Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations
Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations
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DOI：
10.1111/nan.12057
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发表时间：
2014-08-01
影响因子：
5
通讯作者：
Takahashi, H.
中科院分区：
文献类型：
--
作者：
Fu, Y. -J.;Aida, I.;Takahashi, H.
目的：SCARB2基因突变导致一种罕见的常染色体隐性疾病，进行性肌阵挛性癫痫（PME）伴或不伴肾功能衰竭，前者也被称为行动性肌阵挛-肾功能衰竭综合征。虽然报告的病例越来越多，但只有少数人描述了其神经病理学。我们研究了两名日本无肾功能衰竭的PME患者，他们的发病年龄和病程分别为45岁和20岁，14岁和8.5岁。方法：进行SCARB2基因测序、酶切分析及免疫组化神经病理检查。结果：基因分析显示SCARB2基因出现了新的纯合移码和无义突变。两例均表现出棕色色素沉积在大脑，特别是小脑和大脑皮层。超微结构上，色素颗粒定位于星形胶质细胞。在大脑中，包括苍白球和小脑-橄榄系统，神经元丢失和胶质瘤也很明显。脊髓也受到了影响。一名迟发性疾病患者的这种变化较另一名早发性疾病患者轻。在脑和肾切片中，针对人SCARB2 c端抗体的免疫染色分别显示该蛋白水平降低和不表达。结论：在迟发性疾病患者中检测到的移码突变是一种迄今未被描述的独特类型的SCARB2基因突变。目前的两例患者是首次报道清楚地表明神经元外棕色色素沉积和系统神经变性是SCARB2突变的PME的神经病理特征。
Aims: Mutations in the SCARB2 gene cause a rare autosomal recessive disease, progressive myoclonus epilepsy (PME) with or without renal failure, the former also being designated action myoclonus-renal failure syndrome. Although reported cases have been accumulating, only a few have described its neuropathology. We studied two Japanese patients with PME without renal failure, in whom the ages at onset and disease durations were 45 and 20 years, and 14 and 8.5 years respectively. Methods: Sequencing and restriction analysis of the SCARB2 gene and neuropathological examination with immunohistochemistry were performed. Results: Gene analyses revealed novel homozygous frameshift and nonsense mutations in the SCARB2 gene. Both cases exhibited deposition of brown pigment in the brain, especially the cerebellar and cerebral cortices. Ultrastructurally, the pigment granules were localized in astrocytes. Neuronal loss and gliosis were also evident in the brain, including the pallidoluysian and cerebello-olivary systems. The spinal cord was also affected. Such changes were less severe in one patient with late-onset disease than in the other patient with early-onset disease. In brain and kidney sections, immunostaining with an antibody against the C-terminus of human SCARB2 revealed decreased levels and no expression of the protein respectively. Conclusions: The frameshift mutation detected in the patient with late-onset disease is a hitherto undescribed, unique type of SCARB2 gene mutation. The present two patients are the first reported to have clearly demonstrated both extraneuronal brown pigment deposition and system neurodegeneration as neuropathological features of PME with SCARB2 mutations.