目的:5-10%的肌萎缩侧索硬化症是家族性的,最常见的遗传原因是C9ORF72、SOD1、TARDBP和FUS基因突变。血管生成素基因突变,ANG,已在欧洲和北美多个人群的家族性和散发性患者中发现。这项研究的目的是在来自英格兰北部的517名患者的大队列中确定ANG突变的发生率,并建立与这些病例相关的神经病理学。
方法:扩增单外显子ANG基因,测序和分析突变。脑部病理检查,脊髓和骨骼肌包括常规组织学和免疫组织化学。
结果:突变筛查鉴定出一例P.K54E突变的散发性肌萎缩侧索硬化症,这在278个神经正常对照样品中不存在。临床表现为肢体起病肌萎缩侧索硬化,疾病进展迅速,没有认知障碍的证据。神经病理学检查确定了特征性泛素化和TDP-43阳性神经元和神经胶质内含物的存在,但血管生成素蛋白分布无异常.
结论:以前只有一份报告描述了p.K17IANG突变的单个病例的神经病理学,该突变突出了海马中嗜酸性粒细胞神经元核内包涵体的存在。在本病例中不存在此特征表明,具有ANG突变的患者并不总是具有与散发性肌萎缩性侧索硬化症可区分的病理变化。
OBJECTIVE: Five to 10% of cases of amyotrophic lateral sclerosis are familial, with the most common genetic causes being mutations in the C9ORF72, SOD1, TARDBP and FUS genes. Mutations in the angiogenin gene, ANG, have been identified in both familial and sporadic patients in several populations within Europe and North America. The aim of this study was to establish the incidence of ANG mutations in a large cohort of 517 patients from Northern England and establish the neuropathology associated with these cases.
METHODS: The single exon ANG gene was amplified, sequenced and analysed for mutations. Pathological examination of brain, spinal cord and skeletal muscle included conventional histology and immunohistochemistry.
RESULTS: Mutation screening identified a single sporadic amyotrophic lateral sclerosis case with a p.K54E mutation, which is absent from 278 neurologically normal control samples. The clinical presentation was of limb onset amyotrophic lateral sclerosis, with rapid disease progression and no evidence of cognitive impairment. Neuropathological examination established the presence of characteristic ubiquitinated and TDP-43-positive neuronal and glial inclusions, but no abnormality in the distribution of angiogenin protein.
CONCLUSIONS: There is only one previous report describing the neuropathology in a single case with a p.K17I ANG mutation which highlighted the presence of eosinophilic neuronal intranuclear inclusions in the hippocampus. The absence of this feature in the present case indicates that patients with ANG mutations do not always have pathological changes distinguishable from those of sporadic amyotrophic lateral sclerosis.