Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration
Genetic and Clinical Features of Progranulin-Associated Frontotemporal Lobar Degeneration
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DOI：
10.1001/archneurol.2011.53
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发表时间：
2011-04-01
影响因子：
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通讯作者：
Van Deerlin, Vivianna M.
中科院分区：
文献类型：
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作者：
Chen-Plotkin, Alice S.;Martinez-Lage, Maria;Van Deerlin, Vivianna M.
目的：研究97例额颞叶变性(FTLD)的重要病因前颗粒蛋白(GRN)基因突变的相对频率及其相关特征。参与者与设计：为收集FTLD伴TDP-43阳性包涵体TAR DNA结合蛋白(FTLD-TDP)的病例，成立了一个46位点的国际额颞叶变性协作组织。我们鉴定了97例具有致病GRN突变(GRN+FTLD-TDP)的FTLD-TDP患者，评估了他们的遗传学和临床特征，并与453例排除GRN突变的FTLD-TDP患者(GRN-FTLD-TDP)进行了比较。目前还没有患者有亲属关系。结果：GRN+FTLD-TDP与GRN-FTLD-TDP相比，FTLD-TDP的发病年龄较早(中位数分别为58.0vs61.0岁；P<；.001)和死亡年龄(中位数分别为65.5vs69.0岁；P<；.001)。GRN+FTLD-TDP组与GRN-FTLD-TDP组合并运动神经元疾病的发生率明显低于GRN-FTLD-TDP组(5.4%vs26.3%；P<；.001)。共观察到50个不同的GRN突变，其中包括2个新突变：c.139delG(p.D47TfsX7)和c.378C>；A(p.C126X)。最常见的两个GRN突变是c.1477C>；T(p.R493X，发现18例，占GRN病例的18.6%)和c.26C>；A(p.A9D，发现6例，占6.2%)。带有C.1477C和GT；T突变的患者在17号染色体上有相同的单倍型；临床上，他们与其他GRN突变的患者相似。与其他GRN突变的患者相比，具有c.26C>；A突变的患者出现FTLD的发病年龄和死亡年龄更小，帕金森病特征更多。结论：GRN+FTLD-TDP与GRN-FTLD-TDP的关键特征不同。
Objective: To assess the relative frequency of unique mutations and their associated characteristics in 97 individuals with mutations in progranulin (GRN), an important cause of frontotemporal lobar degeneration (FTLD).Participants and Design: A 46-site International Frontotemporal Lobar Degeneration Collaboration was formed to collect cases of FTLD with TAR DNA-binding protein of 43-kDa (TDP-43)-positive inclusions (FTLD-TDP). We identified 97 individuals with FTLD-TDP with pathogenic GRN mutations (GRN+ FTLD-TDP), assessed their genetic and clinical characteristics, and compared them with 453 patients with FTLD-TDP in which GRN mutations were excluded (GRN- FTLD-TDP). No patients were known to be related. Neuropathologic characteristics were confirmed as FTLD-TDP in 79 of the 97 GRN+ FTLD-TDP cases and all of the GRN- FTLD-TDP cases.Results: Age at onset of FTLD was younger in patients with GRN+ FTLD-TDP vs GRN- FTLD-TDP (median, 58.0 vs 61.0 years; P < .001), as was age at death (median, 65.5 vs 69.0 years; P < .001). Concomitant motor neuron disease was much less common in GRN+ FTLD-TDP vs GRN- FTLD-TDP (5.4% vs 26.3%; P < .001). Fifty different GRN mutations were observed, including 2 novel mutations: c.139delG (p.D47TfsX7) and c.378C>A (p.C126X). The 2 most common GRN mutations were c.1477C>T (p.R493X, found in 18 patients, representing 18.6% of GRN cases) and c.26C>A (p.A9D, found in 6 patients, representing 6.2% of cases). Patients with the c.1477C>T mutation shared a haplotype on chromosome 17; clinically, they resembled patients with other GRN mutations. Patients with the c.26C>A mutation appeared to have a younger age at onset of FTLD and at death and more parkinsonian features than those with other GRN mutations.Conclusion: GRN+ FTLD-TDP differs in key features from GRN- FTLD-TDP.