PRRT2基因突变良性婴儿癫痫家系临床特征及遗传学特点

Clinical characteristics and genetic features of benign infantile epilepsy with PRRT2 mutation

目的总结PRRT2基因突变良性婴儿癫痫家系的临床特征和遗传学特点，以提高对本病的认识。方法收集2002年1月至2017年10月首都医科大学附属北京儿童医院神经内科收治的40例PRRT2基因突变良性婴儿癫痫患儿及受累家系成员的临床资料及遗传学改变，进行回顾性病例分析。结果40例患儿中男18例、女22例，癫痫起病年龄3-15月龄，中位起病年龄4.6月龄，表现为局灶性发作或局灶性发作继发全面性发作，常见发作表现为反应减慢、双眼凝视、面色发绀。20例患儿起病初期呈丛集性发作，但发作间期反应良好。2例患儿在癫痫发作停止后分别于2岁6月龄和12岁出现发作性运动障碍。24例患儿的家系中有发作性疾病史者34例，包括婴儿期无热抽搐史19例，儿童期或成年期发作性运动障碍史6例，婴儿期无热抽搐且成年期有发作性运动障碍史8例，婴儿期发热抽搐史1例。发作间期脑电图32例未见异常，8例可见少量散在棘波、棘慢波。36例予抗癫痫药物治疗，服药后发作易于控制；4例未用抗癫痫药未再发作（均于2岁以内停止）。随访6个月-15年，24例1岁内发作停止，10例1-2岁发作停止，2例2-3岁发作停止。40例患儿均发现PRRT2基因突变，7例PRRT2基因为整体杂合缺失，33例PRRT2基因为杂合突变，包括28例移码突变和5例错义突变，其中30例为家族遗传性突变，3例为新生突变（2例c.649dupC、1例c.213_214del），9例患儿的父母一方携带相同致病基因突变但无临床症状。 结论PRRT2基因突变所致良性婴儿癫痫，绝大多数在6月龄前起病，表现为局灶性发作或继发全面性发作，丛集性发作为其突出特点，抗癫痫药物治疗发作易于短期控制，绝大多数患儿在2岁内发作停止。部分患儿随年龄增长可能出现发作性运动障碍。PRRT2基因突变多数为杂合突变，少数为PRRT2基因整体杂合缺失。

ObjectiveTo summarize the detailed clinical characteristics and genetic features of benign infantile epilepsy with PRRT2 mutation, in order to improve the understanding of the disease.MethodsThe clinical data and genetic results of 40 benign infantile epilepsy patients with PRRT2 mutation who were diagnosed and treated in the neurology department of National Center for Children＇s Health （Beijing） , Beijing Children＇s Hospital affiliated to Capital Medical University from January 2002 to October 2017 and their affected family members were analyzed.ResultsForty benign infantile epilepsy patients were recruited for this study, with 18 males and 22 females. The age at onset ranged from 3 to 15 months （median： 4.6 months）. All patients presented focal seizures with or without secondary generalization. Decreased responsiveness, eyes stare and cyanosis were commonly observed. A cluster of seizures was observed in 20 patients at the beginning of the disease, but interictal clinical conditions were normal. Interictal electroencephalograms were normal in 32 cases but 8 cases showed small amount scattered spike and spike wave. Two patients developed paroxysmal kinesigenic dyskinesia in 30 months and 12 years respectively after the cessation of the seizure. Thirty-four affected pedigree members had a history of paroxysmal episodes in 24 families, including 19 individuals of infantile afebrile convulsion, 6 individuals of paroxysmal kinesigenic dyskinesia during childhood or adulthood, 8 individuals of infantile convulsion and paroxysmal kinesigenic dyskinesia during adulthood, one individual of infantile febrile convulsion. The follow-up time ranged from 6 months to 15 years. Thirty-six patients were treated with antiepileptic drugs and their seizures were easy to control. Four patients stayed seizure free without medication （all 〈2 years）. Seizure stopped in 24 patients within 1 year of age, in 10 patients stopped during 12-24 months and in 2 patients stopped during 24-36 months. All cases had PRRT2 mutations, 7 cases of a complete PRRT2 deletion, 33 cases of PRRT2 heterozygous mutations consisted of 28 frameshift mutations and 5 missense mutations. Of these heterozygous mutations, 30 cases were hereditary mutations while 3 were de novo mutations. Nine family members harbored the same PRRT2 mutations without any symptom. ConclusionsBenign infantile epilepsy with PRRT2 mutation is characterized by early onset of seizure mostly before 6 months, focal seizures with or without secondary generalization, a high incidence of a cluster of seizures, rapid resolution of seizure by antiepileptic drugs and cessation of seizure mostly before 2 years of age. Partial patients may develop paroxysmal kinesigenic dyskinesia increasing with age. Most PRRT2 gene mutations are heterozygous mutations, and a few are the overall deletion of PRRT2 gene.