Medical Research Council (MRC) Prion Unit (S.M., J.B., C.C., S.J., J.M.L., H.A.-D., B.S., M.K.S., S.B., J.D.F.W., J.C.), Department of Molecular Neuroscience (S.G., N.W.W.), and Dementia Research Centre, Department of Neurodegenerative Disease (J.D.W.), and MRC Centre for Neuromuscular Diseases (M.M.R.), University College London (UCL) Institute of Neurology; the National Prion Clinic (S.M., D.C., D.G., H.H., P.R., J.C.), National Hospital for Neurology and Neurosurgery (M.K.), UCL Hospitals National Health Service Trust (A.F.); and the Queen Square Brain Bank (H.A., T.L., T.R., J.L.H.) - all in London.
N Engl J Med. 2013 Nov 14;369(20):1904-14. doi: 10.1056/NEJMoa1214747.
Human prion diseases, although variable in clinicopathological phenotype, generally present as neurologic or neuropsychiatric conditions associated with rapid multifocal central nervous system degeneration that is usually dominated by dementia and cerebellar ataxia. Approximately 15% of cases of recognized prion disease are inherited and associated with coding mutations in the gene encoding prion protein (PRNP). The availability of genetic diagnosis has led to a progressive broadening of the recognized spectrum of disease.
We used longitudinal clinical assessments over a period of 20 years at one hospital combined with genealogical, neuropsychological, neurophysiological, neuroimaging, pathological, molecular genetic, and biochemical studies, as well as studies of animal transmission, to characterize a novel prion disease in a large British kindred. We studied 6 of 11 affected family members in detail, along with autopsy or biopsy samples obtained from 5 family members.
We identified a PRNP Y163X truncation mutation and describe a distinct and consistent phenotype of chronic diarrhea with autonomic failure and a length-dependent axonal, predominantly sensory, peripheral polyneuropathy with an onset in early adulthood. Cognitive decline and seizures occurred when the patients were in their 40s or 50s. The deposition of prion protein amyloid was seen throughout peripheral organs, including the bowel and peripheral nerves. Neuropathological examination during end-stage disease showed the deposition of prion protein in the form of frequent cortical amyloid plaques, cerebral amyloid angiopathy, and tauopathy. A unique pattern of abnormal prion protein fragments was seen in brain tissue. Transmission studies in laboratory mice were negative.
Abnormal forms of prion protein that were found in multiple peripheral tissues were associated with diarrhea, autonomic failure, and neuropathy. (Funded by the U.K. Medical Research Council and others.).
人类朊病毒病，尽管临床表现和病理学表型各异，通常表现为与快速多灶性中枢神经系统退行性变相关的神经或神经精神疾病，通常以痴呆和小脑共济失调为主。已识别的朊病毒病约有 15%为遗传性，与编码朊病毒蛋白（PRNP）的基因突变相关。遗传诊断的出现导致了疾病谱的逐渐扩大。
我们使用一家医院 20 年来的纵向临床评估，结合家系、神经心理学、神经生理学、神经影像学、病理学、分子遗传学和生物化学研究，以及动物传播研究，对一个大型英国家系中的一种新型朊病毒病进行了特征描述。我们详细研究了 11 名受影响的家族成员中的 6 名，以及 5 名家族成员的尸检或活检样本。
我们发现了 PRNP Y163X 截断突变，并描述了一种独特而一致的表型，即慢性腹泻伴自主神经衰竭和长度依赖性、主要是感觉的、周围轴索性多发性神经病，其发病年龄在成年早期。当患者进入 40 多岁或 50 多岁时，会出现认知能力下降和癫痫发作。朊病毒蛋白淀粉样沉积可见于包括肠道和周围神经在内的外周器官。在终末期疾病的神经病理学检查中，发现朊病毒蛋白以皮质淀粉样斑块、脑淀粉样血管病和 tau 病的形式沉积。脑组织中出现了一种独特的异常朊病毒蛋白片段模式。在实验室小鼠中的传播研究为阴性。
在多种外周组织中发现的异常朊病毒蛋白与腹泻、自主神经衰竭和神经病有关。（由英国医学研究理事会等资助）。
