Electrophysiological features: The next precise step for SCN2A developmental epileptic encephalopathy

• Published in: Molecular genetics & genomic medicine Vol. 8; no. 7; pp. e1250 - n/a
• Main Authors: Miao, Pu, Tang, Siyang, Ye, Jia, Wang, Jianda, Lou, Yuting, Zhang, Bijun, Xu, Xiaoxiao, Chen, Xiaoquan, Li, Yuezhou, Feng, Jianhua
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01-07-2020; John Wiley and Sons Inc; Wiley
• Subjects: Action Potentials - drug effects; Age; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Carbamazepine; Child, Preschool; Choreoathetosis; Convulsions & seizures; Deactivation; Developmental Disabilities - diagnosis; Developmental Disabilities - drug therapy; Developmental Disabilities - genetics; developmental epileptic encephalopathy; Electroencephalography; Electrophysiological recording; Electrophysiology; Encephalopathy; Epilepsy; Epilepsy - diagnosis; Epilepsy - drug therapy; Epilepsy - genetics; Experiments; Female; Functional analysis; Gain of Function Mutation; Genotype & phenotype; Genotypes; HEK293 Cells; Humans; Inactivation; Infant; Intellectual disabilities; Ion Channel Gating; Loss of Function Mutation; Magnetic resonance imaging; Male; NAV1.2 Voltage-Gated Sodium Channel - chemistry; NAV1.2 Voltage-Gated Sodium Channel - genetics; NAV1.2 Voltage-Gated Sodium Channel - metabolism; Original; Oxcarbazepine; patch‐clamp; Patients; Pharmacology; Phenotype; Phenotypes; Phenytoin; precise treatment; Precision Medicine; Recovery time; SCN2A; Seizures; Sodium Channel Blockers - pharmacology; Sodium Channel Blockers - therapeutic use; Sodium channels (voltage-gated); Traumatic brain injury; developmental epileptic encephalopathy; precise treatment; SCN2A; patch-clamp
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.1250

Background
To investigate the relationships among phenotypes, genotypes, and funotypes of SCN2A‐related developmental epileptic encephalopathy (DEE).
Methods
We enrolled five DEE patients with five de novo variants of the SCN2A. Functional analysis and pharmacological features of Nav1.2 channel protein expressed in HEK293T cells were characterized by whole‐cell patch‐clamp recording.
Results
The phenotypes of c.4712T>C(p. I1571T), c.2995G>A(p.E999K), and c.4015A>G(p. N1339D) variants showed similar characteristics, including early seizure onset with severe to profound intellectual disability. Electrophysiological recordings revealed a hyperpolarizing shift in the voltage dependence of the activation curve and smaller recovery time constants of fast‐inactivation than in wild type, indicating a prominent gain of function (GOF). Moreover, pharmacological electrophysiology showed that phenytoin inhibited over a 70% peak current and was more effective than oxcarbazepine and carbamazepine. In contrast, c.4972C>T (p.P1658S) and c.5317G>A (p.A1773T) led to loss of function (LOF) changes, showing reduced current density and enhanced fast inactivation. Both showed seizure onset after 3 months of age with moderate development delay. Interestingly, we discovered that choreoathetosis was a specific phenotype feature.
Conclusion
These findings provided the insights into the phenotype–genotype–funotype relationships of SCN2A‐related DEE. The preliminary evaluation using the distinct hints of GOF and LOF helped plan the treatment, and the next precise step should be electrophysiological study.
In this manuscript, we report the clinical and electrophysiological results of five patients of SCN2A‐related developmental epileptic encephalopathy (DEE). Furthermore, we reviewed published data and combined our results to propose a protocol of diagnosis and treatment for SCN2A‐related DEE. These findings provided the insights into the phenotype‐genotype relationships and the electrophysiological function‐based precision treatment of SCN2A‐related DEE.