When considering megalencephaly, discovering the underlying etiology can often be challenging. Although previous reports have implicated mutations in the PI3K-AKT pathway, we now know there is significant heterogeneity in etiology and presentation. Over the past century, numerous associated syndromes and many molecular mutations have been identified as causes for megalencephaly but SCN2A mutations have not been previously reported [1-3].

The SCN2A gene encodes the alpha subunit of the voltage gated sodium channel which is involved with neuronal firing [4]. SCN2A variants are inherited in an autosomal dominant manner. Pathogenic variants causing encephalopathy are typically de novo, while inherited variants often result in milder phenotypes and may exhibit incomplete penetrance [5]. To our knowledge, the L210R variant in the SCN2A gene has not been classified as a pathogenic variant prior to this patient. On review of large scale human genomic datasets, we know that the L210R variant is not observed in large population cohorts [6]. The L210R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution in p. Leu210Arg (L210R) (CTG>CGG): c.629 T>G in exon 6 of the SCN2A gene is predicted to be within the extracellular loop between the S3 and S4 transmembrane segments of the first homologous domain. Additionally, missense variants in nearby residues that have a gain-of-function effect lead to a spectrum of SCN2A-related disorders, ranging from benign familial neonatal-infantile seizures (BFNIS) to epileptic encephalopathies, including Ohtahara syndrome and epilepsy of infancy with migrating focal seizures (EIMFS) [4,6,7]. Therefore, in consideration of the available literature in combination with the clinical context, we conclude L210R as a pathogenic variant and the likely cause of refractory seizures in our patient. In our case, there was a lack of phenotypic diagnostic clues given the infant’s normal prenatal anatomy scan, normal physical exam and non-specific brain imaging. Therefore, if the clinical suspicion is high, genetic testing via the comprehensive epilepsy panel should be considered for a definitive diagnosis.

To date, there is sparse data on an association between SCN2A-related disorders and megalencephaly. There is no comprehensive overview of possible SCN2A phenotypes and the genotype-phenotype correlation remains poorly understood. In general, there are 4 recognized phenotype groups: 1) benign neonatal or infantile epilepsies, 2) neurodevelopmental /neuropsychiatric disorders, including schizophrenia, autism and intellectual disability, 3) Infantile Spasms, and 4) early onset epileptic encephalopathies. Severe neonatal epileptic encephalopathies can also be associated with cortical abnormalities including cortical dysplasia but megalencephaly has not been described [8]. Similarly, there have been case reports with severe non-SCN2A related epilepsy as a consequence of hemi-megalencephaly but only one case report to date documented neonatal epileptogenic disorder concurrent with bilateral megalencephaly [9]. Sawaishi et.al described a neonate with megalencephaly, persistent hyponatremia, and severe epilepsy responsive only to lidocaine, suggesting a sodium channelopathy as the etiology [10]. Although formal testing for channelopathies was not discussed, a SCN mutation is a plausible explanation.

Currently we have no direct link between SCN2A mutations and megalencephaly, but our patient highlights the potential overlap in disease processes. Many of the genes implicated in neuronal migration disorders such as megalencephaly have a strong genetic and biochemical component that directly affects the cytoskeleton of the brain. It is possible that the biochemical disturbance associated with abnormal neuronal migration also affects the neuronal circuitry, thus increasing the propensity for electrical dysfunction and manifesting as seizures. In regards, to intractable neonatal seizures and megalencephaly, it is prudent to consider if there is a common pathway that could explain our patient’s clinical presentation. Our findings support a previous case described by Bernado et al. of a neonate with SCN2A epileptic encephalopathy with severe cortical dysplasia [8]. The diagnosis was heralded by a prenatal MRI at 32 weeks which demonstrated dysplasia, corpus callosum dysgenesis, and pachygyria. Our case highlights a severe presentation in the absence of abnormal prenatal and postnatal MRI findings. The identified variant thus further adds to our knowledge of the vast spectrum of SCN2A-related disorders and highlights the need for continued investigation and discovery.