A New SYNGAP1 Stop Mutation in a Patient with Idiopathic Generalized Epilepsy Showing Photosensitivity and Electroencephalography Normalization after Eye Opening

Background: SYNGAP1, which encodes a RAS-GTPase-activating protein that influences α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking and excitatory synaptic transmission, is located on the short arm of chromosome 6 (6p21.3). SYNGAP1 gene mutations have been associated to autism spectrum disorders, delay of psychomotor development, acquired microcephaly, and several forms of idiopathic generalized epilepsy like Tassinari syndrome.

Patient: This 15-year-old, mentally retarded girl developed drop attacks at the age of 3.25 years, later clonic and clonic-tonic, as well as myoclonic seizures. Two seizures were associated with fever. The epilepsy was well-controlled by valproic acid (VPA). The electroencephalography (EEG) was characterized by generalized spike-wave activity and photosensitivity; eye opening lead to complete EEG normalization. MRI was normal, and there were no dysmorphic signs. Genetic analysis revealed a mutation (c.348C>A, p.Y116*), which is a de novo mutation in exon 4 of the SYNGAP1 gene, in a heterozygous state. This mutation is predicted to lead to a premature stop codon.

Discussion: This is the first description of a so far not reported de novo SYNGAP1 mutation in a patient with generalized idiopathic epilepsy with only mild mental retardation and slight speech impairment together with a special EEG phenomenon and a good therapeutic response to VPA. This might help to further elucidate the SYNGAP1 phenotype. The reported cases in the literature showed mainly a good anticonvulsive effect of VPA and topiramate (TPM). Therefore, mutations in SYNGAP1 should be considered when a patient with generalized epilepsy, speech impairment, and nonsyndromic mental retardation is presented. In these patients, VPA and TPM could be first choice anticonvulsive drugs.