SCN3A-Related Neurodevelopmental Disorder

Clinical characteristics.

SCN3A-related neurodevelopmental disorder (SCN3A-ND) encompasses a spectrum of clinical severity associated with epilepsy and/or brain malformation. Affected individuals may have (a) developmental and epileptic encephalopathy (DEE) (i.e., intractable seizures with developmental delays associated with ongoing epileptiform EEG activity) with or without malformations of cortical development; or (b) malformations of cortical development with or without mild focal epilepsy. Some degree of early childhood developmental delay is seen in all affected individuals; the severity varies widely, ranging from isolated speech delay to severe developmental delay. Infantile hypotonia is common but may be mild or absent in those without DEE. In those with DEE, seizure onset is typically in the first six to 12 months of life. A variety of seizure types have been described. Seizures remain intractable to multiple anti-seizure medications in approximately 50% of individuals with DEE without malformations of cortical development (MCD) and in 90% of individuals with DEE and MCD. Seizures may be absent or infrequent in those without DEE. Brain MRI findings range from normal to showing thinning or hypoplasia of the corpus callosum, to various malformations of cortical development. Autonomic dysregulation, oromotor dysfunction leading to the need for gastrostomy tube placement, progressive microcephaly, hyperkinetic movement disorder, and cortical visual impairment can also be seen in those with DEE.

Diagnosis/testing.

The diagnosis of SCN3A-related neurodevelopmental disorder is established in a proband with suggestive findings and a heterozygous pathogenic variant in SCN3A identified by molecular genetic testing.

Management.

Treatment of manifestations: Empiric treatment of seizures with standard anti-seizure medications (no specific anti-seizure medication has been shown to be more efficacious than another); feeding therapy and consideration of gastrostomy tube placement in those with dysphagia; standard treatment for developmental delay / intellectual disability, spasticity, hyperkinetic movements, autonomic dysfunction, and central visual impairment.

Surveillance: At each visit: measurement of growth parameters; evaluation for signs/symptoms of a movement disorder or autonomic dysfunction; monitor for new seizures or changes in seizures; assessment of developmental progress, educational needs, behavioral issues, mobility and self-help skills; annual ophthalmology evaluation to assess for visual impairment.

Agents/circumstances to avoid: There is no evidence that specific anti-seizure medications can worsen seizures associated with SCN3A-ND. There is no evidence that sleep deprivation or fever exacerbate seizures associated with SCN3A-ND.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early treatment.

Pregnancy management: Use of anti-seizure medication during pregnancy reduces the risk for mortality during pregnancy, but exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). The risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible.

Genetic counseling.

SCN3A-ND is inherited in an autosomal dominant manner. The majority of probands diagnosed with SCN3A-ND have the disorder as the result of a de novo pathogenic variant. If a parent of the proband is affected and/or is known to have the SCN3A pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Once the SCN3A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Suggestive Findings

SCN3A-ND should be considered in individuals with the following clinical features, seizure types, brain MRI findings, and/or family history.

Clinical features

• Intractable seizures beginning in the first year of life, particularly in the first month of life (median age 2 weeks)
• Developmental delay or intellectual disability, often in the severe-to-profound range in those with early-onset developmental and epileptic encephalopathy (DEE)
• Progressive microcephaly
• Ictal or non-ictal autonomic disturbances, including facial flushing, sweating, apnea and desaturation, anisocoria, and bradycardia
• Significant axial hypotonia, often progressing to spastic quadriplegia
• Oromotor dyspraxia and dysarthria in individuals with malformations of cortical development with or without mild focal epilepsy.

Seizure types

• Generalized and focal tonic seizures (the most common presenting seizure type)
• Focal autonomic seizures
• Focal motor seizures
• Epileptic spasms

Brain MRI findings

• Bilateral dysgyria, pachygyria, or polymicrogyria that can be focal, multifocal, or diffuse (affecting all lobes of the neocortex)
• Less commonly, other malformations of cortical development with features of lissencephaly
• Hypoplasia of the corpus callosum with or without malformation of cortical development
• Cerebral atrophy

Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Note: (1) A positive family history is often seen in individuals without DEE. (2) Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of SCN3A-ND is established in a proband with suggestive findings and a heterozygous pathogenic (or likely pathogenic) variant in SCN3A identified by molecular genetic testing (see Table 1).

Note: (1) 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. (2) Identification of a heterozygous SCN3A variant of uncertain significance does not establish or rule out the diagnosis of this disorder.

Because the phenotype of SCN3A-ND is broad and sometimes indistinguishable from other inherited disorders with seizures and/or malformations of cortical development, molecular genetic testing typically includes either a multigene panel or exome sequencing.

Note: Single-gene testing (sequence analysis of SCN3A, followed by gene-targeted deletion/duplication analysis) is typically NOT recommended.

An epilepsy or brain malformation multigene panel that includes SCN3A 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; 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

SCN3A-related neurodevelopmental disorder (SCN3A-ND) encompasses a spectrum of clinical severity associated with epilepsy and/or malformation of cortical development (MCD). Affected individuals may have developmental and epileptic encephalopathy (DEE) (i.e., intractable seizures with developmental delays associated with ongoing epileptiform EEG activity) with or without MCD, or MCD with or without mild focal epilepsy.

To date, 38 individuals from 31 families have been identified with a pathogenic variant in SCN3A [Iossifov et al 2014, Lamar et al 2017, Trujillano et al 2017, Miyatake et al 2018, Smith et al 2018, Tumienė et al 2018, Zaman et al 2018, Li et al 2019, Inuzuka et al 2020, Zaman et al 2020, Ziats et al 2020]. The following summarizes the clinical findings in these individuals.

SCN3A-ND represents a clinical spectrum in which three main phenotypes are described:

• Developmental and epileptic encephalopathy without malformation of cortical development: 6/38 (16%) of affected individuals [Lamar et al 2017, Zaman et al 2020, Inuzuka et al 2020]
• Developmental and epileptic encephalopathy with malformation of cortical development: 16/38 (42%) of affected individuals [Miyatake et al 2018, Smith et al 2018, Zaman et al 2018, Li et al 2019, Inuzuka et al 2020, Zaman et al 2020, Ziats et al 2020]
• Malformation of cortical development with or without mild focal epilepsy: 13/38 (34%) of affected individuals [Smith et al 2018, Zaman et al 2020]

Note: One known affected individual was a fetus whose clinical features could not be further categorized. Two additional individuals with pathogenic SCN3A variants could not be categorized because of incomplete clinical and neuroimaging data [Iossifov et al 2014, Zaman et al 2020].

Because the small number of recognized affected individuals with each phenotype and the fact that the clinical overlap between these phenotypes is broad, the following discussion applies to all three phenotypes.

Developmental delay (DD) / intellectual disability (ID). Some degree of early childhood DD is seen in all affected individuals – although the severity varies widely, ranging from isolated speech delay to severe developmental delay.

In those with intractable seizures with ongoing epileptiform EEG activity:

• All affected individuals have severe-to-profound developmental delays and are nonverbal and nonambulatory.
• Ongoing ID is present in older individuals, ranging from severe to profound.

In those who have mild focal epilepsy or no epilepsy, long-term cognitive outcomes include:

• Normal cognition in 2/11 (18%)
• Borderline/mild ID in 7/11 (64%)
• Moderate/severe ID in 2/11 (18%)

Neurologic. Most affected individuals have infantile hypotonia, although this may be absent or mild in those who have mild focal epilepsy or no epilepsy.

• In individuals with DEE, neurologic examination typically reveals significant truncal or generalized hypotonia with prominent head lag in younger children.
• In those with malformation of cortical development:
  • Hypotonia often progresses to spastic quadriplegia in later childhood in those who also have DEE;
  • In those without DEE, older individuals may have pyramidal signs, mild spasticity, or mild hemiparesis.

Epilepsy. The type and course of seizures are variable, and depend on whether an affected individual has DEE and on the presence or absence of a malformation of cortical development.

In those with DEE:

• Seizure onset is typically in the first six to 12 months of life, most often in the first week of life (median age 1-2 weeks), although seizure onset can range from day of birth to age five years.
• The most common presenting seizure types in those without MCD are generalized tonic seizures or epileptic spasms. In those with MCD, the most common presenting seizure types are generalized tonic and focal autonomic seizures.
  Tonic seizures may have a prominent autonomic or apneic component, consistent with apparent life-threatening events (ALTEs) in infants.
• Affected individuals typically develop additional seizure types, which can include the following:
  • Epileptic spasms
  • Generalized tonic-clonic seizures
  • Myoclonic seizures
  • Focal tonic seizures
  • Focal impaired awareness seizures
  • Focal autonomic seizures
  • Focal motor seizures
• Seizures remain intractable to multiple anti-seizure medications in approximately 50% of individuals without MCD and in 90% of individuals with MCD.

In those with MCD without DEE:

• A majority (11/13; 85%) do not have a history of seizures or epilepsy;
• A minority (2/13; 15%) have a single unprovoked focal or generalized tonic-clonic seizure in late childhood or adolescence not requiring anti-seizure medication.

EEG findings. The DEEs include many defined syndromes characterized by a range of seizure types and EEG findings. Interictal EEG patterns include diffuse, multifocal, or focal slowing; generalized or multifocal epileptiform discharges; burst-suppression seen in Ohtahara syndrome; attenuation/low voltage; generalized polyspike-wave or slow spike-wave discharges; hypsarrhythmia as seen in association with infantile spasms syndrome; and others. EEG findings seen in SCN3A-ND may include:

• Multifocal epileptiform discharges or hypsarrhythmia in those with DEE but without MCD;
• Burst-suppression early in the disease course, then multifocal epileptiform discharges, and hypsarrhythmia in those with MCD;
• Focal epileptiform abnormalities on EEG even in the absence of clinical seizures in 70% (10/13) of reported individuals with SCN3A-ND with MCD without DEE.

Brain MRI findings can vary from normal to showing thinning or hypoplasia of the corpus callosum to various malformations of cortical development (see Suggestive Findings, Brain MRI findings and Figure 1) [Smith et al 2018, Zaman et al 2020]. As some individuals with severe DEE are without MCD, the presence and extent of MCD does not appear to correlate with clinical phenotype. However, diffuse dysgyria is typically associated with severe/profound DEE (14/15; 93%), while focal unilateral or bilateral perisylvian polymicrogyria (PMG) is most often seen in those with a more mild phenotype ranging from normal neurocognitive function to mild/moderate ID, and no history or seizures or infrequent seizures only (11/13; 85%).

Autonomic dysregulation. Ictal and/or non-ictal autonomic disturbances are observed in 45% (9/20) of individuals with DEE [Lamar et al 2017, Zaman et al 2020]. Features include episodes of the following:

• Asymmetric or unilateral flushing / color change of the face, which may be confused with Harlequin syndrome
• Brady- or tachycardia
• Apnea and cyanosis with oxygen desaturation
• Excessive sweating
• Anisocoria with sluggish pupillary response to light

These episodes may occur several times per day and may or may not be associated with ictal abnormalities on EEG.

Oropharyngeal/Feeding

• Oromotor dysfunction is seen in a majority of individuals [Smith et al 2018, Zaman et al 2020], and represents a prominent component of the clinical presentation in those with SCN3A-ND who have bilateral perisylvian PMG. Clinical features may include the following:
  • Abnormal tongue movements
  • Speech/language difficulties, including dysarthria
  • Difficulties whistling, blowing
  • Abnormal brisk jaw jerk
• Some affected individuals with the severe SCN3A-ND phenotype exhibit chronic failure to thrive with G-tube dependence for feeding.

Other associated features in some individuals with DEE:

• Progressive microcephaly
• Dyskinesia, including choreoathetosis in those without MCD and dystonia and/or hyperkinetic movements in those with MCD [Zaman et al 2020]
• Cortical visual impairment
• Features of autism spectrum disorder
• Early-childhood death in two individuals, one due to sudden unexpected death in epilepsy and the other of an undetermined cause [Zaman et al 2020]

Genotype-Phenotype Correlations

c.2624T>C (p.Ile875Thr) is the most common recurrent pathogenic variant, identified in 26% of individuals with SCN3A-ND [Miyatake et al 2018, Smith et al 2018, Zaman et al 2018, Li et al 2019, Zaman et al 2020]. The phenotype associated with this variant is relatively homogeneous, severe, and with poor outcomes from a developmental and epilepsy management perspective. Clinical features include:

• Profound developmental delay / intellectual disability (in 10/10 individuals; 100%)
• Neonatal onset intractable seizures (median onset 2 weeks) (8/9; 89%)
• Multiple seizure types, often generalized tonic seizures
• Diffuse, bilateral polymicrogyria (10/10; 100%)
• Microcephaly (7/9;78%)
• Paroxysmal ictal and non-ictal autonomic dysregulation (4/9; 44%)

A clear genotype-phenotype correlation between other variants or classes of variants has not yet been established.

Nomenclature

Outdated terms previously used to describe SCN3A-ND:

• Cryptogenic pediatric partial epilepsy
• Epilepsy, familial focal, with variable foci 4
• Epileptic encephalopathy, early infantile, 62

Prevalence

The prevalence of SCN3A-ND is not known. Approximately 38 individuals have been reported in the literature to date. Due to the de novo nature of SCN3A pathogenic variants associated with DEE phenotypes, it is expected that the prevalence is consistent across populations.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SCN3A-ND, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Surveillance

Agents/Circumstances to Avoid

There is NO evidence that:

• Specific anti-seizure medications can worsen seizures associated with SCN3A-N;
• Sleep deprivation or fever exacerbates seizures associated with SCN3A-ND.

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early treatment.

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

Pregnancy Management

In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [Sarma et al 2016].

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Therapeutic trials of anti-seizure medications that target sodium channels may be indicated in cases of severe, treatment-resistant epilepsy or epileptic encephalopathy associated with SCN3A-ND based on theoretic considerations [Zaman et al 2018, Brunklaus 2020, Musto et al 2020, Zaman et al 2020].

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.

Mode of Inheritance

SCN3A-ND is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• The majority of probands diagnosed with SCN3A-ND have the disorder as the result of a de novo pathogenic variant [Iossifov et al 2014, Lamar et al 2017, Trujillano et al 2017, Miyatake et al 2018, Smith et al 2018, Tumienė et al 2018, Zaman et al 2018, Li et al 2019, Inuzuka et al 2020, Zaman et al 2020, Ziats et al 2020].
  All probands with SCN3A-related developmental and epileptic encephalopathy (DEE) reported to date have represented simplex cases (i.e., the only affected family member) and are presumed to have the disorder as the result of a de novo pathogenic variant.
• Vertical transmission of an SCN3A pathogenic variant from an affected parent to an affected child has been reported in one family. In this family, the proband inherited a pathogenic SCN3A variant from a similarly affected parent [Zaman et al 2020]. The affected parent had bilateral perisylvian polymicrogyria, a single generalized tonic-clonic seizure at age five years, oromotor dysfunction, and mild intellectual disability.
• Transmission of an SCN3A pathogenic variant from an apparently unaffected parent to a proband has been reported in three families [Smith et al 2018, Zaman et al 2020]. (Note: True penetrance estimates cannot be calculated based on these families because the apparently asymptomatic heterozygous family members did not undergo complete neurologic, neuroimaging, and EEG examinations to evaluate for more subtle presentations of disease.)
• 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, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant. Note: A pathogenic variant is reported as "de novo" if: (1) the pathogenic variant found in the proband is not detected in parental DNA; and (2) parental identity testing has confirmed biological maternity and paternity. If parental identity testing is not performed, the variant is reported as "assumed de novo" [Richards et al 2015].
  • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
    Parental mosaicism not been reported in SCN3A-ND to date; however, it is estimated that approximately 10% of individuals (who represent simplex cases) with any form of genetic developmental and epileptic encephalopathy have the disorder as the result of a pathogenic variant inherited from an asymptomatic, mosaic parent [Myers et al 2018].
• The family history of some individuals diagnosed with SCN3A-ND may appear to be negative because of failure to recognize the disorder in family members (possibly because family members have not undergone neuroimaging or a thorough neurologic examination to evaluate for oromotor dysfunction). 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 genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the SCN3A pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%.
• The likelihood that a sib who inherits an SCN3A pathogenic variant will have manifestations similar to those of the proband is unknown. Although three multiplex families have been reported with heterozygous family members with no apparent manifestations of SCN3A-ND [Smith et al 2018, Zaman et al 2020], penetrance cannot be estimated based on these families because the purportedly asymptomatic heterozygous family members did not undergo detailed evaluation (including neurologic examination, neuroimaging, and EEG), which would detect milder manifestations of the disorder such as early speech/language delay and focal brain malformation.
• If the proband has a known SCN3A pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is estimated to be 1%-2% because of the theoretic possibility of parental germline mosaicism [Rahbari et al 2016]. Although parental mosaicism has not been reported in SCN3A-ND, it is estimated that approximately 10% of individuals (who represent simplex cases) with any form of genetic developmental and epileptic encephalopathy have the disorder as the result of a pathogenic variant inherited from an asymptomatic, mosaic parent [Myers et al 2018].
• If the parents have not been tested for the SCN3A pathogenic variant but have undergone detailed evaluation (including neurologic examination, neuroimaging, and EEG) and are clinically unaffected, the risk to the sibs of a proband appears to be low; however, sibs are still presumed to be at increased risk for SCN3A-ND because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism.

Offspring of a proband. Each child of an individual with SCN3A-ND has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the SCN3A pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

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 and young adults who are affected.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the SCN3A 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

SCN3A encodes the type III voltage-gated sodium (Na+) α subunit Nav1.3. Voltage-gated Na+ channels are molecular complexes formed by one pore-forming α-subunit, two non-pore-forming auxiliary β-subunits, and accessory proteins that regulate localization, cell surface expression, and channel physiology. The α subunits – including Nav1.3 – are 24-pass transmembrane proteins with four domains (DI-IV), each of which contains six subunits (S1-6); subunit 4 of each domain is known to be critical for sensing transmembrane voltage (the "voltage sensor") and transducing this into mechanical changes that alter channel gating. Subunits S5-6 of each domain form the channel pore through which Na+ flux occurs [Catterall 2000, Catterall 2012].

Pathogenic missense variants that cause SCN3A-related neurodevelopmental disorder are located throughout the Nav1.3 channel protein, although the pathogenic variants identified in cases of severe or profound developmental disability appear to be clustered in S4-6 of DII-IV (Figure 2) [Miyatake et al 2018, Zaman et al 2018, Inuzuka et al 2020, Zaman et al 2020].

SCN3A is known to be expressed in the developing brain of rodents [Beckh et al 1989, Felts et al 1997] and humans [Whitaker et al 2000] including in radial glia, in intermediate progenitor cells, and in developing neurons [Pollen et al 2015, Smith et al 2018]. In utero electroporation of disease-associated variant SCN3A DNA into fetal ferret brain produced polymicrogyria. How pathogenic variants in a Na+ channel might lead to malformation of cortical development (MCD) such as polymicrogyria, pachygyria, or other dysgyria, is not known, but may relate to abnormal electrogenesis in developing/migrating neurons or neuronal progenitors.

Pathogenic variants in SCN3A lead to alterations in the amino acid sequence of Nav1.3 and have been shown to alter the biophysical function of the channel in various ways. Electrophysiologic recordings in heterologous systems demonstrate increased slowly-inactivating ("persistent") Na+ current and impaired fast inactivation, consistent with gain of function at the ion channel level. How dysfunction at the channel level impacts the function of neurons and neuronal circuits to produce seizures and epilepsy is unclear.

Mechanism of disease causation. Gain of function

Author Notes

Ethan M Goldberg is Assistant Professor in the Division of Neurology at the Children's Hospital of Philadelphia and Department of Neurology & Neuroscience at the University of Pennsylvania Perelman School of Medicine and Attending Physician in the Neurogenetics Clinic at the Children's Hospital of Philadelphia. His laboratory studies mechanisms of epilepsy in experimental models of genetic epilepsies including of SCN3A-related neurodevelopmental disorder.

The Epilepsy Neurogenetics Initiative at Children's Hospital of Philadelphia integrates genetic testing into the comprehensive care plan of children with difficult-to-treat or unexplained epilepsies and provides access to expert care for children with genetic epilepsy syndromes. Our team of child neurologists and genetic counselors has particular expertise in the clinical care of children with SCN3A-related neurodevelopmental disorder. More information can be found at www.chop.edu.

Revision History

• 4 November 2021 (ma) Revision: frequency of de novo SCN3A-ND clarified (Risk to Family Members)
• 3 June 2021 (ma) Review posted live
• 9 November 2020 (klh) Original submission

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