<em>C9ORF72</em> Repeat Expansion in Australian and Spanish Frontotemporal Dementia Patients

A hexanucleotide repeat expansion in C9ORF72 has been established as a common cause of frontotemporal dementia (FTD). However, the minimum repeat number necessary for disease pathogenesis is not known. The aims of our study were to determine the frequency of the C9ORF72 repeat expansion in two FTD patient collections (one Australian and one Spanish, combined n = 190), to examine C9ORF72 expansion allele length in a subset of FTD patients, and to examine C9ORF72 allele length in ‘non-expansion’ patients (those with <30 repeats). The C9ORF72 repeat expansion was detected in 5–17% of patients (21–41% of familial FTD patients). For one family, the expansion was present in the proband but absent in the mother, who was diagnosed with dementia at age 68. No association was found between C9ORF72 non-expanded allele length and age of onset and in the Spanish sample mean allele length was shorter in cases than in controls. Southern blotting analysis revealed that one of the nine ‘expansion-positive’ patients examined, who had neuropathologically confirmed frontotemporal lobar degeneration with TDP-43 pathology, harboured an ‘intermediate’ allele with a mean size of only ∼65 repeats. Our study indicates that the C9ORF72 repeat expansion accounts for a significant proportion of Australian and Spanish FTD cases. However, C9ORF72 allele length does not influence the age at onset of ‘non-expansion’ FTD patients in the series examined. Expansion of the C9ORF72 allele to as little as ∼65 repeats may be sufficient to cause disease.C9ORF72基因的六核苷酸重复扩增（hexanucleotide repeat expansion）已被证实为额颞叶痴呆（frontotemporal dementia, FTD）的常见病因。然而，导致疾病发病机制所需的最小重复拷贝数仍未明确。本研究的目的为：明确两个额颞叶痴呆患者队列（分别来自澳大利亚与西班牙，合并总样本量n=190）中C9ORF72重复扩增的检出频率；分析部分额颞叶痴呆患者的C9ORF72扩增等位基因长度；以及检测“非扩增”患者（即重复拷贝数<30的患者）的C9ORF72等位基因长度。5%~17%的患者（其中家族性额颞叶痴呆患者的检出率为21%~41%）可检测到C9ORF72重复扩增。在一个家族中，先证者携带该扩增等位基因，但其68岁时确诊痴呆的母亲未携带该扩增。未发现C9ORF72非扩增等位基因长度与发病年龄存在关联；在西班牙队列中，患者的平均等位基因长度短于健康对照。Southern印迹杂交（Southern blotting）分析显示，在9名经检测为“扩增阳性”的患者中，有1名经神经病理学证实为伴TDP-43（transactive response DNA-binding protein 43）病理改变的额颞叶变性（frontotemporal lobar degeneration）患者，其携带的“中间型”等位基因平均仅含约65个重复拷贝。本研究表明，C9ORF72重复扩增在澳大利亚与西班牙的额颞叶痴呆病例中占相当大的比例。但在本次研究纳入的“非扩增”额颞叶痴呆患者中，C9ORF72等位基因长度并不会影响其发病年龄。C9ORF72等位基因扩增至仅约65个重复拷贝即可致病。