A new prionopathy

In this issue of Annals of Neurology, Gambetti and colleagues describe a new form of prion disease designated proteinase-sensitive prionopathy (PSPr). The discovery of any new form of disease is a milestone. The identification of this novel phenotype of prion disease reflects the value of a rigorous systematic surveillance program and underlines the importance of neuropathological examination and prion protein (PrP) typing in prion disease classification. PSPr is characterized clinically by a rather nonspecific phenotype involving progressive dementia, with ataxia and Parkinsonism occurring in a proportion of cases. Although it is possible that the relatively short total duration of illness (mean, 20 months) alerted clinicians to the possibility of the diagnosis, it is of note that none of the investigations generally used in the screening for human prion disease (electroencephalogram, cerebrospinal fluid 14-3-3, or magnetic resonance imaging brain scan) provided support for the diagnosis of Creutzfeldt–Jakob Disease (CJD). It was fortunate that these cases were referred by the National Prion Disease Pathology Surveillance Center and one can only speculate that additional cases of this condition were likely not to have been notified to the surveillance system. PSPr accounted for 3% of all sporadic CJD cases identified by the National Prion Disease Pathology Surveillance Center, and with an overall annual incidence rate in sporadic CJD of about 1 to 1.5 cases/ million, this may be a rare form of dementia assuming that a significant proportion of all cases was identified. The authors make the important point that PSPr might be misclassified clinically as a form of nonAlzheimer’s dementia, but all cases had spongiform change on neuropathological examination in the cortex, basal ganglia, and thalamus, with positive PrP immunostaining in a similar distribution. In contrast with other forms of sporadic CJD (and control subjects), treatment with proteinase K almost abolished the immunostaining. It will be interesting to see whether a review of cases of CJD identified by other CJD surveillance systems will identify similar cases. Although final classification as PSPr requires detailed biochemical analysis of the PrP deposited in the brain, the diagnosis of a form of CJD may be made on routine histopathology. Thus, it is likely that cases of PSPr would have been identified as CJD (even if not appropriately subclassified), at least in countries with high postmortem rates for rapidly progressive dementia illnesses. That PSPr is a novel form of human prion disease is supported by the unusual clinical phenotype, the distinctive neuropathological features, including clusters of PrP-positive granules in the cerebrum, cerebellum, and less frequently the white matter, and the presence of abnormal PrP that is overall more sensitive to proteolytic digestion, less highly aggregated, and yielding protease-resistant core fragments distinct from those found in other forms of CJD. The identification of any new form of prion disease inevitably raises questions about the origin of the condition. In PSPr, there was a family history of dementia in 8 of 10 cases (a family history was not available in 1 case), but sequencing of the open reading frame of the prion protein gene (PRNP) did not identify any of the mutations associated with genetic forms of human prion disease. In sporadic CJD, a family history of dementia is present in 15% of cases, and although this may be related to the occasional misclassification of the cause of death in preceding generations, many of these cases also lack mutations in PRNP, which raises the possibility of genetic influences on human prion diseases outside of PRNP. This possibility is also consistent with studies in laboratory animals. Further study of the genetics of PSPr and other human prion diseases may provide important insights into the pathogenesis of these conditions. It is also noteworthy that all of the cases were valine homozygous at codon 129 of PRNP. With informed consent, genetic analysis is now performed routinely in many CJD surveillance centers, and the identification of this genotype in a suspect case may now raise suspicions of PSPr, particularly in cases with a relatively indolent onset and a family history of dementia. The identification of PSPr raises a number of fundamental questions about prion diseases. This class of conditions was formally known as the transmissible spongiform encephalopathies, but there are examples of these conditions that are not transmissible and/or have no spongiform change. An unanswered question is whether PSPr is a transmissible disease, and appropriate laboratory investigations are under way. The term prion disease has become in many but not all circles the conventional terminology for this group of diseases, but it is now clear that the biochemical spectrum of abnormal forms of the PrP that characterize these diseases is broad and cannot be defined simply as those in which conventional PrP27-30 is readily detectable. In addition to diseases such as some forms of Gerstmann-Straussler-Scheinker Disease (GSS) in which abnormal PrP is present but evidence of transmission lacking, there are examples of experimental “spongiform encephalopathies” that are transmissible but that EDITORIAL