P4.032: The Genetic Landscape of the Pathogenicity of Lennox-Gastaut Syndrome

Background: Lennox–Gastaut syndrome (LGS) is a severe developmental and epileptic encephalopathy that typically begins in childhood and persists into adulthood. It is characterized by drug-resistant epilepsy with multiple seizure types, a slow spike-wave pattern on electroencephalogram (EEG), and cognitive impairment. While several structural and metabolic causes have been identified, many LGS cases remain of unknown origin. In cases where no clear cause is identified, genetic predisposition is believed to play a crucial role in the pathogenesis of LGS. This systematic review aims to examine the current literature on genetic variants associated with LGS, focusing on mutation prevalence, inheritance patterns, and genotype-phenotype associations.

Methods: A systematic search of PubMed and Cochrane up to March 2025 was conducted to identify studies published over the past 15 years that report genetic findings in patients with Lennox-Gastaut Syndrome (LGS). The search targeted studies with genetically tested LGS patients. After screening 61 deduplicated articles, a total of 7 cohort studies were included in the review. Data were extracted based on mutation types, inheritance patterns, and seizure types. The search terms used were related to “Lennox-Gastaut Syndrome,” “mutation,” and “genetic abnormality.” In our study, we used the Newcastle-Ottawa Scale (NOS) to assess quality. This tool includes eight items across three domains: selection, comparability, and outcome. The NOS results were converted to the AHRQ (Agency for Healthcare Research and Quality) standards, which classify studies as good, fair, or poor based on the number of stars given per domain. Two reviewers independently assessed study quality, resolving any conflicts by consensus.

Results: Among our 7 included studies, 3 were conducted in China, 2 in Norway, and 1 each in Canada and Italy. A total of 433 patients diagnosed with Lennox-Gastaut Syndrome according to the latest diagnostic criteria were identified. Of these, 358 (82.7%) underwent genetic testing, including 151 (34.9%) with LGS of unknown etiology. Among them, 72 (16.6%) had positive genetic findings, including 34 with pathogenic results. Our review revealed 58 different mutations, of which 36 were de novo. CHD2 was the most common mutation (13.79%), followed by STXBP1 (6.9%), and 15q11.2-q13.3 duplication, CACNA1H, and GABRB3 (each 5.17%). Of the 72 patients with positive results, seizure types were reported in 42. Tonic seizures were most frequent (59.5%), followed by atypical absence (30.9%). Atonic, generalized tonic-clonic, and myoclonic seizures were each reported in 23.8% of cases.

Conclusion: Lennox-Gastaut Syndrome (LGS) is a severe epilepsy syndrome that develops in young children and often leads to lifelong disability. Our systematic review provides expanded insight into the genetic profile of LGS. However, larger studies are needed to better define genetic mechanisms and guide future therapies.