Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.
Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.
复制标题
p102l遗传性prion病的表型异质性和国际遗传疾病的遗传修饰。
作者：
Webb, T. E. F.;Poulter, M.;Beck, J.;Uphill, J.;Adamson, G.;Campbell, T.;Linehan, J.;Powell, C.;Brandner, S.;Pal, S.;Siddique, D.;Wadsworth, J. D.;Joiner, S.;Alner, K.;Petersen, C.;Hampson, S.;Rhymes, C.;Treacy, C.;Storey, E.;Geschwind, M. D.;Nemeth, A. H.;Wroe, S.;Collinge, J.;Mead, S.
患有遗传性朊病毒病 P102L 的最大家族，即历史上的 Gerstmann-Sträussler-Scheinker 综合征，起源于英格兰中部，现在有移民居住在英语世界的各个地区。我们收集了来自英国大型亲属和众多小型无关谱系的 84 名患者的数据，以研究表型异质性和修饰因素。该集合代表了迄今为止报道的最大的 P102L 患者系列。对八个不同的欧洲亲属的微卫星和谱系分析支持胞嘧啶-磷酸二酯-胍二核苷酸突变热点处的多个不同突变事件。所有较小的 P102L 亲属都与多态性人朊病毒蛋白基因密码子 129M 连锁，并且通过家谱或微卫星单倍型背景与大亲属或彼此之间没有联系。虽然许多人患有经典的 Gerstmann-Sträussler-Scheinker 综合征，这是一种缓慢进展的小脑性共济失调，伴有较晚发生的认知障碍，但存在显着的异质性。一部分患者具有显着的认知和精神特征，有些患者符合散发性克雅氏病的诊断标准。我们发现，多态性人朊病毒蛋白基因密码子 129 改变了发病年龄：最早的 8 例临床发病均为 MM 纯合子，与 MV 杂合子相比，MM 的总体发病年龄早 7 岁（P = 0.02）。出乎意料的是，载脂蛋白E4携带者的发病年龄延迟了10年（P = 0.02）。我们发现女性患者比男性患者多（54 名女性对 30 名男性，P = 0.01），这可能与确定偏差有关。然而，这些修饰剂对 10 名尸检患者的半定量病理表型没有影响。这些数据可以让我们了解临床表型、现代成像和分子研究的范围，并且可以为高危个体的遗传咨询提供信息，并识别出两种遗传修饰因子。
The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.
登录
查看更多内容
影响因子：
11.2
作者：
Dagvadorj, A;Petersen, RB;Goldfarb, LG
通讯作者：
Goldfarb, LG
影响因子：
6.4
作者：
HAINFELLNER, JA;BRANTNERINTHALER, S;BUDKA, H
通讯作者：
BUDKA, H
影响因子：
64.8
作者：
PALMER, MS;DRYDEN, AJ;COLLINGE, J
通讯作者：
COLLINGE, J
影响因子：
9.9
作者：
Arata, H.;Takashima, H.;Arimura, K.
通讯作者：
Arimura, K.
影响因子：
9.8
作者：
Finckh, U;Müller-Thomsen, T;Gal, A
通讯作者：
Gal, A