New Genes for Focal Epilepsies with Speech and Language Disorders

Abstract

The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20% of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS; copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes.

Next-generation DNA sequencing identifies novel gene variants and pathways involved in specific language impairment

“…In a dataset of 43 well-phenotyped probands, based on validation, bioinformatics characterization and previous associations, we observed potentially pathogenic variants in several genes that have already been implicated in speech- and language-related syndromes. Specifically, we identified a private start-loss variant in ERC1 , a gene previously implicated in childhood apraxia of speech45; a novel de novo substitution disrupting GRIN2A , a gene mutated in epilepsy-aphasia spectrum disorders366263; and a hemizygous disruption of SRPX2 that has previously been identified in people with Rolandic epilepsy with speech apraxia34. Thus, although the language difficulties in SLI must (by definition) be unexpected, our findings suggest that a proportion of affected children might actually represent cases of undiagnosed developmental syndromes that may be clinically identifiable.…”

Aetiology of childhood apraxia of speech: A clinical practice update for paediatricians

“…35 Further clinical enquiry into children with epilepsy since this time has revealed a broad spectrum of epilepsy aphasias, which represents an association between epilepsy, speech (including CAS) and language disorders and the electroencephalography (EEG) signature of centro-temporal spikes. 36 In recent years, mutations or very small deletions in GRIN2A have been identified in patients with focal epilepsy and speech and language dysfunction. 37 Variable epilepsy and linguistic phenotypes may be associated with the GRIN2A genotype, but in relation to speech, CAS, dysarthria and oral-motor impairments have been consistently reported across families regardless of the associated form of epilepsy.…”

Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders

“…Domain names and functions are reported in the legend. Black stars indicate missense mutations associated to ASD, ID, SCZ, and other neurodevelopmental disorders 33, 79, 82, 120–123 . …”

“…Whereas the evolutionary history of DLG4 seems to be dominated by purifying selection, three of its direct interactors ( GRIN2A , SYNGAP1 , and MAP1A , in addition to MDM2 ) showed evidence of positive selection on the mammalian branch. Mutations in GRIN2A have been associated with a variety of neurological disorders 82 . NMDA receptors are both ligand-gated and voltage-dependent, and play a fundamental role in brain development and function.…”