Epileptic spasms related to neuronal differentiation factor 2 (NEUROD2) mutation

Sakpichaisakul K, Boonkrongsak R, Lertbutsayanukul P, Iemwimangsa N, Klumsathian S, Panthan B, Trachoo O. Epileptic spasms related to neuronal differentiation factor 2 (NEUROD2) mutation respond to combined vigabatrin and high dose prednisolone therapy. BMC Neurol. 2022 Dec 9;22(1):461. doi: 10.1186/s12883-022-02992-9. PMID: 36494631; PMCID: PMC9733267. 

Abstract

Background: Epileptic spasms are a devastating form of early infantile epileptic encephalopathy (EIEE) with various etiologies. Early diagnosis and a shorter lead time to treatment are crucial to stop the seizures and optimize the neurodevelopmental outcome. Genetic testing has become an integral part of epilepsy care that directly guides management and family planning and discovers new targeted treatments. Neuronal differentiation Factor 2 (NEUROD2) variants have recently been a cause of neurodevelopmental disorders (NDDs) and EIEEs with distinctive features. However, there is limited information about the clinical and electroencephalographic response of epileptic spasm treatment in NEUROD2-related NDD syndrome.

Case presentation: We report a female patient of Southeast Asian ethnicity with global developmental delay and epileptic spasms commencing in the first few months of life. A novel de novo heterozygous pathogenic NEUROD2 variant, p. E130Q, was subsequently identified by whole-exome sequencing. Electroencephalogram before treatment showed multifocal independent spikes predominantly in both posterior head regions and demonstrated marked improvement following combined vigabatrin and high-dose prednisolone treatment. However, multiple courses of relapse occurred after weaning off the antiseizure medication.

Conclusions: We propose that epileptic spasms related to de novo NEUROD2 pathogenic variant respond well to combined vigabatrin and high-dose prednisolone therapy. These findings may imply the benefit of using combination therapy to treat epileptic spasms in NEUROD2-related NDD syndrome.

Sega AG, Mis EK, Lindstrom K, Mercimek-Andrews S, Ji W, Cho MT, Juusola J, Konstantino M, Jeffries L, Khokha MK, Lakhani SA. De novo pathogenic variants in neuronal differentiation factor 2 (NEUROD2) cause a form of early infantile epileptic encephalopathy. J Med Genet. 2019 Feb;56(2):113-122. doi: 10.1136/jmedgenet-2018-105322. Epub 2018 Oct 15. PMID: 30323019.

Abstract

Background: Early infantile epileptic encephalopathies are severe disorders consisting of early-onset refractory seizures accompanied often by significant developmental delay. The increasing availability of next-generation sequencing has facilitated the recognition of single gene mutations as an underlying aetiology of some forms of early infantile epileptic encephalopathies.

Objectives: This study was designed to identify candidate genes as a potential cause of early infantile epileptic encephalopathy, and then to provide genetic and functional evidence supporting patient variants as causative.

Methods: We used whole exome sequencing to identify candidate genes. To model the disease and assess the functional effects of patient variants on candidate protein function, we used in vivo CRISPR/Cas9-mediated genome editing and protein overexpression in frog tadpoles.

Results: We identified novel de novo variants in neuronal differentiation factor 2 (NEUROD2) in two unrelated children with early infantile epileptic encephalopathy. Depleting neurod2 with CRISPR/Cas9-mediated genome editing induced spontaneous seizures in tadpoles, mimicking the patients' condition. Overexpression of wild-type NEUROD2 induced ectopic neurons in tadpoles; however, patient variants were markedly less effective, suggesting that both variants are dysfunctional and likely pathogenic.

Conclusion: This study provides clinical and functional support for NEUROD2 variants as a cause of early infantile epileptic encephalopathy, the first evidence of human disease caused by NEUROD2 variants.