (DEE)
  • 10% (3/29) of individuals with SCN8A-related mild-to-moderate DEE (also referred to as intermediate epilepsy)
  • 47% (7/15) of individuals with SCN8A-related self-limited familial infantile epilepsy (also referred to as benign familial infantile epilepsy)
  • 33% (5/15) of individuals with SCN8A-related neurodevelopmental disorder (NDD) with generalized epilepsy
  • 60% (9/15) of individuals with SCN8A-related NDD without epilepsy
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level somatic mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, should therefore be considered.
    * A parent with somatic and germline mosaicism for an SCN8A pathogenic variant may be mildly/minimally affected.
• The family history of some individuals diagnosed with an SCN8A-related phenotype may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.

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

• If a parent of the proband is affected and/or is known to have the SCN8A pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• If the SCN8A pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the possibility of parental mosaicism [Johannesen et al 2022].
• If the parents have not been tested for the SCN8A pathogenic variant but are not known to have had manifestations consistent with an SCN8A-related phenotype, the sibs of a proband are still presumed to be at increased risk of an SCN8A-related phenotype because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism.

Offspring of a proband. Each child of an individual with an SCN8A-related phenotype has a 50% chance of inheriting the SCN8A pathogenic variant.

Other family members. The risk to other family members depends on the genetic status of the proband's parents: if a parent has the SCN8A pathogenic variant, the parent's family members may be at risk.

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

Once the SCN8A pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

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

Molecular Pathogenesis

SCN8A encodes the sodium channel protein type 8 subunit alpha (isoform Na_v1.6), one of four voltage-gated sodium channels expressed in the human brain and predominantly expressed in excitatory as well as inhibitory neurons. 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 (see 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.

Figure 1.

Intron-exon organization of SCN8A. Horizontal bars mark the positions of the introns of the sodium channel protein type 8 subunit alpha (Na_v1.6) superimposed on the secondary structure of the sodium channel. Adapted from Plummer et al [1998]

Most pathogenic variants associated with SCN8A-related epilepsy and/or neurodevelopmental disorders result in substitution of a single amino acid (see Figure 2 for a distribution of missense variants). 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 Na_v1.6 leads to neuronal hyperexcitability and seizures in a mouse model of SCN8A-related epilepsy with encephalopathy [Wagnon et al 2015b]. Na_v1.6 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 may have a cardiac component [Frasier et al 2016].

Figure 2.

Positions of SCN8A missense pathogenic variants in the sodium channel protein type 8 subunit alpha (Na_v1.6). The protein has four homologous domains (DI to DIV), each containing six transmembrane segments (S1-S6). Data from www.scn8a.net

Mechanism of disease causation

• Gain of function in SCN8A-related developmental and epileptic encephalopathy (DEE), SCN8A-related mild-to-moderate DEE, and SCN8A-related self-limited familial infantile epilepsy
• Loss of function in SCN8A-related neurodevelopmental disorder with generalized epilepsy and SCN8A-related neurodevelopmental disorder without epilepsy

SCN8A-specific laboratory technical considerations

• SCN8A includes 26 coding exons. The approximate position of each exon is indicated in Figure 1. During the first year of postnatal life, the "neonatal" and the "adult" exons are expressed in roughly equal proportions [O'Brien et al 2012].
• There are several alternatively spliced exons: 6A (adult) and 6N (neonatal) that encode segment 3/4 of domain I, as well as alternatively spliced exons 21A and 21N that encode segment 3/4 of domain III.
• Exon 21N is a "poison" exon that contains an in-frame stop codon and encodes a truncated protein terminating in domain III that does not have channel activity. Therefore, the reference sequence for missing exon 21 should not be used for sequence comparisons: NM_001177984.2 (ENST00000545061).
• The most complete full-length reference transcript contains exon 6N and exon 21A: NM_014191.3 (ENST00000354534).

Author Notes

Michael F Hammer, PhD (moc.liamg@ofni.a8ncs), is actively involved in clinical research regarding individuals with SCN8A-related epilepsy and related disorders. He would be happy to communicate with persons who have any questions regarding diagnosis of SCN8A-related epilepsy and/or neurodevelopmental disorders or other considerations.

John M Schreiber, MD, is actively involved in treating patients with SCN8A-related epilepsy and related disorders and is also interested in hearing from clinicians treating families affected by this disorder or in whom no causative variant has been identified through molecular genetic testing.

Contact Michael F Hammer (moc.liamg@ofni.a8ncs) to inquire about review of SCN8A variants of uncertain significance.

The Hammer lab identified the first case of SCN8A-related epilepsy and has established a registry and an online database of the clinical features of patients with pathogenic variants in SCN8A (www.scn8a.net). The Hammer lab is also performing experiments using mouse models of SCN8A-related epilepsy and/or neurodevelopmental disorders.

Acknowledgments

We thank Wishes for Elliott (www.wishesforelliott.com) for funding the first SCN8A workshop in association with an American Academy of Neurology meeting in Washington, DC (April 20, 2015).

Author History

Michael F Hammer, PhD (2016-present)
Heather C Mefford, MD, PhD; St Jude Children's Research Hospital (2016-2023)
Miriam H Meisler, PhD; University of Michigan (2016-2023)
John M Schreiber, MD (2023-present)
Jacy L Wagnon, PhD; University of Michigan (2016-2023)
Maya Xia, BA (2023-present)

Revision History

• 6 April 2023 (gm) Comprehensive updated posted live
• 25 August 2016 (bp) Review posted live
• 29 September 2015 (mfh) Original submission

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