朊蛋白基因突变致格斯特曼综合征家系临床表型分析

Phenotype analysis of the families with Gerstmann-Sträussler-Scheinker syndrome caused by prion protein gene mutations

目的探讨3例以共济失调起病的格斯特曼综合征(GSS)家系患者的临床表型、影像学特征和致病基因突变。方法采用二代测序外显子捕获方法对2014年以来中日友好医院运动障碍与神经遗传病研究中心收集的137个已排除脊髓小脑共济失调1、2、3、6、7、8、12、17和齿状核红核苍白球路易体萎缩致病基因重复扩展突变的拟诊共济失调家系先证者进行检测,对于阳性病例进行Sanger测序和家系共分离验证,分析先证者的临床表现和影像学特点。结果基因检测发现3个GSS家系先证者携带朊蛋白基因(PRNP)杂合错义突变c.305C>T(p.P102L),均为成年起病。3例先证者临床均表现为行走不稳、构音障碍,同时家系1先证者还表现为帕金森病样症状,家系2先证者伴有认知功能障碍。头颅磁共振成像显示家系2、3先证者表现为不同程度的小脑萎缩,家系1先证者还表现为苍白球对称高信号。结论GSS作为朊蛋白病的一种罕见亚型,临床可表现为共济失调,易被误诊漏诊。对于临床表现为共济失调的家系患者,在基因检测时需要关注GSS致病基因突变,及时诊断,有助于对家系成员开展遗传咨询和出生缺陷干预。

Objective To explore the clinical,imaging features and pathogenic mutations in three cases of Gerstmann-Sträussler-Scheinker syndrome(GSS)with ataxia.Methods Since 2014,totally 137 probands with autosomal dominant or sporadic ataxia were treated in the Department of Neurology,China-Japan Friendship Hospital.They were screened for mutations in prion protein(PRNP)gene using next-generation sequencing.Spinocerebellar ataxia 1,2,3,6,7,8,12,17 and dentatorubral-pallidoluysian atrophy were excluded by capillary electrophoresis.Potential pathogenic variants were confirmed by Sanger sequencing.Pathogenicity assessment was interpreted according to the American College of Medical Genetics standards and guidelines.Clinical phenotypes and imaging features of patients were analyzed in detail.Results Three pedigrees of GSS caused by PRNP gene variants were found.The probands of three pedigrees carried reported heterozygous missense mutation c.305C>T(p.P102L),all onset in adults.All of the three probands showed walking instability and dysarthria,additionally,the proband of pedigree 1 showed parkinsonian signs,the proband of pedigree 2 had cognitive impairment.Brain magnetic resonance imaging showed cerebellar atrophy of different degrees in probands 2 and 3,while pallidum hyperintense signal in proband 1.Conclusions GSS as a rare subtype of prion disease,could be characterized by cerebellar ataxia.For patients with ataxia,attention should be paid to GSS disease-causing gene mutations in genetic testing.Early diagnosis based on genetic testing will be instrumental in genetic counseling and birth defect intervention in pedigree members.