Chen-Plotkin Alice S, Martinez-Lage Maria, Sleiman Patrick M A, Hu William, Greene Robert, Wood Elisabeth McCarty, Bing Shaoxu, Grossman Murray, Schellenberg Gerard D, Hatanpaa Kimmo J, Weiner Myron F, White Charles L, Brooks William S, Halliday Glenda M, Kril Jillian J, Gearing Marla, Beach Thomas G, Graff-Radford Neill R, Dickson Dennis W, Rademakers Rosa, Boeve Bradley F, Pickering-Brown Stuart M, Snowden Julie, van Swieten John C, Heutink Peter, Seelaar Harro, Murrell Jill R, Ghetti Bernardino, Spina Salvatore, Grafman Jordan, Kaye Jeffrey A, Woltjer Randall L, Mesulam Marsel, Bigio Eileen, Lladó Albert, Miller Bruce L, Alzualde Ainhoa, Moreno Fermin, Rohrer Jonathan D, Mackenzie Ian R A, Feldman Howard H, Hamilton Ronald L, Cruts Marc, Engelborghs Sebastiaan, De Deyn Peter P, Van Broeckhoven Christine, Bird Thomas D, Cairns Nigel J, Goate Allison, Frosch Matthew P, Riederer Peter F, Bogdanovic Nenad, Lee Virginia M Y, Trojanowski John Q, Van Deerlin Vivianna M
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, USA.
Arch Neurol. 2011 Apr;68(4):488-97. doi: 10.1001/archneurol.2011.53.
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).
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.
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.
GRN+ FTLD-TDP differs in key features from GRN- FTLD-TDP.
评估97例颗粒蛋白前体（GRN）突变患者中独特突变的相对频率及其相关特征，GRN突变是额颞叶变性（FTLD）的一个重要病因。
成立了一个46个位点的国际额颞叶变性协作组，以收集伴有43 kDa TAR DNA结合蛋白（TDP - 43）阳性包涵体的FTLD病例（FTLD - TDP）。我们鉴定出97例患有致病性GRN突变的FTLD - TDP患者（GRN + FTLD - TDP），评估了他们的遗传和临床特征，并将其与453例排除GRN突变的FTLD - TDP患者（GRN - FTLD - TDP）进行比较。已知患者之间无亲缘关系。97例GRN + FTLD - TDP病例中的79例以及所有GRN - FTLD - TDP病例的神经病理学特征均被确认为FTLD - TDP。
GRN + FTLD - TDP患者的FTLD起病年龄比GRN - FTLD - TDP患者年轻（中位数分别为58.0岁和61.0岁；P < 0.001），死亡年龄也是如此（中位数分别为65.5岁和69.0岁；P < 0.001）。与GRN - FTLD - TDP相比，GRN + FTLD - TDP患者合并运动神经元病的情况要少得多（5.4%对26.3%；P < 0.001）。观察到50种不同的GRN突变，包括2种新突变：c.139delG（p.D47TfsX7）和c.378C>A（p.C126X）。2种最常见的GRN突变是c.1477C>T（p.R493X，在18例患者中发现，占GRN病例的18.6%）和c.26C>A（p.A9D，在6例患者中发现，占病例的6.2%）。携带c.1477C>T突变的患者在17号染色体上共享一个单倍型；临床上，他们与其他GRN突变患者相似。与其他GRN突变患者相比，携带c.26C>A突变的患者FTLD起病年龄和死亡年龄似乎更小，且帕金森特征更明显。
GRN + FTLD - TDP与GRN - FTLD - TDP在关键特征上存在差异。
