GRIN2A – childhood epilepsy with centrotemporal spikes

Heterozygous variants in GRIN2A, encoding the GluN2A subunit of the N-methyl-D-aspartate receptor (NMDAR), have been repeatedly implicated in Rolandic epilepsy, also known as childhood epilepsy with centrotemporal spikes ([MONDO:0007295]). Mutations cluster in diverse functional domains and segregate in autosomal dominant fashion, consistent with a gain-of-function epileptogenic mechanism.

In a Chinese cohort of 122 patients with epilepsy-aphasia spectrum disorders, pathogenic GRIN2A variants were detected in 7.1% of atypical benign partial epilepsy and 11.1% of Landau-Kleffner syndrome cases, but not in benign epilepsy with centrotemporal spikes ([PMID:29056244]). One recurrent missense change, c.2278G>A (p.Gly760Ser), was identified in two unrelated probands, supporting variant recurrence in this population ([PMID:29056244]).

In a separate study of 359 individuals with idiopathic focal epilepsy, GRIN2A variants were found in 27 cases (7.5%), with mutation rates increasing from 4.9% in benign epilepsy with centrotemporal spikes to 17.6% in continuous spike-and-wave during sleep ([PMID:23933819]). A spectrum of variant classes was observed, including missense, splice-site, frameshift and microdeletions, demonstrating allelic heterogeneity.

Analysis of 519 probands across diverse epileptic encephalopathy syndromes identified four families (9% of epilepsy-aphasia spectrum cases) with fully segregating GRIN2A variants and no pathogenic changes in other NMDAR subunits ([PMID:23933818]). This multi-family segregation confirms GRIN2A as a monogenic cause of Rolandic epilepsy in a subset of patients.

Overall, at least 35 unrelated probands have been reported with GRIN2A heterozygous variants in Rolandic epilepsy or related epilepsy-aphasia phenotypes, including missense, splice-site and loss-of-function alleles (e.g., c.2278G>A (p.Gly760Ser)) ([PMID:29056244]; [PMID:23933819]). The inheritance is autosomal dominant, often with de novo occurrence and occasional familial transmission.

Functional studies of GRIN2A variants demonstrate altered NMDAR gating and pharmacology consistent with neuronal hyperexcitability. The de novo p.Leu812Met change increases agonist potency, reduces magnesium block and prolongs synaptic current decay ([PMID:24504326]). Similarly, p.Asn447Lys enhances glutamate sensitivity and reduces Mg2+ inhibition, confirming gain-of-function in vitro ([PMID:28936771]).

Together, the genetic and functional data support a Strong clinical validity classification for the GRIN2A–Rolandic epilepsy association based on >35 probands, segregation in four families and concordant electrophysiological evidence.

Key Take-home: GRIN2A testing should be considered in children with centrotemporal spike epilepsy, as identification of gain-of-function variants guides diagnosis and opens avenues for precision therapy with NMDAR modulators.

References

• Brain & development • 2018 • GRIN2A mutations in epilepsy-aphasia spectrum disorders. PMID:29056244
• Brain • 2013 • Idiopathic focal epilepsy with rolandic spikes is associated with GRIN2A mutations. PMID:23933819
• Human Molecular Genetics • 2013 • Pathogenic deletions that include GRIN2A in epileptic encephalopathies. PMID:23933818
• Nature Communications • 2014 • Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy. PMID:24504326
• Neuroscience Bulletin • 2018 • Functional Investigation of a GRIN2A Variant Associated with Rolandic Epilepsy. PMID:28936771

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