Progress in genetic mechanisms and precise treatment of neurocutaneous syndrome-related epilepsy

Yang Li¹Xiaojie Hu²Xueqing Chen³Yawei Cheng⁴Yanhong Jiang⁴Xingchen Wang^4*

• ¹The Second Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
• ²Department of Neurology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
• ³Department of Cardiology, Zibo Central Hospital, Zibo, China
• ⁴Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China

Neurocutaneous syndromes are a group of genetic disorders involving the nervous and cutaneous systems, including Tuberous Sclerosis Complex (TSC), neurofibromatosis type 1 (NF1), and Sturge-Weber syndrome (SWS), and others. The incidence of epilepsy, a core clinical manifestation, is significantly higher than in the general population. The purpose of this narrative review is to provide an updated overview of the genetic mechanisms and recent advances in precise treatment for neurocutaneous syndrome-related epilepsy. We conducted a comprehensive search of the PubMed, Scopus, EMBASE, and Web of Science databases using all MeSH terms related to 'Neurocutaneous Syndromes', 'Epilepsy/genetics', 'Signal Transduction', and 'Precision Medicine'. Selected papers underwent review and risk of bias (RoB) assessment to evaluate core questions. Somatic or germline mutations dysregulate key signaling pathways (e.g., mTOR, Ras-MAPK, PI3K-AKT), inducing malformations of cortical development (MCD) and neuronal-glial dysfunction that collectively form epileptogenic networks. This constitutes the primary pathogenic mechanism underlying neurocutaneous syndrome-related epilepsy. Precise treatment strategies based on molecular mechanisms have achieved breakthroughs: mTOR inhibitors significantly reduce seizure frequency in TSC patients, and cannabidiol (CBD) demonstrates broad-spectrum antiepileptic efficacy in TSC and Dravet syndrome. Advances in surgical techniques, such as multimodal imaging-guided resection, improve outcomes in refractory epilepsy. However, clinical translation faces challenges including technical limitations in detecting mosaic mutations, insufficient specificity of targeted drugs, and interdisciplinary collaboration gaps. Future directions require integrating multi-omics technologies, developing novel gene therapies (e.g., CRISPR-based approaches), and establishing multicenter databases linking genotype-phenotype-treatment responses to advance personalized precision medicine.