Novel variants of SYNGAP1 associated epileptic encephalopathy: two cases report and literature review

Abstract

Background: SYNGAP1 is a significant genetic risk factor for global developmental delay, autism spectrum disorder, and epileptic encephalopathy. De novo loss-of-function variants in this gene cause a neurodevelopmental disorder, for example, early-onset and drug-refractory seizures. We report two children with global developmental delay and epileptic encephalopathy, which are caused by SYNGAP1 gene novel mutations, and drug treatment is effective.

Case presentation: We report a boy and a girl presented with global developmental delay when they were young babies; as they grew up, cognitive impairment and social-communication disorder became more and more prominent; unfortunately, the patients developed into various seizure types, including eyelid myoclonia, myoclonic and absences when the boy was 1 year 8 mouths old and the girl was 3 years old. The two patients were found two previously unknown mutations by high throughput sequencing [c.3271_ c.3272insT; (p.L1091L fs*62), c.2515A > T (p.K839*)] in exon 15 of the SYNGAP in the proband. Sanger sequencing confirmed the heterozygous nature, and neither of their parents carried the same mutation. The girl treated with valproic acid and prednisone became seizure-free, and valproic acid and levetiracetam combined with clonazepam were influential in the other.

Conclusions: The global developmental delay and epileptic encephalopathy of the children were probably due to the pathogenic mutation of the SYNGAP1 gene, and prednisone and clonazepam may be effective in achieving seizure-free.

Keywords: SYNGAP1; Case report; Clonazepam; Epilepsy; Prednisone.

Fig. 1

(EEG results of case 1): a. Before treatment, interictal sleep VEEG showed that in seizure interval there were extensive 1.5-2.5 Hz, high amplitude slow spike slow waves and focal spinous slow waves in occipital or prefrontal region; b-c. Epileptic discharges could be seen in the seizure period before treated, considering eyelid myoclonus and atypical absence seizures (In the picture b, the child sitting on the bed with her head slightly tilted back and her eyes blinking; in the picture c, the child sitting on the bed with her eyes looking forward without obvious movement); d. After treatment, EEG during sleep proved no obvious epileptiform discharge. Electromyogram: a,b,c (on both deltoid muscles) & d (on both deltoid muscles and both quadriceps femoris muscles)

Fig. 2

Sanger sequencing results of case 1. A denovo heterozygous frameshift mutation in the SYNGAP1 gene: c.3271(exon15)_c.3271(exon15) insT (p.leu1091Leufs*62) (NM_006772) in the proband of case1, and the mutation was not found in the her parents

Fig. 3

Conservative analysis. Fig.3-a shows that the ectopic site of case1 is highly conserved in different species. Fig.3-b shows that the ectopic site of case 2 is highly conserved in different species

Fig. 4

(EEG results of case 2): a Before treatment, spikes and slow waves in all regions of the whole brain could be seen in the EEG during the attack period; b Before treatment, fast rhythm or multi spike slow wave intermittent burst could be seen in EEG during seizure interval and awake period; c-d There was no obvious epileptiform discharge in EEG during sleep and awake after treatment. Electromyogram: on both deltoid muscles

Fig. 5

Sanger sequencing results of case 2. A denovo heterozygous missense mutation in the SYNGAP1 gene: c.2515(exon15) A > T (p.Lys839stop, 505) (NM_006772) in the proband of case 2, and themutation was not found in his parents