PRRT2基因突变患者的基因突变类型、临床表型及二者与患者预后的关系

Gene mutation type and clinical phenotype of patients with PRRT2 mutation and their relations with prognosis

目的分析PRRT2基因突变患者的基因突变类型和临床表型,探讨二者与患者预后的关系。方法以空军军医大学第一附属医院神经内科自2018年1月至2023年7月收治的18例PRRT2基因突变患者(1例PRRT2基因新发突变患者、17个PRRT2基因突变家系中17例先证者)为研究对象。收集患者血清进行全外显子测序,分析患者PRRT2基因突变位点及类型,应用SWISS-MODEL网站预测PRRT2基因突变所致蛋白质结构的变化。分析患者基因突变类型、临床表型与预后的关系。结果(1)18例患者均为杂合突变,其中移码突变12例,错义突变5例,整码突变1例;临床表型为良性家族性婴儿癫痫(BFIE)5例,癫痫6例,运动诱发性运动障碍(PKD)5例,家族性婴儿惊厥伴舞蹈手足徐动症(ICCA)2例。18例患者中共发现8个突变位点,其中3个突变位点已被报道,5个突变位点目前尚未被报道[c.647(exon2)C>A、c.647(exon2)C>G、c.170(exon2)delC、c.981(exon3)C>G、lossl(EXON:2)(all)]。(2)18例患者主要采用奥卡西平、左乙拉西坦、丙戊酸联合或单药治疗,其中5例BFIE、2例ICCA及3例癫痫患者治疗后均达到无发作,PKD患者服用奥卡西平效果不佳。(3)3种移码突变[突变位点分别为c.649(exon2)c.650(exon2)insC、c.640(exon2)c.641(exon2)insC、c.170(exon2)delC]导致蛋白质翻译过早终止,引起蛋白质结构显著变化。4种错义突变[突变位点分别为c.640(exo2)G>C、c.647(exon2)C>A、c.647(exon2)C>G、c.981(exon3)C>G]对蛋白质结构的变化影响较小。未发现各突变类型所致蛋白质结构的改变与预后有关。结论临床表型为BFIE、ICCA的PRRT2基因突变患者预后良好,但各突变类型与患者预后无关。

Objective To analyze the gene mutation type and clinical phenotype of patients with PRRT2 mutation,and explore their relations with prognosis.Methods A total of 18 patients with PRRT2 gene mutation(1 patient with novel mutation in PRRT2 gene,and 17 probands in 17 families with PRRT2 gene mutation)were enrolled in Department of Neurology,First Affiliated Hospital of Air Force Medical University from January 2018 to July 2023.Serum of the patients was collected for whole exon sequencing,and mutation sites and types of PRRT2 gene were analyzed.SWISS-MODEL website was used to predict the changes in protein structure caused by PRRT2 gene mutation.The relations of gene mutation type and clinical phenotype with prognosis of these patients were analyzed.Results (1)All 18 patients with PRRT2 gene mutation were heterozygous mutation,including 12 frameshift mutations,5 missense mutations,and 1 integer mutation.The clinical phenotype included benign familial infantile epilepsy(BFIE)in 5 patients,epilepsy in 6 patients,exercise-induced paroxysmal kinesigenic dyskinesia(PKD)in 5 patients,and infantile convulsion and choreoathetosis(ICCA)in 2 patients.A total of 8 mutation sites were found in 18 patients with PRRT2 gene mutation,of which 3 mutation sites have been reported,and 5 mutation sites have not been reported,including c.647(exon2)C>A,c.647(exon2)C>G,c.170(exon2)delC,c.981(exon3)C>G,and lossl(EXON:2)(all).(2)Eighteen patients mainly accepted oxcarbazepine,levetiracetam,and sodium valproate in combination or monotherapy.Among them,5 BFIE patients,2 ICCA patients and 3 epilepsy patients were seizure-free after treatment.PKD patients did not respond well to oxcarbazepine.(3)Three frameshift mutations(mutation sites:c.649[exon2]_c.650[exon2]insC,c.640[exon2]_c.641[exon2]insC,and c.170[exon2]delC)led to premature termination of protein translation,resulting in significant changes in protein structure.Four missense mutations(mutation sites:c.640[exo2]G>C,c.647[exon2]C>A,c.647[exon2]C>G,and c.981[exon3]C>G)had little effect on protein structure changes.No relation was found between changes of protein structure caused by different mutation types and prognosis.Conclusion PRRT2 gene mutation patients with clinical phenotypes of BFIE and ICCA have good prognosis,but the mutation type is not related with the prognosis of patients.