Clinical Guidance

The most common recurrent SCN3A pathogenic variant is , identified in 26% of individuals with SCN3A-NDD [, , , , ]. 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.

Source: GeneReviews — "SCN3A-Related Neurodevelopmental Disorder"

Diagnostic Criteria

Clinical diagnostic criteria for SCN3A-related neurodevelopmental disorder (SCN3A-NDD) have not been published.

Suggestive Findings

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

Clinical features

Source: GeneReviews — "SCN3A-Related Neurodevelopmental Disorder"

Differential Diagnosis

The phenotype(s) observed in SCN3A-related neurodevelopmental disorder (SCN3A-NDD) are not sufficient to diagnose an SCN3A-NDD without genetic testing, as other conditions may be associated with clinical features and neuroimaging findings within the same range of phenotypes. Epilepsy. The epilepsy phenotype of SCN3A-NDD cannot be definitively distinguished from other causes of early-infantile epileptic encephalopathies (80 genetic causes have been identified; see OMIM Phenotypic Series). Malformation of cortical development (MCD). A key element of the differential diagnosis is to distinguish SCN3A-NDD from other causes of MCD as these may be associated with a different clinical course and/or mode of inheritance. Other causes of MCD include:

Source: GeneReviews — "SCN3A-Related Neurodevelopmental Disorder"

Management Guidelines

Treatment of SCN3A-related neurodevelopmental disorder (SCN3A-NDD) is best led by a physician familiar with pharmacotherapy of treatment-resistant epilepsy, such as a pediatric neurologist or pediatric epileptologist. No clinical practice guidelines for SCN3A-NDD have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with SCN3A-NDD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 4. Recommended Evaluations Following Initial Diagnosis in Individuals with SCN3A-Related Neurodevelopmental Disorder

Source: GeneReviews — "SCN3A-Related Neurodevelopmental Disorder"

Clinical Guidance

There is NO evidence that:

• Specific anti-seizure medications can worsen seizures associated with SCN3A-NDD;

• Sleep deprivation or fever exacerbates seizures associated with SCN3A-NDD.

Source: GeneReviews — "SCN3A-Related Neurodevelopmental Disorder"

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-NDD based on theoretic considerations [, , , ]. 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.

Source: GeneReviews — "SCN3A-Related Neurodevelopmental Disorder"

Surveillance Guidelines

Table 6. Recommended Surveillance for Individuals with SCN3A-Related Neurodevelopmental Disorder

Source: GeneReviews — "SCN3A-Related Neurodevelopmental Disorder"