Rationale:
Heterozygous pathogenic variants in SCN2Aare an important cause of the developmental-epileptic encephalopathies (DEE) of infancy and early childhood. The predictors of and relationship between long-term seizure and developmental outcomes are still to be understood.
Method:
A review of the hospital records of children who underwent comprehensive evaluation and next generation sequencing demonstrating ACMG class 4 or 5 variants in the SCN2A gene was conducted. A follow-up period of 1 year with developmental information was mandatory for inclusion. In addition to electro-clinical syndromic diagnosis and seizure frequency data, the developmental status at baseline and last available follow-up was assessed in a retrospective case-note analysis using historical details and Denver developmental quotient.
Results:
In the study period between 2000-2019 out of 52 children diagnosed with SCN2A-related epilepsy, 29 children had long term developmental data documented on serial follow-up. Novel genetic variants were identified in 12 (41.4%). Denovo inheritance was established in 25 (85.7%) and a familial variant was noted in 1 child. Variant subtypes included heterozygous missense in 27, deletion in 1 and compound heterezygous in 1.The lag-time to genetic diagnosis ranged from 3 months to 17 yrs. Early infantile-onset epilepsy (< 6months ) was noted in 25 (86.2%) with 19 (65.5%) presenting as neonatal-onset epilepsy. Onset >1yr age was noted in 4 (13.8%). The age at onset ranged from 1-1095 days. Family history of epilepsy was apparent in 8 (28.6%). Electro-clinical diagnosis at baseline included focal epilepsy (unknown cause) in 14 (48.3%), DEE with suppression burst in 8 (27.6%), West syndrome in 2 (6.9%), epilepsy of infancy with migrating focal seizures in 2 (6.9%) and self-limited familial epilepsy in 3 (10.3%). At last follow-up global developmental delay was apparent in 21 (72.4%) with co-existent autism (27.6%) in 8 and specific language, learning or social disorder in 4 (13.8%). Neurological deficits included spasticity in 14 (48.3%), cortical visual impairment in 8 (27.6%) and movement disorders in 9 (31%). One patient had a co-existent malformation of cortical development (MCD). Non-specific MRI findings were noted in 16(55.2%). After exclusion of 2 children established as self-limited familial epilepsy, comparisons between a) neonatal-onset (17) and post-neonatal onset (10) DEE and b) between drug-resistant (17 ) and seizure free patients (10) are detailed in Tables 1 and 2 respectively. One patient underwent epilepsy surgery for MCD and continues to remain drug refractory.
Conclusion:
SCN2A mediated epilepsy is an important cause of DEE with heterogeneous phenotypes, resulting in significant morbidity. Early genetic diagnosis is paramount to improving seizure outcomes which may not necessarily translate to normalisation of the developmental trajectory. With the caveat that this was a retrospective study, neonatal onset DEE is associated with more significant developmental delay, background EEG abnormalities at baseline and non lateralized ictal rhythms. Factors associated with long-term seizure freedom include an early genetic diagnosis, low seizure frequency at 1 year of follow-up, less developmental lag at last follow-up, family history of seizures, absence of epileptic spasm as a seizure subtype and response to sodium channel blocking drugs, especially carbamazepine.
Funding:
:Commonwealth Scholarship Commission (This work was done during the period of Commonwealth Medical Fellowship of RNM- Fellowship no. INCM-2018-165)
FIGURES
Figure 1