Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p
Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p
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DOI：
10.1093/brain/awr354
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发表时间：
2012-03-01
期刊：
影响因子：
14.5
通讯作者：
Mackenzie, Ian R. A.
中科院分区：
文献类型：
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作者：
Hsiung, Ging-Yuek R.;DeJesus-Hernandez, Mariely;Mackenzie, Ian R. A.
额颞叶痴呆与肌萎缩侧索硬化症是密切相关的临床综合征，其分子发病机制重叠。据报道，有几个家族的成员患有额颞叶痴呆、肌萎缩侧索硬化症或两者兼而有之，这些家族的成员与染色体9p21上的一个区域有遗传联系。最近，两项研究发现9p染色体上的FTD/ALS基因缺陷为9号染色体开放阅读框72基因（C9ORF72）非编码区GGGGCC六核苷酸重复扩增。在本研究中，我们对16例无亲属关系的C9ORF72突变所致额颞叶痴呆的临床特征和神经病理学进行了详细分析。所有患者均为常染色体显性遗传。8个家庭有额颞叶痴呆和肌萎缩侧索硬化症的组合，而其他8个家庭有纯粹的额颞叶痴呆表型。已获得16个家庭中30名受影响成员的临床资料。发病年龄（平均54.3岁，范围34 ~ 74岁）和病程（平均5.3岁，范围1 ~ 16岁）差异较大。早期诊断包括行为变异性额颞叶痴呆（n = 15）、进行性非流畅性失语（n = 5）、肌萎缩侧索硬化（n = 9）和进行性非流畅性失语-肌萎缩侧索硬化（n = 1）。临床表现的异质性在家庭中也很常见。然而，有一种趋势，表型与疾病进展趋同；7名受试者最终临床诊断为额颞叶痴呆和肌萎缩侧索硬化症，所有最初诊断为进行性非流畅性失语症的患者随后出现了明显的行为异常。21名受影响的家庭成员进行了尸检，发现所有人都有交互反应的DNA结合蛋白与M-r 43 kD （TDP-43）病理，在广泛的神经解剖分布。所有患者均累及运动外新皮层和海马（额颞叶变性- tdp），除一例（临床纯粹额颞叶痴呆）外，其余均累及下运动神经元，这是肌萎缩性侧索硬化症的特征。此外，一致且相对特定的病理发现是小脑皮层中存在泛素/p62阳性但tdp -43阴性的神经元包涵体。我们的研究结果表明，C9ORF72突变是家族性额颞叶痴呆伴TDP-43病理的主要原因，这可能解释了大多数合并额颞叶痴呆/肌萎缩侧索硬化症的家庭，并进一步支持了额颞叶痴呆和肌萎缩侧索硬化症代表了一种具有重叠分子发病机制的疾病临床病理谱的概念。
Frontotemporal dementia and amyotrophic lateral sclerosis are closely related clinical syndromes with overlapping molecular pathogenesis. Several families have been reported with members affected by frontotemporal dementia, amyotrophic lateral sclerosis or both, which show genetic linkage to a region on chromosome 9p21. Recently, two studies identified the FTD/ALS gene defect on chromosome 9p as an expanded GGGGCC hexanucleotide repeat in a non-coding region of the chromosome 9 open reading frame 72 gene (C9ORF72). In the present study, we provide detailed analysis of the clinical features and neuropathology for 16 unrelated families with frontotemporal dementia caused by the C9ORF72 mutation. All had an autosomal dominant pattern of inheritance. Eight families had a combination of frontotemporal dementia and amyotrophic lateral sclerosis while the other eight had a pure frontotemporal dementia phenotype. Clinical information was available for 30 affected members of the 16 families. There was wide variation in age of onset (mean = 54.3, range = 34-74 years) and disease duration (mean = 5.3, range = 1-16 years). Early diagnoses included behavioural variant frontotemporal dementia (n = 15), progressive non-fluent aphasia (n = 5), amyotrophic lateral sclerosis (n = 9) and progressive non-fluent aphasia-amyotrophic lateral sclerosis (n = 1). Heterogeneity in clinical presentation was also common within families. However, there was a tendency for the phenotypes to converge with disease progression; seven subjects had final clinical diagnoses of both frontotemporal dementia and amyotrophic lateral sclerosis and all of those with an initial progressive non-fluent aphasia diagnosis subsequently developed significant behavioural abnormalities. Twenty-one affected family members came to autopsy and all were found to have transactive response DNA binding protein with M-r 43 kD (TDP-43) pathology in a wide neuroanatomical distribution. All had involvement of the extramotor neocortex and hippocampus (frontotemporal lobar degeneration-TDP) and all but one case (clinically pure frontotemporal dementia) had involvement of lower motor neurons, characteristic of amyotrophic lateral sclerosis. In addition, a consistent and relatively specific pathological finding was the presence of neuronal inclusions in the cerebellar cortex that were ubiquitin/p62-positive but TDP-43-negative. Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology, that likely accounts for the majority of families with combined frontotemporal dementia/amyotrophic lateral sclerosis presentation, and further support the concept that frontotemporal dementia and amyotrophic lateral sclerosis represent a clinicopathological spectrum of disease with overlapping molecular pathogenesis.