结节性硬化症患者基因突变与临床表型的关系

Relationship between gene mutation and clinical phenotype in patients with tuberous sclerosis complex

目的分析结节性硬化症（TSC）患者基因突变特点及其与临床表型的关系。方法入组了2007年5月至2014年5月在广东三九脑科医院就诊的临床确诊的TSC患者共76例，收集患者临床资料，并进行TSC基因检测，以进一步明确患者基因型与临床表型的关系。结果在76例患者中男性50例（66％），女性26例（34％）。19例存在类囊状结节（31％），69例存在皮肤改变（92％），16例存在肾脏病变（30％），存在智力低下者50例（69％），随访1年以上仍有癫痫发作者36例（49％）。发现TSC1基因突变者22例（29％），TSC2基因突变者39例（51％），未发现基因突变者15例（20％），TSC1基因突变：TSC2基因突变比率大约为3：5。在有TSC基因突变家族史的患者中，TSC1基因突变：TSC2基因突变比率为1：1；在无TSC家族史患者中，TSC1基因突变：TSC2基因突变比率大约为1：2。与TSC1基因突变和未发现突变组相比，TSC2基因突变组在癫痫发病年龄（Z=1．688，P=0．007）、癫痫发病年龄小于1岁（X2=10．584，P=0．001）、癫痫病程（X2=4．996，P=0．025）、痉挛发作（X2=10．111，P=0．001）、类囊状结节（X2=9．182，P=0．002）、皮肤改变（X2=9．016，P=0．003）和肾脏病变（X2=6．079，P=0．014）等方面差异有统计学意义。未发现基因型与智力的关系。结论TSC1基因突变和未发现基因突变者临床表型较轻，TSC2基因突变者临床表型重，TSC2基因突变患者癫痫发病年龄小，尤其好发于1岁以内，更容易出现痉挛发作、颅内类囊状结节、皮肤改变和肾脏病变等。因此对于TSC2基因突变患者应给予积极的治疗。

Objective To study the relationship between gene mutation and clinical phenotype in patients with tuberous sclerosis complex （TSC）. Methods The clinical data of 76 patients with TSC diagnosed in Guangdong 999 Brain Hospital were collected between May 2007 and May 2014 and then TSC gene mutation analysis was performed. Genotype-phenotype analyses for all the patients were also carried out. Results Fifty of the 76 （66%） patients were male, and 26 （34%） were female, in which 19 （31%） patients presented with cyst-like cortical tuber, 69 （92%） with skin lesions, 16 （30%） with renal lesions, 50 （69%） with mental retardation and 39 still suffered seizures after a year. In this study, 22 （29%） cases showed TSC1 gene mutation, 31 （59%） presented TSC2 gene mutation, and 15 （20%） cases had no mutation identified. The mutation ratio of TSC1 ： TSC2 was approximately 3 ： 5, while the mutation ratio of TSC1 ： TSC2 was 1 ： 1 for familial TSC patients, and 1 ： 2 for sporadic TSC patients. Comparing to those with TSC1 gene mutation and no mutation identified, patients with TSC2 gene mutation exhibited statistical meaning on the aspects of the onset age of seizure （ Z = 1. 688, P = 0. 007 ）, seizure onset before 1-year-old （X2 = 10. 584, P = 0. 001 ） , epilepsy duration （ X2 = 4. 996, P = 0. 025 ）, spasms onset （ X2 = 10. 111, P = 0. 001 ）, cyst-like cortical tuber （ X2 = 9. 182, P = 0. 002）, skin lesions （ X2 = 9. 016, P =0. 003）, as well as renal lesions （X2 = 6. 079, P = 0. 014）. No apparent relation was found between genotype and intelligence outcome. Conclusions severer symptoms in seizure onset than those with TSC1 The patients with TSC2 gene mutations presented gene mutation and no mutation identified. The patients with TSC2 gene mutation were characterized by early onset of seizure, especially before 1-year-old, others like spasms onset, cyst-like cortical tuber, skin lesions, as well as renal lesions being more vulnerable. Therefore, more active treatment should be given to the patients with TSC2 gene mutation.