Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance

• Published in: Scientific reports Vol. 14; no. 1; pp. 21606 - 13
• Main Authors: Nguyen, Yen Thi My, Vu, Bao-Quoc, Nguyen, Duy-Khai, Quach, Ngoc-Vinh, Bui, Liem Thanh, Hong, Jeonghan, Bui, Chi-Bao
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 16.09.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Anticonvulsants - therapeutic use; Clinical sequencing; DEE; Diet; Diet, Ketogenic; Drug resistance; Drug Resistance - genetics; Drug Resistant Epilepsy - drug therapy; Drug Resistant Epilepsy - genetics; Drug response; Encephalitis; Encephalopathy; Epilepsy; Epilepsy - drug therapy; Epilepsy - genetics; Exome Sequencing; Female; Gene regulation; Genetic abnormalities; Genetic analysis; Genetic diversity; Genetic variance; Genotype; Genotypes; Glucose transport; High fat diet; Humans; Infant; Infant, Newborn; Ion channels; Ketogenesis; Ketogenic diet; Kinases; Low carbohydrate diet; Male; Metabolic epilepsy; Metabolism; NAV1.1 Voltage-Gated Sodium Channel - genetics; NAV1.2 Voltage-Gated Sodium Channel - genetics; NAV1.2 Voltage-Gated Sodium Channel - metabolism; Neonates; Seizures; Sodium channels (voltage-gated); Treatment Outcome; Whole genome sequencing; Metabolic epilepsy; Drug response; Clinical sequencing; DEE; Ketogenic diet
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-72683-7

Neonatal intensive care unit (NICU), particularly in treating developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep understanding of their complex etiologies and treatment responses. After excluding treatable cases such as infectious or autoimmune encephalitis, our focus shifted to a more challenging subgroup of 59 patients for in-depth genetic analysis using exome sequencing (ES). The ES analysis identified 40 genetic abnormalities, significantly including de novo variants. Notably, we found structural variation as duplications in regions 2q24.3, including SCN1A and SCN2A were observed in 7 cases. These genetic variants, impacting ion channels, glucose transport, transcription regulation, and kinases, play a crucial role in determining medication efficacy. More than one-third (34.2%) of patients with DEE had an unfavorable response to anti-seizure medications (ASMs) in the chronic phase. However, since the ketogenic supplementary diet showed a positive effect, more than three-quarters (80%) of these drug-resistant patients improved during a 3-month follow-up. In contrast, the ME had a lower adverse reaction rate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and 10 cases with unidentified genetic etiologies. This study suggests the potential of categorizing drug-resistant variants and that a ketogenic diet could be beneficial in managing DEE and ME. It also opens new perspectives on the mechanisms of the ketogenic diet on the discovered genetic variants.