Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72.
Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72.
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DOI：
10.1007/s00401-011-0907-y
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发表时间：
2011-12
影响因子：
12.7
通讯作者：
Dickson DW
中科院分区：
文献类型：
--
作者：
Murray ME;DeJesus-Hernandez M;Rutherford NJ;Baker M;Duara R;Graff-Radford NR;Wszolek ZK;Ferman TJ;Josephs KA;Boylan KB;Rademakers R;Dickson DW
额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）是与TDP-43病理学相关的疾病谱的一部分。支持这一点的有力证据是家族成员存在FTD、ALS或FTD和ALS的混合特征（称为FTD-MND）的运动障碍。这些家族中的一些与9号染色体连锁，在C9 ORF 72的非编码区具有六核苷酸扩展突变。突变的发现定义了c9 FTD/ALS。在发现C9 ORF 72突变之前，假设c9 FTD/ALS中TDP-43病理学是一致的。在这项研究中，我们检查了20例c9 FTD/ALS的神经病理学和临床特征，这些病例来自神经退行性疾病脑库。包括6名临床诊断为ALS的患者，8名FTD，1名FTD-MND和4名阿尔茨海默型痴呆症。1例患者的临床信息不可用。病理学检查均为TDP-43病理，但主要分为ALS、FTLD-MND和FTLD-TDP三组。ALS病例在形态学上与典型的散发性ALS相似，几乎没有运动外TDP-43病理学;所有病例均具有少突胶质细胞胞质内含物。FTLD-MND主要显示麦肯齐3型TDP-43病理学，并且在运动神经元中均具有ALS样病理学，但更广泛的运动外病理学，具有少突胶质细胞胞质内含物和罕见的海马硬化。由于颗粒蛋白前体基因突变，FTLD-TDP病例具有与FTLD-TDP相似的几个特征，包括伴有神经元核内包涵体和海马硬化的麦肯齐1型TDP-43病理学。FTLD-TDP患者年龄较大，有些人被认为患有阿尔茨海默型痴呆症。除FTD和ALS临床表现外，本研究还表明c9 FTD/ALS可能存在其他表现，可能与发病年龄和海马硬化相关。此外，不仅ALS和FTLD之间存在病理异质性，而且FTLD组内也存在病理异质性。需要进一步研究以解决C9 ORF 72突变导致的c9 FTD/ALS临床和病理异质性的分子机制。
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72.
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DOI：
10.1111/j.1440-1789.2009.01091.x
发表时间：
2010-04
期刊：
Neuropathology : official journal of the Japanese Society of Neuropathology
影响因子：
--
作者：
Geser F;Lee VM;Trojanowski JQ
通讯作者：
Trojanowski JQ
影响因子：
12.7
作者：
Brandmeir, Nicholas J.;Geser, Felix;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
--
作者：
Geser, Felix;Brandmeir, Nicholas J.;Trojanowski, John Q.
通讯作者：
Trojanowski, John Q.
影响因子：
12.7
作者：
Gitcho MA;Bigio EH;Mishra M;Johnson N;Weintraub S;Mesulam M;Rademakers R;Chakraverty S;Cruchaga C;Morris JC;Goate AM;Cairns NJ
通讯作者：
Cairns NJ
影响因子：
12.7
作者：
Josephs, Keith A.;Stroh, Alex;Dickson, Dennis W.
通讯作者：
Dickson, Dennis W.