Prince of Wales Clinical School, University of New South Wales, Sydney, Australia2Neuroscience Research Australia, Sydney, Australia.
Neuroscience Research Australia, Sydney, Australia3School of Medical Sciences, University of New South Wales, Sydney, Australia.
JAMA Neurol. 2014 Mar;71(3):331-9. doi: 10.1001/jamaneurol.2013.6002.
While advances have been made in characterizing the C9ORF72 clinical phenotype, the hallmark features that discriminate between carriers and noncarriers remain unclear.
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.
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.
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.
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.
虽然在描述 C9ORF72 临床表型方面已经取得了进展，但仍不清楚区分携带者和非携带者的标志性特征。
确定 C9ORF72 突变在额颞叶痴呆（FTD）队列中的频率，并在一个明确的行为变异型（bv）-FTD 队列中，与非携带者相比，定义 C9ORF72 突变携带者的临床、神经心理学、行为和影像学特征。
设计、地点和参与者：这是一项前瞻性队列研究，于 2008 年 1 月 1 日至 2012 年 12 月 31 日期间在 FTD 专家转诊中心（FRONTIER）对患者进行评估。共有 114 名 FTD、FTD-肌萎缩侧索硬化症（ALS）和皮质基底节综合征患者在 FRONTIER 接受了评估。在 FRONTIER，对携带 C9ORF72 突变的 10 名 bvFTD 患者（n=10）与非携带者（n=19）和健康对照组（n=35）进行了比较。这些组在年龄、性别和教育史方面进行了匹配。在获得知情同意后，进行血液取样进行基因分析。
临床、行为、认知和神经心理学缺陷、磁共振成像视觉评分的皮质萎缩以及通过 Goldman 量表量化的家族史。
在 114 例 FTD 病例的队列中，14 例患者表达了 C9ORF72 突变，在 bvFTD 中占 34%，在 FTD-ALS 中占 17%。突变携带者的 ALS（P=0.001）和精神疾病（P=0.02）家族史更为常见。携带 C9ORF72 的患者也更有可能出现精神病症状（P=0.03）。C9ORF72 组的脑萎缩程度明显较低，且许多患者的进展较为缓慢。C9ORF72 携带者的临床表现与国际 bvFTD 共识诊断标准进行了比较，大多数病例未能满足可能的 bvFTD 标准。
C9ORF72 突变似乎是 bvFTD 的常见原因。许多 C9ORF72 携带者有 ALS 或精神疾病家族史。精神病特征是突变携带者和非携带者之间最具鉴别性的临床特征。进展通常较慢，且与 bvFTD 的非突变病例相比，脑萎缩程度较轻。这些发现对诊断和选择患者进行基因检测均具有临床意义。
