Journal article
Clinical and Molecular Genetic Characterization of Landau Kleffner Syndrome: An Observational Cohort and Experimental Study
Annals of Neurology, Vol.98(5), pp.951-966
2025
PMCID: PMC12577679
PMID: 40944498
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
Details
- Title
- Clinical and Molecular Genetic Characterization of Landau Kleffner Syndrome: An Observational Cohort and Experimental Study
- Authors
- Adeline Ngoh - KK Women's and Children's HospitalMaria Clark - Great Ormond Street HospitalRebecca Greenaway - Great Ormond Street HospitalXiumin Chen - The University of QueenslandKimberley M Reid - University College LondonKaty Barwick - University College LondonEsther Meyer - University College LondonDale Moulding - University College LondonNatalie Trump - University College LondonJ Helen Cross - University College LondonSean D Fraser - University of the Sunshine Coast, Queensland, School of Health - BiomedicineLachlan de Hayr - University of the Sunshine Coast, Queensland, School of Health - BiomedicineDimitri M Kullmann - University College LondonJoseph W Lynch - The University of QueenslandRobert J Harvey - University of the Sunshine Coast, Queensland, School of HealthManju A Kurian - Great Ormond Street Hospital
- Publication details
- Annals of Neurology, Vol.98(5), pp.951-966
- Publisher
- John Wiley & Sons, Inc.
- Date published
- 2025
- DOI
- 10.1002/ana.27306
- ISSN
- 1531-8249
- PMID
- 40944498; PMC12577679
- Copyright note
- © 2025 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
- Data Availability
- De-identified data collected and presented in this study, including individual participant data, can be made available upon reasonable request after publication of this article. Data can be requested by contacting the corresponding author.
- Grant note
- Action Medical Research for Children; Guarantors of Brain, FOLKS: Friends of Landau Kleffner Syndrome, Wellcome Trust, National Institute for Health Research, Sir Jules Thorn Trust, Great Ormond Street Hospital Children's Charity, Rosetrees Trust.
- Organisation Unit
- School of Health - Biomedicine; School of Health; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 991163245902621
- Output Type
- Journal article
Metrics
27 Record Views
InCites Highlights
These are selected metrics from InCites Benchmarking & Analytics tool, related to this output
- Collaboration types
- Domestic collaboration
- International collaboration
- Web Of Science research areas
- Clinical Neurology
- Neurosciences
UN Sustainable Development Goals (SDGs)
This output has contributed to the advancement of the following goals:
Source: SDGs from InCites