Clinicopathological description of two cases with SQSTM1 gene mutation associated with frontotemporal dementia
Clinicopathological description of two cases with SQSTM1 gene mutation associated with frontotemporal dementia
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DOI：
10.1111/neup.12233
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发表时间：
2016-02-01
期刊：
影响因子：
2.3
通讯作者：
Matej, Radoslav
中科院分区：
文献类型：
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作者：
Kovacs, Gabor G.;van der Zee, Julie;Matej, Radoslav
与额颞叶变性(FTLD)和额颞叶痴呆(FTD)相关的临床病理表型有很强的遗传影响。TDP-43的细胞内沉积是一组常见病例的典型特征。绝缘体1(SQSTM1)基因突变在FTD患者中很少发现。在这里，我们提供了一个全面的临床病理描述的两个病例的SQSTM1突变。患者1的临床表型(突变p.Glu396*)与FTD的行为变异(BV)相容。TDP-43病理符合FTLD-TDP病理的B型特点。然而，通过与少突胶质细胞标记物TPPP/p25的共同定位，也可以看到显著的神经元颗粒胞浆TDP-43免疫反应和丰富的少突胶质包涵体。患者2的临床表型与晚期伴有帕金森综合征和延髓症状的bvFTD相容。患者2的基因检测发现了SQSTM1中的C9orf72重复扩增突变和错义突变(p.Arg212Cys)。TDP-43的病理特点是与A型神经炎基本一致。与患者1不同，P62病理更多地表现为神经元中的TDP-43免疫反应。使用一种抗体来检测通过重复相关的非ATG翻译产生的与C9orf72基因中扩展的六核苷酸重复相关的多(GP)肽，我们证实了病原包涵体的存在。本研究支持先前对肌萎缩侧索硬化症(ALS)的观察，即SQSTM1突变与TDP-43病理一致相关。C9orf72突变的并存可能会影响表型，因此发现一个与FTLD(或ALS)相关的突变并不排除存在进一步的有影响的基因改变。少突胶质细胞的TDP-43病理在某些形式的FTLD-TDP中相当明显，因此它们的评估可被考虑纳入分类系统。
There is a strong genetic influence on the clinicopathological phenotypes associated with frontotemporal lobar degeneration (FTLD) and frontotemporal dementia (FTD). Intracellular deposition of TDP-43 is the phenotypical hallmark of a frequent subgroup of cases. Mutations in the sequestosome 1 (SQSTM1) gene have rarely been found in individuals with FTD. Here we provide a comprehensive clinicopathological description of two cases with a SQSTM1 mutation. The clinical phenotype of patient 1 (mutation p.Glu396*) was compatible with the behavioural variant (bv) of FTD. TDP-43 pathology was consistent with the features of type B of FTLD-TDP pathology. However, prominent neuronal granular cytoplasmic TDP-43 immunoreactivity and abundant oligodendroglial inclusions, proven by colocalization with the oligodendroglial-marker TPPP/p25, were also seen. The clinical phenotype of patient 2 was compatible with bvFTD associated with parkinsonism and bulbar symptoms in the later stage. Genetic testing of patient 2 identified a C9orf72 repeat expansion mutation together with a missense mutation (p.Arg212Cys) in SQSTM1. TDP-43 pathology was characterized by neuritic profiles compatible mostly with type A. In contrast to patient 1, p62 pathology was seen to a greater extent as TDP-43 immunoreactivity in neurons. Using an antibody that detects poly(GP) peptides produced via repeat associated non-ATG translation associated with expanded hexanucleotide repeat in the C9orf72 gene, we confirmed the presence of pathognomonic inclusions. The present study supports previous observations on amyotrophic lateral sclerosis (ALS) that SQSTM1 mutations consistently associate with TDP-43 pathology. The co-presence of C9orf72 mutation may influence the phenotype, thus finding one FTLD (or ALS) related mutation does not exclude the presence of further influential genetic alterations. Oligodendroglial TDP-43 pathology is considerable in some forms of FTLD-TDP, thus their evaluation might be considered to be included in classification systems.