Table_1_Case Report: Histopathology and Prion Protein Molecular Properties in Inherited Prion Disease With a De Novo Seven-Octapeptide Repeat Insertion.docx

The insertion of additional 168 base pair containing seven octapeptide repeats in the prion protein (PrP) gene region spanning residues 51–91 is associated with inherited prion disease. In 2008, we reported the clinical features of a novel de novo seven-octapeptide repeat insertion (7-OPRI) mutation coupled with codon 129 methionine (M) homozygosity in the PrP gene of a 19-year-old man presenting with psychosis and atypical dementia, and 16-year survival. Here, we describe the histopathological and PrP molecular properties in the autopsied brain of this patient. Histopathological examination revealed widespread brain atrophy, focal spongiform degeneration (SD), cortical PrP plaques, and elongated PrP formations in the cerebellum. Overall, these histopathological features resemble those described in a Belgian pedigree with 7-OPRI mutation except for the presence of PrP plaques in our case, which are morphologically different from the multicore plaques described in some OPRI mutations and in Gerstmann–Sträussler–Scheinker (GSS) syndrome. The comparative characterization of the detergent-soluble and detergent-insoluble PrP in our patient and in sporadic Creutzfeldt–Jakob disease (CJD) revealed distinct molecular signatures. Proteinase K digestion of the pathogenic, disease-associated PrP (PrPD) revealed PrPD type 1 in the cerebral cortex and mixed PrPD types 1 and 2 in the cerebellum. Altogether, the present study outlines the importance of assessing the phenotypical and PrP biochemical properties of these rare conditions, thereby widening the spectrum of the phenotypic heterogeneity of the 7-OPRI insertion mutations. Further studies are needed to determine whether distinct conformers of PrPD are associated with two major clinico-histopathological phenotypes in prion disease with 7-OPRI.

在跨越残基51-91的朊蛋白（prion protein, PrP）基因区域中，插入包含7个八肽重复序列的额外168个碱基对，与遗传性朊病毒病相关。2008年，我们报道了一例新发七八肽重复插入（seven-octapeptide repeat insertion, 7-OPRI）突变的临床特征：该突变伴随19岁男性患者PrP基因129位密码子甲硫氨酸（methionine, M）纯合性，患者以精神病和非典型痴呆起病，生存期达16年。本文我们对该患者的尸检脑组织进行了组织病理学与PrP分子特性分析。组织病理学检查显示广泛脑萎缩、局灶性海绵状变性（spongiform degeneration, SD）、皮层PrP斑块，以及小脑内细长形PrP结构。总体而言，这些组织病理学特征与携带7-OPRI突变的比利时家系报道的表现相似，但本病例存在PrP斑块，且该斑块在形态上与部分八肽重复插入突变及格斯特曼-斯特劳斯勒-申克尔综合征（Gerstmann–Sträussler–Scheinker, GSS）中描述的多核心斑块存在差异。对本病例患者与散发性克雅氏病（sporadic Creutzfeldt–Jakob disease, CJD）样本中去污剂可溶性与去污剂不溶性PrP的对比分析显示，二者具有不同的分子特征。对致病性疾病相关朊蛋白（pathogenic, disease-associated PrP, PrP^D）的蛋白酶K（Proteinase K）消化结果显示，大脑皮层中的PrP^D为1型，而小脑中的PrP^D为1型与2型混合。综上，本研究阐明了评估此类罕见疾病表型与PrP生化特性的重要性，从而拓展了7-OPRI插入突变相关表型异质性的谱范围。未来仍需进一步研究，以明确携带7-OPRI突变的朊病毒病中，是否存在不同的PrP^D构象体与两种主要的临床-组织病理学表型相关联。