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Landau-Kleffner syndrome (LKS) is a rare childhood epilepsy-aphasia spectrum disorder characterized by acquired auditory verbal agnosia, cognitive decline and focal EEG abnormalities. Recent genetic studies have implicated heterozygous variants in the GRIN2A gene, encoding the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR), as a cause of LKS. These variants present with an autosomal dominant inheritance pattern, often occurring de novo, and cluster within domains critical for agonist binding and channel gating.
Genetic evidence includes six unrelated LKS probands harboring de novo GRIN2A missense mutations such as c.2146G>A (p.Ala716Thr) and c.2191G>A (p.Asp731Asn), identified by targeted epilepsy panels and exome sequencing (PMID:26806548, PMID:28182669, PMID:29056244). Multi-cohort screening of 122 EAS patients detected GRIN2A variants in 11.1% of LKS cases, and similar rates were observed in broader idiopathic focal epilepsy cohorts (PMID:29056244, PMID:23933819). No familial segregation beyond probands has been reported, consistent with de novo occurrence.
The variant spectrum in LKS comprises primarily missense changes within the ligand-binding S1 and S2 domains and the transmembrane/linker regions, with no recurrent founder alleles yet described. Functional assays demonstrate that mutations in the agonist-binding domain (e.g., GluN2A-D731N) reduce glutamate potency >3,000-fold and decrease channel open probability, whereas others (e.g., GluN2A-L812M) increase agonist potency and prolong synaptic currents (PMID:28182669, PMID:24504326). Rescue pharmacology with memantine restored normal receptor activity in gain-of-function variants, illustrating therapeutic potential (PMID:24839611).
Functional studies in heterologous systems and neuronal cultures confirm that GRIN2A mutations disrupt NMDAR trafficking, gating kinetics and sensitivity to negative modulators (Mg²⁺, Zn²⁺, protons). Loss-of-function variants show reduced surface expression and agonist response, while gain-of-function variants prolong channel open time and resist Mg²⁺ block, both perturbations aligning with neuronal hyperexcitability in LKS (PMID:28611597, PMID:28242877).
There is minimal conflicting evidence; one variant (p.Ile184Ser) demonstrated negligible kinetic change in vitro, suggesting possible phenotypic modifiers or incomplete penetrance in some cases (PMID:28611597). No alternative genetic etiologies have been consistently reported in GRIN2A-positive LKS patients.
Integration of genetic and experimental data supports a model in which de novo GRIN2A heterozygous variants perturb NMDAR function to drive the epilepsy-aphasia phenotype of LKS. Clinical response to immunotherapy in a patient with the p.Ala716Thr variant underscores the utility of targeted approaches and suggests immune mechanisms may modulate disease severity (PMID:26806548). Additional evidence from larger cohorts and longitudinal studies would strengthen the association.
Key Take-home: Heterozygous de novo GRIN2A variants confer a moderate clinical validity for LKS via dominant-negative or gain-of-function effects on NMDARs, informing diagnostic sequencing and potential precision therapies.
Gene–Disease AssociationModerateSix unrelated LKS probands with de novo GRIN2A missense variants and replication in multi-cohort studies; functional data concordant with NMDAR dysregulation Genetic EvidenceModerateSix de novo missense variants (e.g., c.2146G>A (p.Ala716Thr), c.2191G>A (p.Asp731Asn)) in unrelated LKS probands; autosomal dominant model Functional EvidenceStrongElectrophysiological analyses of multiple GRIN2A missense mutations demonstrate altered NMDAR agonist sensitivity and channel kinetics consistent with LKS pathogenesis |