Sheffield Institute for Translational Neuroscience, University of Sheffield, 385A Glossop Road, Sheffield S10 2HQ, UK.
Brain. 2012 Mar;135(Pt 3):751-64. doi: 10.1093/brain/awr365.
Intronic expansion of the GGGGCC hexanucleotide repeat within the C9ORF72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis/motor neuron disease in both familial and sporadic cases. Initial reports indicate that this variant within the frontotemporal dementia/amyotrophic lateral sclerosis spectrum is associated with transactive response DNA binding protein (TDP-43) proteinopathy. The amyotrophic lateral sclerosis/motor neuron disease phenotype is not yet well characterized. We report the clinical and pathological phenotypes associated with pathogenic C9ORF72 mutations in a cohort of 563 cases from Northern England, including 63 with a family history of amyotrophic lateral sclerosis. One hundred and fifty-eight cases from the cohort (21 familial, 137 sporadic) were post-mortem brain and spinal cord donors. We screened DNA for the C9ORF72 mutation, reviewed clinical case histories and undertook pathological evaluation of brain and spinal cord. Control DNA samples (n = 361) from the same population were also screened. The C9ORF72 intronic expansion was present in 62 cases [11% of the cohort; 27/63 (43%) familial, 35/500 (7%) cases with sporadic amyotrophic lateral sclerosis/motor neuron disease]. Disease duration was significantly shorter in cases with C9ORF72-related amyotrophic lateral sclerosis (30.5 months) compared with non-C9ORF72 amyotrophic lateral sclerosis/motor neuron disease (36.3 months, P < 0.05). C9ORF72 cases included both limb and bulbar onset disease and all cases showed combined upper and lower motor neuron degeneration (amyotrophic lateral sclerosis). Thus, clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis associated with both familial and sporadic presentations. Dementia was present in the patient or a close family member in 22/62 cases with C9ORF72 mutation (35%) based on diagnoses established from retrospective clinical case note review that may underestimate significant cognitive changes in late disease. All the C9ORF72 mutation cases showed classical amyotrophic lateral sclerosis pathology with TDP-43 inclusions in spinal motor neurons. Neuronal cytoplasmic inclusions and glial inclusions positive for p62 immunostaining in non-motor regions were strongly over-represented in the C9ORF72 cases. Extra-motor pathology in the frontal cortex (P < 0.0005) and the hippocampal CA4 subfield neurons (P < 0.0005) discriminated C9ORF72 cases strongly from the rest of the cohort. Inclusions in CA4 neurons were not present in non-C9ORF72 cases, indicating that this pathology predicts mutation status.
C9ORF72 基因中的 GGGGCC 六核苷酸重复序列的内含子扩展导致额颞叶痴呆和肌萎缩侧索硬化症/运动神经元病，无论是家族性还是散发性病例。最初的报告表明，这种在额颞叶痴呆/肌萎缩侧索硬化症谱内的变体与反式激活反应 DNA 结合蛋白（TDP-43）蛋白病有关。肌萎缩侧索硬化症/运动神经元病表型尚未得到很好的描述。我们报告了在英格兰北部的 563 例队列中与致病性 C9ORF72 突变相关的临床和病理表型，包括 63 例有肌萎缩侧索硬化症家族史的病例。该队列中的 158 例（21 例家族性，137 例散发性）是死后大脑和脊髓供体。我们筛选了 DNA 中的 C9ORF72 突变，回顾了临床病例史，并对大脑和脊髓进行了病理评估。同一人群的对照 DNA 样本（n=361）也进行了筛选。C9ORF72 内含子扩展存在于 62 例病例中[队列的 11%；27/63（43%）家族性，500 例散发性肌萎缩侧索硬化症/运动神经元病中有 35 例]。与非 C9ORF72 肌萎缩侧索硬化症/运动神经元病相比，C9ORF72 相关肌萎缩侧索硬化症的疾病持续时间明显缩短（30.5 个月）（36.3 个月，P<0.05）。C9ORF72 病例包括肢体和延髓起病的疾病，所有病例均显示上下运动神经元变性（肌萎缩侧索硬化症）。因此，在临床上，C9ORF72 病例表现出一种相对快速进展但其他方面典型的肌萎缩侧索硬化症变异，与家族性和散发性表现均有关。根据回顾性临床病历审查确定的诊断，在 62 例 C9ORF72 突变病例中，有 22 例（35%）患者或其近亲存在痴呆，这可能低估了晚期疾病中显著的认知变化。所有 C9ORF72 突变病例均显示出经典的肌萎缩侧索硬化症病理学，脊髓运动神经元中存在 TDP-43 包涵体。非运动区中 p62 免疫染色阳性的神经元细胞质包涵体和神经胶质包涵体在 C9ORF72 病例中强烈过度表达。额皮质的额外运动病理学（P<0.0005）和海马 CA4 亚区神经元（P<0.0005）强烈区分了 C9ORF72 病例与队列的其余部分。非 C9ORF72 病例中不存在 CA4 神经元包涵体，表明这种病理学可预测突变状态。
