Clinical Guidance

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

Source: GeneReviews — "SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders"

Penetrance

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

Source: GeneReviews — "SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders"

Diagnostic Criteria

No consensus clinical diagnostic criteria for SCN8A-related epilepsy and/or neurodevelopmental disorders have been published.

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.

Clinical Findings

Epilepsy features

• Childhood-onset seizures: seizure onset variable, ranges from the first few months to the first few years of life

• Development of multiple seizure types, including focal, multifocal, or generalized seizures

• May be intractable in some individuals or treatable (especially using sodium channel blockers)

Source: GeneReviews — "SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders"

Differential Diagnosis

Because the phenotypic features associated with SCN8A-related epilepsy and/or neurodevelopmental disorders are not sufficient to diagnose these conditions, all genes associated with epilepsy and/or developmental delay/ intellectual disability without other distinctive findings should be considered in the differential diagnosis. See OMIM Phenotypic Series for genes associated with:

• Autosomal dominant intellectual developmental disorders

• Autosomal recessive intellectual developmental disorders

• Nonsyndromic X-linked intellectual developmental disorders

• Syndromic X-linked intellectual developmental disorders

• Developmental and epileptic encephalopathy

• Childhood absence epilepsy

• Familial adult myoclonic epilepsy

• Familial focal epilepsy with variable foci

• Familial temporal lobe epilepsy

Source: GeneReviews — "SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders"

Management Guidelines

No clinical practice guidelines for SCN8A-related epilepsy and/or neurodevelopmental disorders have been published. 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 (if not performed as part of the evaluation that led to diagnosis) are recommended. Table 3. Recommended Evaluations Following Initial Diagnosis in Individuals with SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders

Source: GeneReviews — "SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders"

Clinical Guidance

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

Source: GeneReviews — "SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders"

Therapies Under Investigation

NBI-921352, a Nav1.6 selective sodium channel inhibitor, is currently in Phase II clinical trials for individuals with SCN8A-related developmental and epileptic encephalopathy (SCN8A-DEE) (NCT04873869) . 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.

Source: GeneReviews — "SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders"

Surveillance Guidelines

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

Table 5.

Recommended Surveillance for Individuals with SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders

System/Concern | Evaluation | Frequency

Neurologic

| • Monitor seizures as clinically indicated.

• Assess for new manifestations such as seizures, changes in tone, movement disorders.

| At each visit

Sleep

| Assess for any sleep issues/ sleep apnea.

SUDEP

| • Query for factors that SUDEP risk, incl generalized tonic-clonic seizures nighttime seizures.

• Assess seizure monitoring strategies.

Development

| Monitor developmental progress educational needs.

Psychiatric/

Behavioral

| Behavioral assessment for anxiety, attention, aggressive or self-injurious behavior

Musculoskeletal

| Physical medicine, OT/PT assessment of mobility, self-help skills

Family/Community

| Assess family need for social work support (e.g., palliative/respite care, home nursing, other local resources), care coordination, or follow-up genetic counseling if new questions arise (e.g., family planning).

OT = occupational therapy; PT = physical therapy; SUDEP = sudden unexpected death in epilepsy

Source: GeneReviews — "SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders"