Phenotypic diversity of genetic Creutzfeldt-Jakob disease: a histo-molecular-based classification.
Phenotypic diversity of genetic Creutzfeldt-Jakob disease: a histo-molecular-based classification.
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DOI：
10.1007/s00401-021-02350-y
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发表时间：
2021-10
影响因子：
12.7
通讯作者：
Parchi P
中科院分区：
文献类型：
--
作者：
Baiardi S;Rossi M;Mammana A;Appleby BS;Barria MA;Calì I;Gambetti P;Gelpi E;Giese A;Ghetti B;Herms J;Ladogana A;Mikol J;Pal S;Ritchie DL;Ruf V;Windl O;Capellari S;Parchi P
散发性克雅氏病（sCJD）的当前分类包括由病理性朊病毒蛋白（PrPSc）的蛋白酶抗性核心的物理化学性质定义的六种主要临床病理亚型，定义了两种主要的PrPSc类型（即，1和2），以及朊病毒蛋白基因（PNP）的甲硫氨酸（M）/缬氨酸（V）多态性密码子129。这些sCJD亚型与遗传性CJD（gCJD）的表型异质性之间的关系尚不完全清楚。我们分析了208例携带17种不同突变的gCJD患者的分子和表型特征，并将其与一系列sCJD病例进行了比较。我们根据PRNP突变等位基因上PrPSc型和密码子129基因型的组合，确定了6个主要的gCJD组，每个组均显示出独特的组织病理学特征，而与PRNP相关突变无关。五个gCJD组，命名为M1，M2 C，M2 T，V1和V2，在很大程度上再现了先前在sCJD亚型中描述的那些。第六组与V2组共享表型特征，并且仅在携带E200 K-129 M单倍型的患者中检测到，该单倍型与介于1型和2型之间的中间大小（“i”）的PrPSc型相关。另外的突变特异性效应涉及PrP沉积的模式（例如，E200 K携带者中的“增厚”突触模式，插入突变者中的小脑“条纹状线性颗粒沉积物”，以及E200 K-V2或-M“i”中的神经元内球状点）。一些孤立的病例与罕见的PRNP单倍型有关（例如，T183 A-129 M）表现出非典型的表型特征，这使得它们不能被分为六个主要的组。gCJD的表型变异性与先前在sCJD中发现的表型变异性基本一致。与sCJD一样，PrPSc的密码子129基因型和理化性质与gCJD的表型变异显著相关。与克雅氏病相关的最常见的突变似乎对疾病表型具有可变的和总体上不太显著的影响，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适用于gCJD，以提供具有分子基础的疾病的更新分类。在线版本包含补充材料，可通过10.1007/s 00401 -021-02350-y获得。
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 (PrPSc), defining two major PrPSc 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 PrPSc 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 PrPSc 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 PrPSc 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. The online version contains supplementary material available at 10.1007/s00401-021-02350-y.
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影响因子：
12.7
作者：
Bartz JC
通讯作者：
Bartz JC
影响因子：
82.9
作者：
Chen, SG;Parchi, P;Gambetti, P
通讯作者：
Gambetti, P
影响因子：
6
作者：
Capellari, S;Parchi, P;Petersen, RB
通讯作者：
Petersen, RB
影响因子：
11.4
作者：
Cancellotti, Enrico;Mahal, Sukhvir P.;Manson, Jean C.
通讯作者：
Manson, Jean C.
影响因子：
3.2
作者：
Areskeviciute, Ausrine;Hogh, Peter;Lund, Eva Lobner
通讯作者：
Lund, Eva Lobner