Mead Simon, Poulter Mark, Beck Jon, Webb Thomas E F, Campbell Tracy A, Linehan Jacqueline M, Desbruslais Melanie, Joiner Susan, Wadsworth Jonathan D F, King Andrew, Lantos Peter, Collinge John
MRC Prion Unit, Department of Neurodegenerative Diseases, Institute of Neurology, King's College Hospital, London, UK.
Brain. 2006 Sep;129(Pt 9):2297-317. doi: 10.1093/brain/awl226.
By far the largest known kindred with an inherited prion disease caused by a prion protein (PrP) octapeptide repeat insertion mutation originates from southeast England. This extended family shows very marked phenotypic heterogeneity and provides a unique opportunity to characterize this diversity and examine possible modifying factors amongst a large number of individuals in whom prion disease has been initiated by the same defined genetic mutation. As the inherited prion diseases comprise a significant proportion of familial early-onset dementia, an appreciation of their wide range of clinical presentation is important for differential diagnosis. Genealogical and clinical record review, together with the characterization of the mutation-linked single nucleotide polymorphism and microsatellite haplotype, suggested a single founder for both this large kindred and a smaller family in the mid-18th century. Here we report the phenotype of 86 affected individuals; at least another 84 individuals are known to be at risk of inheriting the disease. Clinical onset, typically with cognitive impairment, can be strikingly early in this kindred when compared with other inherited or sporadic prion diseases. We have investigated the effect of PrP genotype, candidate genes and prion strain type on clinical, neuroradiological and neuropathological phenotype. The transmission characteristics of prions from affected individuals resembled those of classical sporadic Creutzfeldt-Jakob disease. One surprising finding was a strong inverse correlation between age of onset and disease duration. The PrP gene polymorphic codon 129 was found to confer 41% of the variance in age of onset but interestingly this polymorphism had no effect on disease duration suggesting different molecular mechanisms are involved in determining disease onset and rate of clinical progression.
目前已知由朊病毒蛋白（PrP）八肽重复插入突变引起的遗传性朊病毒病的最大谱系来自英格兰东南部。这个大家族表现出非常明显的表型异质性，为研究这种多样性以及在大量由相同特定基因突变引发朊病毒病的个体中研究可能的修饰因素提供了独特的机会。由于遗传性朊病毒病在家族性早发性痴呆中占很大比例，了解其广泛的临床表现对于鉴别诊断很重要。通过系谱和临床记录回顾，以及对与突变相关的单核苷酸多态性和微卫星单倍型的特征分析，表明这个大家族和一个18世纪中叶的较小家族有同一个奠基者。在此我们报告了86名患病个体的表型；已知至少还有84人有遗传该疾病的风险。与其他遗传性或散发性朊病毒病相比，该家族的临床发病通常伴有认知障碍，发病时间可非常早。我们研究了PrP基因型、候选基因和朊病毒株类型对临床、神经放射学和神经病理学表型的影响。来自患病个体的朊病毒的传播特征与经典散发性克雅氏病相似。一个令人惊讶的发现是发病年龄与疾病持续时间之间存在很强的负相关。发现PrP基因多态密码子129在发病年龄的差异中占41%，但有趣的是，这种多态性对疾病持续时间没有影响，这表明在确定疾病发病和临床进展速度方面涉及不同的分子机制。
