Clinical Guidance

Given the variable expressivity of SCN1A disorders, consistent genotype-phenotype correlations have been infrequently identified. Pathogenic nonsense variants and missense variants in the voltage sensor or pore region often lead to a more severe phenotype . A truncation variant, however, does not necessarily result in a severe phenotype . Affected individuals with missense variants in the pore-forming region and truncations in the SCN1A protein are more likely to have gait changes . These changes may be the result of a direct effect of the SCN1A pathogenic variant in the cerebellar Purkinje cells .

Source: GeneReviews — "SCN1A Seizure Disorders"

Penetrance

SCN1A seizure disorders show incomplete penetrance and variable expressivity. Penetrance varies by phenotype. For example, estimated the penetrance to be 70% for the GEFS+ phenotype, whereas reported the penetrance to be 90% for the familial simple febrile seizure phenotype.

Source: GeneReviews — "SCN1A Seizure Disorders"

Diagnostic Criteria

Suggestive Findings

SCN1A seizure disorders encompass a spectrum of phenotypes that ranges from mild to severe. When the following suggestive features are present, SCN1A molecular genetic testing should be considered:

• Precipitation of seizure with fever, warmth, or vaccination

• Prolonged or hemiconvulsive seizures

• Seizure provocation with overstimulation or flashing/patterned visual stimulus

• Worsening of seizures with medications that inhibit sodium channel function as the primary mechanism of action (e.g., carbamazepine, oxcarbazepine, phenytoin, lamotrigine)

These features can be seen in any one of several clinical epilepsy syndromes that can occur in individuals with a heterozygous SCN1A pathogenic variant. Clinical epilepsy syndromes reported in individuals with SCN1A seizure disorders :

Source: GeneReviews — "SCN1A Seizure Disorders"

Differential Diagnosis

The phenotypes typically seen in individuals with an SCN1A pathogenic variant are neither necessary nor sufficient to diagnose an SCN1A seizure disorder. Other conditions (including those caused by pathogenic variants in other genes) may be associated with the same phenotypes. It is most important to distinguish SCN1A seizure disorders from potentially treatable conditions, including the following :

Source: GeneReviews — "SCN1A Seizure Disorders"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with an SCN1A seizure disorder, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Neurologic examination

• Cognitive neuropsychological evaluation

• Behavioral neuropsychological evaluation

• Electroencephalogram (EEG), including video EEG telemetry where ictal onset or semiology is unclear

• Consideration of polysomnography if obstructive or central sleep apnea is suspected

• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Care is best provided by a physician (e.g., pediatric epileptologist) familiar with the pharmacotherapy for this disorder. Seizure control is critical because children with SCN1A seizure disorder are at high risk for sudden unexplained death in epilepsy (SUDEP). In addition, prolonged acute seizures may cause permanent injury . Pharmacologic treatment focuses on the observations that abnormal SCN1A channels disproportionately affect GABA neurons and that the associated seizures respond optimally to anti-seizure medications (ASMs) that bind to the GABA receptor:

Source: GeneReviews — "SCN1A Seizure Disorders"

Clinical Guidance

Several ASMs that are effective for most forms of epilepsy can worsen SCN1A-related seizures:

• Carbamazepine, lamotrigine, and vigabatrin, which can induce or increase myoclonic seizures

• Phenytoin, which may worsen seizures and can induce choreoathetosis

• Rufinamide, which has a pharmacologic mechanism similar to carbamazepine and phenytoin and may exacerbate seizures as well

• Acetaminophen, which is hepatotoxic in overdose. Given the possibility of interaction with anticonvulsant medications, especially valproate and topiramate , acetaminophen should be avoided. Any of the NSAIDs are effective as antipyretics, and represent much lower risk.

Activities in which a sudden loss of consciousness could lead to injury or death should be avoided (e.g., bathing, swimming, driving, or working/playing at heights).

Source: GeneReviews — "SCN1A Seizure Disorders"

Therapies Under Investigation

Thalamic deep brain stimulation (DBS) was reported by in two children with Dravet syndrome with ten-year follow up. One showed "marked improvement" after implantation, whereas the other received no benefit. Lacosamide has not been studied in SCN1A seizure disorders; however, there are theoretic reasons why it may be effective . Verapamil was reported to help two girls with severe epilepsy resulting from SCN1A pathogenic variants ; however, it has not been formally studied. Search ClinicalTrials.gov in the US for access to information on clinical studies for SCN1A seizure disorders and a wide range of other diseases and conditions. Search EU Clinical Trials Register in Europe.

Source: GeneReviews — "SCN1A Seizure Disorders"

Surveillance Guidelines

• Serial neuropsychological evaluation for neurologic, cognitive, and behavioral deterioration is appropriate.

• Clinical examination for scoliosis and impaired gait at each office visit

• EEG monitoring is appropriate when new or different seizure types are suspected.

• Polysomnography should be considered if obstructive or central sleep apnea is suspected.

Source: GeneReviews — "SCN1A Seizure Disorders"