Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations
Distinct clinical and pathological characteristics of frontotemporal dementia associated with C9ORF72 mutations
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DOI：
10.1093/brain/awr355
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发表时间：
2012-03-01
期刊：
影响因子：
14.5
通讯作者：
Pickering-Brown, Stuart M.
中科院分区：
文献类型：
--
作者：
Snowden, Julie S.;Rollinson, Sara;Pickering-Brown, Stuart M.
C9ORF72基因的六核苷酸重复扩增是9号染色体连锁的额颞叶痴呆和运动神经元疾病的原因，这为更好地了解这些疾病与其他临床形式的额颞叶变性之间的关系提供了机会。在这项研究中，我们筛查了398名额颞痴呆、进行性非流利性失语、语义性痴呆或这些症状的混合型患者的C9ORF72基因突变。运动神经元病55例(14%)。我们确定了32名C9ORF72突变患者，占队列的8%。患者的临床表现各不相同：9例额颞叶痴呆合并运动神经元疾病，19例单纯额颞叶痴呆，1例混合性语义性痴呆合并额叶特征，3例进行性非流利性失语。正如预期的那样，C9ORF72突变与运动神经元病之间存在显著的关联。然而，46名患者，包括22名家族性患者，有运动神经元病，但没有C9ORF72突变。38%的C9ORF72突变患者表现为精神病，28%的患者表现出偏执、妄想或非理性思维，而4%的非突变携带者表现出类似的表现。精神病的存在极大地增加了患者携带突变的几率。突变携带者运动刻板印象的发生率较低，而复杂重复行为的发生率相对较高，这在很大程度上与患者的妄想有关。他们还显示，与没有C9ORF72突变的患者相比，他们后天获得的甜食偏好的发生率更低。5名患者的尸检显示了反式反应DNA结合蛋白43的病理，其中1名患者为A型，3名为B型。然而，一名患者有皮质基底部变性病理。研究结果表明，C9ORF72突变会导致部分但不是所有额颞叶痴呆合并运动神经元疾病。其他突变还有待发现。C9ORF72突变与不同的临床表现和病理有关。然而，这一发现突显了C9ORF72突变与精神病之间的强大关联，并表明C9ORF72突变患者的行为特征在质量上是不同的。C9ORF72基因突变可能不仅是额颞叶运动神经元病痴呆的主要原因，也是迟发性精神病的主要原因。
The identification of a hexanucleotide repeat expansion in the C9ORF72 gene as the cause of chromosome 9-linked frontotemporal dementia and motor neuron disease offers the opportunity for greater understanding of the relationship between these disorders and other clinical forms of frontotemporal lobar degeneration. In this study, we screened a cohort of 398 patients with frontotemporal dementia, progressive non-fluent aphasia, semantic dementia or mixture of these syndromes for mutations in the C9ORF72 gene. Motor neuron disease was present in 55 patients (14%). We identified 32 patients with C9ORF72 mutations, representing 8% of the cohort. The patients' clinical phenotype at presentation varied: nine patients had frontotemporal dementia with motor neuron disease, 19 had frontotemporal dementia alone, one had mixed semantic dementia with frontal features and three had progressive non-fluent aphasia. There was, as expected, a significant association between C9ORF72 mutations and presence of motor neuron disease. Nevertheless, 46 patients, including 22 familial, had motor neuron disease but no mutation in C9ORF72. Thirty-eight per cent of the patients with C9ORF72 mutations presented with psychosis, with a further 28% exhibiting paranoid, deluded or irrational thinking, whereas < 4% of non-mutation bearers presented similarly. The presence of psychosis dramatically increased the odds that patients carried the mutation. Mutation bearers showed a low incidence of motor stereotypies, and relatively high incidence of complex repetitive behaviours, largely linked to patients' delusions. They also showed a lower incidence of acquired sweet food preference than patients without C9ORF72 mutations. Post-mortem pathology in five patients revealed transactive response DNA-binding protein 43 pathology, type A in one patient and type B in three. However, one patient had corticobasal degeneration pathology. The findings indicate that C9ORF72 mutations cause some but not all cases of frontotemporal dementia with motor neuron disease. Other mutations remain to be discovered. C9ORF72 mutations are associated with variable clinical presentations and pathology. Nevertheless, the findings highlight a powerful association between C9ORF72 mutations and psychosis and suggest that the behavioural characteristics of patients with C9ORF72 mutations are qualitatively distinct. Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis.