The prion diseases.

The prion diseases are a family of rare neurodegenerative disorders that result from the accumulation of a misfolded isoform of the prion protein (PrP), a normal constituent of the neuronal membrane. Five subtypes constitute the known human prion diseases; kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal insomnia (FI), and variant CJD (vCJD). These subtypes are distinguished, in part, by their clinical phenotype, but primarily by their associated brain histopathology. Evidence suggests these phenotypes are defined by differences in the pathogenic conformation of misfolded PrP. Although the vast majority of cases are sporadic, 10% to 15% result from an autosomal dominant mutation of the PrP gene (PRNP). General phenotype-genotype correlations can be made for the major subtypes of CJD, GSS, and FI. This paper will review some of the general background related to prion biology and detail the clinical and pathologic features of the major prion diseases, with a particular focus on the genetic aspects that result in prion disease or modification of its risk or phenotype.

Kuru plaques in the brain of two cases with Creutzfeldt-Jakob disease. A common origin for the two diseases?

We present two patients aged 66 and 69, with a rapidly progressive disease (10 and 15 months' duration) in which the presenting symptom was instability of gait. Later dementia was also a prominent feature. One case had myoclonus. Repeated EEGs showed symmetrical slowing in one case and periodic generalised bursts of triphasic waves at 1 cps superimposed upon a slow (3-4 cps) background activity in the other. The pathological findings consisted of classical Creutzfeld-Jakob disease (CJD), Kuru plaques (KP) were disseminated in the brain, but were more numerous in the cerebellum, putamen and thalamus. Neurons with large vacuoles in the cytoplasm were numerous in the putamen, thalamus and anterior horns. Stress is laid upon the common findings in both CJD and Kuru (K) (clinical features, pathological data, lack of antibody response, transmissibility, change in pattern on transmission). The possibility of a common origin of the two diseases is discussed.

Experimental kuru in the spider monkey. Histopathological and ultrastructural studies of the brain during early stages of incubation.

The brains of 10 spider monkeys inoculated intracerebrally with brain suspension from kuru patients have been studied histologically and ultrastructurally. The animals were killed by perfusion of fixative from four to forty-one weeks after inoculation, when healthy and free of neurological signs. Definite histopathological changes had occurred as early as four weeks after inoculation, when moderate numbers of bi-nucleated neurons were found within the limbic cortex, striatum, the hypothalamus and amongst the Purkinje cells of the cerebellum. At later stages of incubation a moderate loss of neurons in the cerebral and cerebellar cortex and a mild to moderate proliferation of fibrous astrocytes here and also in the hypothalamus were the most striking features. None of our cases showed either status spongiosus or the generalized astrocytic proliferation and hypertrophy, characteristic of fully developed experimental kuru, in any region of the brain. The principal ultrastructural abnormalities consisted of the formation of membrane-bound intracytoplasmic vacuoles, predominantly within dendrites, and of concentric laminar arrays derived from the endoplasmic reticulum. The former were seen in all regions of the brain examined and at all stages of incubation. Concentric laminar arrays were confined to the cerebellar nodulus, where they were most numerous in dendrites and neuronal perikarya four weeks after inoculation. Both changes are interpreted as an indication that the kuru agent acts upon the plasma membrane from an early stage onwards and, by stimulating its growth, leads to the formation of complex, membrane-bounded vacuoles and to hyperplasia of the endoplasmic reticulum. The formation of vacuoles is further regarded as the first sign of status spongiosus on an ultrastructural level. Attention is drawn to the great similarities between the changes observed in the present material and those described in the brains of patients dying from kuru and of primates with fully developed experimental kuru. The significance of the relatively rapid spread of the kuru agent throughout the brain is discussed in relation to the concept of "slow virus" diseases.

Creutzfeldt-Jakob disease: further similarities with kuru.

A typical case of Creutzfeldt-Jakob disease is described. Two unusual morphological features-namely, `kuru-like' plaques in the cerebellum and coarsely vacuolated neurones in the striatum-are further similarities between Creutzfeldt-Jakob disease and kuru.