SCN2A encephalopathy: A major cause of epilepsy of infancy with migrating focal seizures

Abstract

Objective: De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy.

Methods: Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping.

Results: Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1-4 in 8, week 2-6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to profound developmental impairment. Other features included movement disorders (10), axial hypotonia (11) with intermittent or persistent appendicular spasticity, early handedness, and severe gastrointestinal symptoms. Mutations arose de novo in 11 patients; paternal DNA was unavailable in one.

Conclusions: Review of our 12 and 34 other reported cases of SCN2A encephalopathy suggests 3 phenotypes: neonatal-infantile-onset groups with severe and intermediate outcomes, and a childhood-onset group. Here, we show that SCN2A is the second most common cause of EIMFS and, importantly, does not always have a poor developmental outcome. Sodium channel blockers, particularly phenytoin, may improve seizure control.

Figure 1. Location of mutations in SCN2A

Mutations are denoted as follows: green = benign familial neonatal infantile seizures; orange = intermediate neonatal-infantile phenotype; red = severe neonatal-infantile phenotype; blue = childhood phenotype; black = intellectual disability without epilepsy; squares = cases in this study; circles = other published cases; 2 (in circles) = mutations at the same residue to 2 different amino acids.

Figure 2. Interictal and ictal EEG features in SCN2A encephalopathy

(A) Interictal EEG in sleep in patient 7 (severe neonatal-infantile phenotype) at age 3 months showing disorganized background with absence of sleep spindles, and frequent multifocal polymorphic interictal epileptiform discharges. (B) Interictal EEG in sleep in patient 9 (intermediate neonatal-infantile phenotype) at age 3 months showing normal background activity including sleep spindles, with frequent multifocal polymorphic interictal epileptiform discharges. (C) Focal seizure in patient 5 at age 4 months arising from the left frontal region in C.a, with intraictal activation of a contralateral ictal rhythm of different frequency beginning in C.b, which recruits over the right parieto-occipital region in C.c. Both rhythms terminate in C.d.

Figure 3. MRI brain scans of patients with SCN2A encephalopathy

(A) T2-weighted axial MRI of patient 6 at age 3 days showing T2 hyperintensity in the white matter (arrow). (B) T2-weighted sagittal MRI of patient 8 at age 18 days showing T2 hyperintensity in the pons (arrow). (C) T2-weighted axial MRI of patient 9 at age 60 days showing T2 hyperintensity in the white matter posteriorly (arrow). (D) T2-weighted axial MRI of patient 9 at age 22 months showing normal white matter including normal terminal zones of myelination and resolution of the white matter signal abnormality.

Figure 4. Clinical features in SCN2A epilepsy phenotypic groups

Gray scale denotes severity: light color = mild; darker color = severe. Ep = epilepsy; ID = intellectual disability; MD = movement disorder.