Frontotemporal Dementia Associated With the C9ORF72 Mutation A Unique Clinical Profile
Frontotemporal Dementia Associated With the C9ORF72 Mutation A Unique Clinical Profile
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DOI：
10.1001/jamaneurol.2013.6002
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发表时间：
2014-03-01
期刊：
影响因子：
29
通讯作者：
Hodges, John R.
中科院分区：
文献类型：
--
作者：
Devenney, Emma;Hornberger, Michael;Hodges, John R.
重要性虽然在表征C9 ORF 72临床表型方面已经取得了进展，但是区分携带者和非携带者的标志性特征仍然不清楚。在一个明确定义的行为变异（bv）-FTD队列中，比较C9 ORF 72突变携带者与非携带者的影像学特征。和参与者一项在FTD专家转诊中心（FRONTIER）评估的患者前瞻性队列研究，为期5年（2008年1月1日至2012年12月31日）。在FRONTIER共评估了114例连续FTD、FTD-肌萎缩侧索硬化症（ALS）和皮质基底动脉综合征患者。将携带C9 ORF 72突变的bvFTD患者（n = 10）与非携带者（n = 19）和健康对照组（n = 35）进行比较。这些人的年龄、性别和教育史相匹配。主要结果和测量临床、行为、认知和神经心理缺陷，磁共振成像视觉评分量表上的皮质萎缩，以及Goldman量表量化的家族史。结果在114例FTD病例的队列中，14例患者表达C9 ORF 72突变，bvFTD中的频率为34%，FTD-ALS中的频率为17%。ALS（P = 0.001）和精神疾病（P = 0.02）的家族史在突变携带者中明显更常见。C9 ORF 72携带者也更容易出现精神病症状（P = 0.03）。在C9 ORF 72队列中，脑萎缩的程度显著较低，并且在许多队列中进展缓慢。目前的功能C9 ORF 72载体进行了比较，对国际共识诊断标准bvFTD，大多数情况下未能满足标准可能bvFTD.CONCLUSIONS和相关性的C9 ORF 72突变似乎是一个共同的原因bvFTD。许多C9 ORF 72携带者有ALS或精神疾病的家族史。精神病特征成为突变携带者和非携带者之间最具鉴别力的临床特征。进展通常缓慢，脑萎缩不像bvFTD非突变病例那么明显。这些发现对于诊断和选择患者进行基因检测具有临床意义。
IMPORTANCE While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear.OBJECTIVES To determine the frequency of the C9ORF72 mutation in a frontotemporal dementia (FTD) cohort and to define the clinical, neuropsychological, behavioral, and imaging features of C9ORF72 mutation carriers in comparison with noncarriers in a well-defined behavioral-variant (bv)-FTD cohort.DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of patients assessed during a 5-year period from January 1, 2008, to December 31, 2012, at an FTD specialist referral center (FRONTIER). A total of 114 consecutive patients with FTD, FTD-amyotrophic lateral sclerosis (ALS), and corticobasal syndrome were assessed at FRONTIER. Patients with bvFTD who carried the C9ORF72 mutation (n = 10) were compared with noncarriers (n = 19) and a healthy control group (n = 35). These were matched for age, sex, and education history. Blood sampling for gene analysis was performed after informed consent was obtained.MAIN OUTCOMES AND MEASURES Clinical, behavioral, cognitive, and neuropsychological deficits, cortical atrophy on a magnetic resonance imaging visual rating scale, and family history as quantified by the Goldman Scale.RESULTS In a cohort of 114 FTD cases, 14 patients expressed the C9ORF72 mutation, representing a frequency rate of 34% in bvFTD and 17% in FTD-ALS. Family histories of ALS (P = .001) and psychiatric disorders (P = .02) were significantly more common in mutation carriers. The C9ORF72 carriers were also more likely to experience psychotic symptoms (P = .03). The degree of brain atrophy was significantly less in the C9ORF72 cohort, and in many the progression was slow. Presenting features of C9ORF72 carriers were compared against International Consensus Diagnostic Criteria for bvFTD, and most cases failed to satisfy criteria for probable bvFTD.CONCLUSIONS AND RELEVANCE The C9ORF72 mutation appears to be a common cause of bvFTD. Many of the C9ORF72 carriers have a family history of ALS or psychiatric illness. Psychotic features emerged as the most discriminating clinical feature between mutation carriers and noncarriers. Progression is often slow and brain atrophy is less pronounced than in nonmutation cases of bvFTD. These findings have clinical relevance for both diagnosis and selection of patients for genetic testing.