Clinical Features Of Generalized Epilepsy With Febrile Seizures Plus And Study On Its Genetics

Objective:Epilepsy is a common disease of the central nervous system caused by abnormal discharge of neurons over paroxysmal. Generalized epilepsy with febrile seizures plus (GEFS+) was named in 2001 by the International League Against Epilepsy (ILAE), with a clear genetic predisposition. Researchers had shown that GEFS+was an autosomal dominant syndrome, with a significant genetic heterogeneity. GEFS+generally shows benign passing normal psychomotor development, mostly stop in aged 25 or late to childhood. In recent years, studies on mutations in genes associated with GEFS+made great progress. Most of them are genes encoding ion channels. Five related genes including SCN1A, SCN1B, GABRG2, GABRD and SCN2A were among the most frequently reported genes associated with GEFS+. This study aims to summarize the clinical features of one GEFS+ pedigree and research its genetic characters, then makes extension on GEFS+ genetic profile and helps clinical diagnosis and treatment.Methods:In June 2013, one proband visited to the Department of Neurology, Qilu Hospital of Shandong University. Through detailed history taking, physical examination and related laboratory examinations, we summarized the clinical features. According to the diagnostic criteria of epilepsy and epileptic syndrome made by International League Against Epilepsy (ILAE) in 2001, the patients in this family were dignosized as GEFS+. The identical twins had EEG and brain MRI. The other four patients underwent routine EEG and brain MRI. Through outpatient and home visits for family members and other ways to access the survey, in strict accordance with national laws and regulations and their families to obtain the consent of the patient, we improved clinical data collection and extracted peripheral venous blood samples of all the 20 family members. Proband and his twin brother’s DNA were sequenced through gene trap and high-throughput sequencing.308 genes related to epilepsy were sequenced, and then the found mutation site were verified in family members.Results:In this study we collected a total of 20 family members and found six cases with epilepsy, idiopathic generalized epilepsy four cases (6 years ago had a history of febrile convulsions), two cases had febrile before 6 years old. The twins patients were given oxcarbazepine therapy, after appropriate dosage adjustments, no seizure onset in the follow-up.2 patients with febrile seizures occuring before the age of 6 were not given medical treatment, the other two patients were treated with oxcarbazepine therapy. Through second generation sequencing, we found a new mutation site on SCN2A gene in this family:c.1399G> A (p.A467T). The HGMD (Human Gene Mutation Database) has no reports of this mutation site. Through first generation sequencing, this mutation site was found in other patients but wasn’t found in the normal individuals.Conclusion:This family shown the clinical phenotypes for FS and FS+, which made a reflection of GEFS+ genetic heterogeneity in some way. Through this study we found a new point mutation, which was a missense mutation that caused amino acid changing which might lead to Na+ channel changing in protein structure, thus affecting the function of Na+ ion channel, leading to seizures. However, functional study on this mutation site should be further carried on. Through this study, spectrum of mutations of SCN2A gene was expanded, which might provide help on gene diagnosis of GEFS+ and the treatment.