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^Sc), defining two major PrP^Sc 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^Sc 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^Sc 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^Sc 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.

目前对散发性克雅氏病 (sCJD) 的分类包括由病理性朊病毒蛋白 (PrP ^Sc ) 的蛋白酶抗性核心的理化特性定义的六种主要临床病理亚型，定义了两种主要的 PrP ^Sc类型（即 1 和 2 )，以及朊病毒蛋白基因 ( PRNP ) 的蛋氨酸 (M)/缬氨酸 (V) 多态密码子 129。这些 sCJD 亚型与遗传性 CJD (gCJD) 的充分记录的表型异质性之间的关系尚不完全清楚。我们分析了 208 名受 gCJD 影响的个体的分子和表型特征，这些个体携带 17 种不同的突变，并将它们与大量 sCJD 病例的那些进行比较。^{我们根据 PrP Sc}组合确定了六大 gCJD 组PRNP突变等位基因上的类型和密码子 129 基因型，每个都显示出独特的组织病理学特征，与PRNP相关突变无关。五个 gCJD 组，分别命名为 M1、M2C、M2T、V1 和 V2，很大程度上复制了之前在 sCJD 亚型中描述的那些。第六组与 V2 组共享表型特征，仅在携带 E200K-129M 单倍型与 PrP ^{Sc相关的患者中检测到}1 型和 2 型之间的中间大小（“i”）类型。其他突变特异性影响涉及 PrP 沉积模式（例如，E200K 携带者中的“增厚”突触模式，小脑“条纹状线性颗粒沉积” E200K-V2 或 -M”i” 中有插入突变和神经元内球状点）。一些与罕见PRNP单倍型（例如，T183A-129M）相关的孤立病例显示出非典型表型特征，这妨碍了将其分类为六个主要组。gCJD 的表型变异性与之前在 sCJD 中发现的变异性基本一致。^{与 sCJD 一样，PrP Sc}的密码子 129 基因型和理化性质与 gCJD 的表型变异性显着相关。与 CJD 相关的最常见突变似乎对疾病表型具有可变且总体上不太显着的影响，但它们通常以菌株特异性方式显着影响疾病易感性。目前用于 sCJD 亚型的标准可以扩展并适应 gCJD，以提供具有分子基础的疾病分类。