UNASSIGNED: The aim of this study was to analyze the phenotypic spectrum, treatment, and prognosis of 72 Chinese children with SCN2A variants.
UNASSIGNED: The SCN2A variants were detected by next-generation sequencing. All patients were followed up at a pediatric neurology clinic in our hospital or by telephone.
UNASSIGNED: In 72 patients with SCN2A variants, the seizure onset age ranged from the first day of life to 2 years and 6 months. The epilepsy phenotypes included febrile seizures (plus) (n = 2), benign (familial) infantile epilepsy (n = 9), benign familial neonatal-infantile epilepsy (n = 3), benign neonatal epilepsy (n = 1), West syndrome (n = 16), Ohtahara syndrome (n = 15), epilepsy of infancy with migrating focal seizures (n = 2), Dravet syndrome (n = 1), early infantile epileptic encephalopathy (n = 15), and unclassifiable developmental and epileptic encephalopathy (n = 8). Approximately 79.2% (57/72) patients had varying degrees of developmental delay. All patients had abnormal MRI findings with developmental delay. 91.7% (55/60) patients with de novo SCN2A variants had development delay, while only 16.7% (2/12) patients with inherited SCN2A variants had abnormal development. 83.9% (26/31) SCN2A variants that were located in transmembrane regions of the protein were detected in patients with development delay. Approximately 69.2% (9/13) SCN2A variants detected in patients with normal development were located in the non-transmembrane regions. Approximately 54.2% (39/72) patients were seizure-free at a median age of 8 months. Oxcarbazepine has been used by 38 patients, and seizure-free was observed in 11 of them (11/38, 28.9%), while 6 patients had seizure worsening by oxcarbazepine. All 3 patients used oxcarbazepine and with seizure onset age > 1 year presented seizure exacerbation after taking oxcarbazepine. Valproate has been used by 53 patients, seizure-free was observed in 22.6% (12/53) of them.
UNASSIGNED: The phenotypic spectrum of SCN2A-related epilepsy was broad, ranging from benign epilepsy in neonate and infancy to severe epileptic encephalopathy. Oxcarbazepine and valproate were the most effective drugs in epilepsy patients with SCN2A variants. Sodium channel blockers often worsen seizures in patients with seizure onset beyond 1 year of age. Abnormal brain MRI findings and de novo variations were often related to poor prognosis. Most SCN2A variants located in transmembrane regions were related to patients with developmental delay.

Pathogenic variants of the SCN2A gene (MIM 182390) are associated with several epileptic syndromes ranging from benign familial neonatal-infantile seizures (BFNIS) to early infantile epileptic encephalopathy. The aim of this work was to describe clinical features among five patients with concomitant SCN2A gene variants and cryptogenic epileptic syndromes, thus expanding the SCN2A spectrum of phenotypic heterogeneity. De novo variants were identified in four patients, while one inherited variant was identified in a patient with an unaffected carrier biological father with somatic mosaicism. Two of five patients were diagnosed with a neonatal epileptic encephalopathy. The remaining three patients manifested a focal epileptic syndrome associated with autistic spectrum disorders (ASD) or with a variable degree of intellectual disability (ID), one of them displaying a hitherto unreported atypical late onset epilepsy. Overall, the pattern of clinical manifestations among these patients suggest that any observed neurological impairment may not be directly related to the severity of the electroclinical pattern, but instead likely associated with the mutation itself. Moreover, our results highlight the importance of SCN2A mutational screening in cases of ID/ASD with or without epilepsy.

Large-scale genetic studies revealed SCN2A as one of the most frequently mutated genes in patients with neurodevelopmental disorders. SCN2A encodes for the voltage-gated sodium channel isoform 1.2 (Nav 1.2) expressed in the neurons of the central nervous system. Homozygous knockout (null) of Scn2a in mice is perinatal lethal, whereas heterozygous knockout of Scn2a (Scn2a+/- ) results in mild behavior abnormalities. The Nav 1.2 expression level in Scn2a+/- mice is reported to be around 50-60% of the wild-type (WT) level, which indicates that a close to 50% reduction of Nav 1.2 expression may not be sufficient to lead to major behavioral phenotypes in mice. To overcome this barrier, we characterized a novel mouse model of severe Scn2a deficiency using a targeted gene-trap knockout (gtKO) strategy. This approach produces viable homozygous mice (Scn2agtKO/gtKO ) that can survive to adulthood, with about a quarter of Nav 1.2 expression compared to WT mice. Innate behaviors like nesting and mating were profoundly disrupted in Scn2agtKO/gtKO mice. Notably, Scn2agtKO/gtKO mice have a significantly decreased center duration compared to WT in the open field test, suggesting anxiety-like behaviors in a novel, open space. These mice also have decreased thermal and cold tolerance. Additionally, Scn2agtKO/gtKO mice have increased fix-pattern exploration in the novel object exploration test and a slight increase in grooming, indicating a detectable level of repetitive behaviors. They bury little to no marbles and have decreased interaction with novel objects. These Scn2a gene-trap knockout mice thus provide a unique model to study pathophysiology associated with severe Scn2a deficiency.

Pathogenic variants in the SCN2A gene are associated with a variety of neurodevelopmental phenotypes, defined in recent years through multicenter collaboration. Phenotypes include benign (self-limited) neonatal and infantile epilepsy and more severe developmental and epileptic encephalopathies also presenting in early infancy. There is increasing evidence that an important phenotype linked to the gene is autism and intellectual disability without epilepsy or with rare seizures in later childhood. Other associations of SCN2A include the movement disorders chorea and episodic ataxia. It is likely that as genetic testing enters mainstream practice that new phenotypic associations will be identified. Some missense, gain of function variants tend to present in early infancy with epilepsy, whereas other missense or truncating, loss of function variants present with later-onset epilepsies or intellectual disability only. Knowledge of both mutation type and functional consequences can guide precision therapy. Sodium channel blockers may be effective antiepileptic medications in gain of function, neonatal and infantile presentations.

BACKGROUND: Migrating focal seizures of infancy are characterized by seizure onset within 7 months of age, migrating focal motor seizures with multifocal ictal electroencephalography discharges intractable to conventional antiepileptic drugs, and poor prognosis. Reported genetic etiologies include SCN1A and KCNT1 mutations and homozygous deletion of the PLCB1 gene. Here we report a novel SCN2A mutation in a child with this syndrome.
METHODS: A 7-week-old girl was admitted to our hospital for management of status epilepticus. She was the product of a full-term unremarkable pregnancy. Seizures started around 5 weeks of age and remained medically refractory. Electroencephalography showed multifocal epileptiform discharges as well as seizures arising from multifocal regions in both cerebral hemispheres. Based on her phenotype, a diagnosis of migrating focal seizures of infancy was made.
RESULTS: A novel de novo missense mutation was identified in the SCN2A gene, exon 22 (coding for voltage-gated sodium channel type II): c.3977T>A (p.V1326D). This mutation affects a highly evolutionarily conserved area of the gene and replaces hydrophobic nonpolar valine with polar aspartic acid; thus, it is predicted to affect protein function and is presumed pathogenic.
CONCLUSIONS: This report expands our knowledge of the genetic basis of migrating focal seizures of infancy to include mutations in SCN2A gene.