A Novel Prion Disease Associated with Diarrhea and Autonomic Neuropathy

BackgroundHuman 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. MethodsWe 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. ResultsWe 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. ConclusionsAbnormal 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.) Prions cause a variety of CNS illnesses, such as Creutzfeldt-Jakob disease. In this British kindred, a prion-associated process was associated with chronic diarrhea and autonomic dysfunction, a finding that extends the known disorders caused by these aberrant proteins. The prion diseases are transmissible, fatal, neurodegenerative disorders that may be inherited or acquired or that may occur spontaneously as sporadic Creutzfeldt-Jakob disease.(1) The transmissible agent, or prion, is thought to comprise misfolded and aggregated forms of the normal cell-surface prion protein. Prion propagation is thought to occur by means of seeded protein polymerization, a process involving the binding and templated misfolding of normal cellular prion protein. Similar processes are increasingly recognized as relevant to other, more common neurodegenerative diseases. In prion and other neurodegenerative disorders, the aggregates of misfolded protein in the central nervous system are highly heterogeneous, occurring ...