Epileptic encephalopathies are severe brain disorders with the epileptic component contributing to the worsening of cognitive and behavioral manifestations. Acquired epileptic aphasia (Landau-Kleffner syndrome, LKS) and continuous spike and waves during slow-wave sleep syndrome (CSWSS) represent rare and closely related childhood focal epileptic encephalopathies of unknown etiology. They show electroclinical overlap with rolandic epilepsy (the most frequent childhood focal epilepsy) and can be viewed as different clinical expressions of a single pathological entity situated at the crossroads of epileptic, speech, language, cognitive and behavioral disorders. Here we demonstrate that about 20% of cases of LKS, CSWSS and electroclinically atypical rolandic epilepsy often associated with speech impairment can have a genetic origin sustained by de novo or inherited mutations in the GRIN2A gene (encoding the N-methyl-D-aspartate (NMDA) glutamate receptor α2 subunit, GluN2A). The identification of GRIN2A as a major gene for these epileptic encephalopathies provides crucial insights into the underlying pathophysiology.

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Benign infantile familial convulsions is an autosomal dominant disorder characterized by nonfebrile seizures, with the first attack occurring at age 3-12 mo. It is one of the rare forms of epilepsy that are inherited as monogenic Mendelian traits, thus providing a powerful tool for mapping genes involved in epileptic syndromes. Paroxysmal choreoathetosis is an involuntary-movement disorder characterized by attacks that occur spontaneously or are induced by a variety of stimuli. Classification is still elusive, and the epileptic nature of this movement disorder has long been discussed and remains controversial. We have studied four families from northwestern France in which benign infantile convulsions was inherited as an autosomal dominant trait together with variably expressed paroxysmal choreoathetosis. The human genome was screened with microsatellite markers regularly spaced, and strong evidence of linkage for the disease gene was obtained in the pericentromeric region of chromosome 16, with a maximum two-point LOD score, for D16S3133, of 6.76 at a recombination fraction of 0. Critical recombinants narrowed the region of interest to a 10-cM interval around the centromere. Our study provides the first genetic evidence for a common basis of convulsive and choreoathetotic disorders and will help in the understanding and classification of paroxysmal neurological syndromes.