Clinical and Molecular Genetic Characterization of Landau Kleffner Syndrome: An Observational Cohort and Experimental Study

Abstract

Objective: Landau–Kleffner syndrome (LKS), is a rare, poorly-understood epileptic encephalopathy with spike–wave activation in sleep associated with mutations in GRIN2A, encoding the N-Methyl-D-Aspartate receptor (NMDAR) GluN2A subunit. Physicians rely on empirical treatments, with scarce information on treatment efficacy and outcomes. This study aims to improve the understanding and clinical management of LKS. Methods: Fifty-two patients with LKS were recruited via one quaternary referral center. Case-notes review delineated clinical features, long-term outcomes, and prognostic factors. Generalized estimating equations were used to determine the longitudinal association among electroencephalogram abnormalities, steroid therapy, and neuropsychological findings. After genetic screening, the impact of identified GRIN2A missense variants on NMDAR function was assessed using homology modeling, cell-surface trafficking assays, and electrophysiology in artificial synapses. Whole exome/genome sequencing was performed on GRIN2A-negative patients to identify novel gene associations. Results: LKS is complex with significant clinical and genetic heterogeneity. Besides speech and language impairment, many patients had other co-morbidities and almost half have long-term disability. Early age at disease onset was associated with worse outcomes. There was no reliable correlation between electroencephalogram findings and developmental scores. Steroid therapy improved language outcomes independently of electroencephalogram findings. GRIN2A mutations were identified in 15.5% of the cohort. Likely pathogenic variants in GABBR2, SCN1A, TRPC1, ERRFI1, CTXN3, IRX6, and IQCA1 were identified in 7 GRIN2A-negative individuals. Interpretation: For LKS, early intervention is important for long-term outcomes. Furthermore, management should not be based solely on electroencephalogram findings. Genetic and functional investigations offer insights into disease pathophysiology and facilitate development of future targeted therapies. ANN NEUROL 2025;98:951–966.