常染色体显性遗传性帕金森病家系临床特征及LRRK2基因分析

Clinical features and mutation analysis of LRRK2 gene in patients with autosomal dominant familial Parkinson＇s disease

目的研究常染色体显性遗传家族性帕金森病（PD）患者的临床特征及其LRRK2基因突变。方法对16例常染色体显性遗传家族史的PD患者LRRK2基因的外显子5、13、31、32、35、37、41邯进行测序检测。利用限制性片段长度多态性（RFLP）分析所发现的新突变c．1432 G〉T Asp478Tyr在240例散发性PD患者及214名健康者中的发生频率。结果常染色体显性遗传家系PD患者与散发性PD患者比较临床特点以晚发为主，首发症状以静止性震颤（9例，56．25％，t=0．558，P=0．679）和动作迟缓（9例，56．25％，t=0．369，P=0．454）最为常见，其次是肌强直（6例，37．50％，t=1．324，P=0．735）和姿势障碍（5例，31．25％，t=2．369，P=0．956），对左旋多巴治疗反应良好，左旋多巴诱导的异动症少见。LRRK2基因突变检测发现6个突变：c．457 T〉C Leu153Leu、c．1432 G〉T Asp478Tyr、c．5457 T〉C Gly1819Gly、c．7153 G〉A Gly2385Arg、IVS31＋28 T〉G、IVS37＋162 T〉C。其中，c．1432 G〉T Asp478Tyr是未报道过的新突变。在240例散发性PD患者及214名健康者中均未发现有此突变。未发现与PD相关的LRRK2基因突变Arg1441Cys／Gly／His、Arg1514Gln、Tyr1699Cys、Ile2012Thr、Gly2019Ser和Ile2020Thr。结论常染色体显性遗传性PD患者临床特征表现为典型的PD临床特征，存在LRRK2基因Asp478Tyr和Gly2385Arg突变。Asp478Tyr是未报道过的新突变。

Objective To investigate the clinical features and LRRK2 gene mutation in patients with autosomal dominant familial Parkinson＇ s disease （PD）. Methods The clinical features of 16 autosomal dominant familial PD probands were analyzed in terms of age at onset, onset symptoms, UPDRS scores, response to the levodopa treatment and drug-induced dyskinesia. The LRRK2 gene exons 5, 13, 31, 32, 35, 37, 41 and 48 of 16 probands were sequenced after polymerase chain reaction. The novel mutation was further screened in 240 sporadic PD patients and 214 controls using PCR-RFLP for the genotype frequency analysis. Results Clinically, most of 16 probands had late-onset age. Resting tremor （9 patients ,56. 25%, t = 0. 558, P = 0. 679 ） and bradykinesia （ 9 patients, 56. 25%, t = 0. 369, P = 0. 454） were common onset symptoms followed by rigidity （6 patients,37. 50%, t = 1. 324 ,P =0. 735） and postural instability （5 patients,31.25%, t = 2. 369,P =0. 956）. Majority of them had good response to levodopa treatment and rare occurrence of drug-induced dyskinesia. Among the 16 autosomal dominant familial PD probands, 6 variants were identified： c. 457 T 〉 C （ Leu153Leu）, c. 1432 G 〉 T （ Asp478Tyr）, c. 5457 T 〉 C （Gly1819Gly）, c. 7153 G 〉 A （ Gly2385Arg）, IVS31 ＋ 28 T 〉 G and IVS37 ＋ 162 T 〉 C. The c. 1432 G 〉 T （Asp478Tyr） variant was a novel mutation and it was not detected in 240 sporadic PD patients and 214 controls. The reported mutations associated with the PD, such as Arg1441Cys/Gly/His, Arg1514Gln, Tyr1699Cys, Ile2012Thr, Gly2019Ser and Ile2020Thr, were not found in our study. Condusions The autosomal dominant familial PD patients present with classical symptoms of PD and bear the LRRK2 variants Asp478Tyr and Gly2385Arg.