IRCCS Istituto delle Scienze Neurologiche di Bologna, Ospedale Bellaria, Via Altura 1/8, 40139, Bologna, Italy.
Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy.
Acta Neuropathol. 2021 Oct;142(4):707-728. doi: 10.1007/s00401-021-02350-y. Epub 2021 Jul 29.
The current classification of sporadic Creutzfeldt-Jakob disease (sCJD) includes six major clinicopathological subtypes defined by the physicochemical properties of the protease-resistant core of the pathologic prion protein (PrP), defining two major PrP types (i.e., 1 and 2), and the methionine (M)/valine (V) polymorphic codon 129 of the prion protein gene (PRNP). How these sCJD subtypes relate to the well-documented phenotypic heterogeneity of genetic CJD (gCJD) is not fully understood. We analyzed molecular and phenotypic features in 208 individuals affected by gCJD, carrying 17 different mutations, and compared them with those of a large series of sCJD cases. We identified six major groups of gCJD based on the combination PrP type and codon 129 genotype on PRNP mutated allele, each showing distinctive histopathological characteristics, irrespectively of the PRNP associated mutation. Five gCJD groups, named M1, M2C, M2T, V1, and V2, largely reproduced those previously described in sCJD subtypes. The sixth group shared phenotypic traits with the V2 group and was only detected in patients carrying the E200K-129M haplotype in association with a PrP type of intermediate size ("i") between type 1 and type 2. Additional mutation-specific effects involved the pattern of PrP deposition (e.g., a "thickened" synaptic pattern in E200K carriers, cerebellar "stripe-like linear granular deposits" in those with insertion mutations, and intraneuronal globular dots in E200K-V2 or -M"i"). A few isolated cases linked to rare PRNP haplotypes (e.g., T183A-129M), showed atypical phenotypic features, which prevented their classification into the six major groups. The phenotypic variability of gCJD is mostly consistent with that previously found in sCJD. As in sCJD, the codon 129 genotype and physicochemical properties of PrP significantly correlated with the phenotypic variability of gCJD. The most common mutations linked to CJD appear to have a variable and overall less significant effect on the disease phenotype, but they significantly influence disease susceptibility often in a strain-specific manner. The criteria currently used for sCJD subtypes can be expanded and adapted to gCJD to provide an updated classification of the disease with a molecular basis.
目前，散发性克雅氏病（sCJD）的分类包括根据病理性朊病毒蛋白（PrP）的蛋白酶抗性核心的理化性质定义的六种主要临床病理亚型，定义了两种主要的 PrP 类型（即 1 型和 2 型），以及朊病毒蛋白基因（PRNP）的蛋氨酸（M）/缬氨酸（V）多态性密码子 129。这些 sCJD 亚型与遗传克雅氏病（gCJD）的众所周知的表型异质性之间的关系尚未完全了解。我们分析了携带 17 种不同突变的 208 名 gCJD 患者的分子和表型特征，并将其与大量 sCJD 病例进行了比较。我们根据 PRNP 突变等位基因上的 PrP 类型和密码子 129 基因型组合，确定了 gCJD 的六个主要组，每组均表现出独特的组织病理学特征，与 PRNP 相关的突变无关。五个 gCJD 组，命名为 M1、M2C、M2T、V1 和 V2，在很大程度上重现了以前在 sCJD 亚型中描述的组。第六组与 V2 组具有相似的表型特征，仅在携带 E200K-129M 单倍型的患者中检测到，与 1 型和 2 型之间的中间大小的 PrP 类型（“i”）相关。其他突变特异性效应涉及 PrP 沉积的模式（例如，E200K 携带者中“增厚”的突触模式、携带插入突变的患者中“小脑条纹状线性颗粒沉积”以及 E200K-V2 或-M“i”中的神经元内球状斑点）。一些与罕见 PRNP 单倍型相关的孤立病例（例如，T183A-129M）表现出非典型的表型特征，这阻止了它们分类为六个主要组。gCJD 的表型变异性与以前在 sCJD 中发现的变异性基本一致。与 sCJD 一样，密码子 129 基因型和 PrP 的理化性质与 gCJD 的表型变异性显著相关。与 CJD 相关的最常见突变似乎对疾病表型具有可变且总体影响较小的作用，但它们通常以菌株特异性的方式显著影响疾病易感性。目前用于 sCJD 亚型的标准可以扩展并应用于 gCJD，以提供一种基于分子的疾病分类更新。
