Human Prion Diseases

Human prion diseases are rare. The yearly incidence is estimated to be 1 to 2 cases per million population. Point mutations, deletions, and insertions in the PrP gene produce a broad spectrum of diseases. The clinical and pathologic phenotypes are determined by homozy-gosity or heterozygosity for methionine or valine at codon 129. The diseases can be sporadic, familial, or acquired (Table 7.1). Sporadic occurrences account for about 85% of cases. About 10% to 15% are familial, with autosomal dominant inheritance. Acquired instances are rare, but the number may increase with the passage of time because incubation takes several years. The disease is acquired iatrogenically or by consumption of infected food products.

The group of human prion diseases encompasses kuru, a now-extinct disease, and four current conditions (see Table 7.1): Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), and new-variant CJD (nv CJD). The first three afflict mostly middle-aged and elderly individuals, and the fourth one affects younger subjects. The clinical presentation varies among the diseases, but all share progressing cognitive decline and neurologic deterioration, inevitably leading to death within several months or a year, seldom more. At present, no curative therapy is available. Genetic counseling is important in familial cases.

The diagnosis may be difficult in early stage of the disease. The differential diagnosis includes degenerative dementias, particularly of frontotemporal type. Electroencephalogram (EEG), magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) abnormalities, along with proper clinical features, support the diagnosis. EEG during the early stage of the disease shows synchronous periodic sharp wave complexes (PSWC) occurring at a rate of 1 to 2 per second. MRI abnormality is characterized by a hyperintensity of the basal ganglia and pulvinar on T2-weighted images. CSF fluid examination often shows elevated 14-3-3 protein and

TABLE 7.1.

Human Prion Diseases

Sporadic Inherited



Iatrogenic Oral route CJD nvCJD Kuru

CJD, Creutzfeldt-Jakob disease; FFI, fatal familial insomnia; GSS, Gerstmann-Sträussler-Scheinker disease; nv, new-variant CJD.

elevated tau protein, but false positives and negatives may occur. Genetic studies reveal mutations in PRNP and identify homozygotes for methionine on codon 129; these homozygotes are at risk for developing the disease. Definite diagnosis rests on pathologic confirmation in autopsy or biopsy specimen.

Pathologically, the diseases share common features and also have distinguishing characteristics. Common features are (a) spongiform degeneration of the gray matter, (b) neuronal losses, (c) astrocytosis, and (d) deposits of prion protein (PrP) as amyloid precipitates. Identifying deposits of prion protein by using antibodies against them confirms the diagnosis.

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