Clinicopathologic correlation in PGRN mutations
Clinicopathologic correlation in PGRN mutations
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DOI：
10.1212/01.wnl.0000267701.58488.69
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发表时间：
2007-09-11
期刊：
影响因子：
9.9
通讯作者：
Bigio, E. H.
中科院分区：
文献类型：
--
作者：
Davion, S.;Johnson, N.;Bigio, E. H.
背景：额颞叶痴呆（FTD）与17号染色体的微管相关蛋白tau（MAPT）基因区有关。然而，许多17号染色体连锁的FTLD不具有MAPT突变或tau蛋白沉积物，但具有泛素阳性、tau和β-核蛋白阴性的内含物。最近在这些个体中的一些个体中发现了位于MAPT 17q21.31的1.7 Mb的颗粒蛋白前体（PGRN）基因的突变。所有病例的病理表型迄今包括泛素化的神经元核内包涵体（NIIs）和神经元胞质包涵体（NCIs）。根据IRB批准的方案，从近亲处获得知情同意书。我们比较了临床和病理结果，在这些情况下，没有PGRN突变。结果：PGRN突变被发现在4例患者中，两个临床FTD和阳性家族史，和两个临床原发性进行性失语症（PPA），一个有，一个没有家族史。所有4例有PGRN突变的病例和8例无PGRN突变的病例中的5例有泛素化的NCI和NII。与没有PGRN突变的FTLD-U病例相比，具有PGRN突变的个体的大脑与更频繁的额叶NCI和营养不良性神经突、更少频率的齿状回NCI和更频繁的纹状体NII相关。17 q21的PGRN突变可能发生在明显散发的额颞叶痴呆伴泛素化包涵体病例中，以及原发性进行性失语或行为变异的病例中。额颞叶痴呆一些没有PGRN突变的病例也有泛素化的神经元核内包涵体。在有和没有PGRN突变的个体中观察到临床病理学差异。
Background: Frontotemporal dementia ( FTD) has been linked to the microtubule associated protein tau ( MAPT) gene region of chromosome 17. However, many chromosome- 17 linked FTLDs do not have MAPT mutations or tau protein deposits, but have ubiquitin positive, tau and alphasynuclein negative inclusions. Mutations in the progranulin ( PGRN) gene, located 1.7 Mb from MAPT at 17q21.31, were recently discovered in some of these individuals. The pathologic phenotype in all cases has thus far included ubiquitinated neuronal intranuclear inclusions ( NIIs) and neuronal cytoplasmic inclusions ( NCIs).Methods: PGRN mutation analysis was performed in 12 individuals. Informed consent was obtained from next of kin under an IRB- approved protocol. We compared clinical and pathologic findings in those cases with and without PGRN mutations.Results: PGRN mutations were found in four patients, two with clinical FTD and a positive family history, and two with clinical primary progressive aphasia ( PPA), one with and one without a family history. All four cases with, and five of eight cases without, PGRN mutations had ubiquitinated NCIs and NIIs. Brains of individuals with PGRN mutations are associated with more frequent frontal NCIs and dystrophic neurites, less frequent dentate gyrus NCIs, and more frequent striatal NIIs than FTLD- U cases without PGRN mutations.Conclusion: PGRN mutations at 17q21 may occur in apparently sporadic frontotemporal lobar dementia with ubiquitinated inclusions cases and in cases presenting with either primary progressive aphasia or the behavioral variant of frontotemporal dementia. Some cases without PGRN mutations also have ubiquitinated neuronal intranuclear inclusions. Clinicopathologic differences are observed among individuals with and without PGRN mutations.