The disruption of SYNGAP1 appears to be associated with a homogeneous clinical phenotype that is characterized by moderate-to-severe mental retardation accompanied by severe language impairment. The absence of specific dysmorphic features and growth abnormalities in these patients is consistent with the fact that SYNGAP1 is exclusively expressed in the brain. The behavioral profile of the three patients and the absence of SYNGAP1 deleterious mutations in the series of patients with autism spectrum disorders indicate that SYNGAP1 disruption is unlikely to be associated with autism spectrum disorders. Two of the patients in our study had been treated for generalized forms of mild epilepsy. The disruption of SYNGAP1 could predispose them to seizures by increasing the recruitment of AMPA receptor at postsynaptic glutamatergic synapses, resulting in increased excitatory synaptic transmission, as has been described in mice with a Syngap1 mutation.12,14 The fact that epilepsy was well controlled in both patients by topiramate or valproate is consistent with this hypothesis. Indeed, topiramate directly inhibits AMPA-receptor activity, whereas valproate reduces the level of GluR1 AMPA-receptor subunit at hippocampal synapses and therefore indirectly reduces AMPA-receptor activity.22,23
