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INTRODUCTION

Prion diseases are a group of less common neurodegenerative disorders characterized by rapidly progressive dementia. Few other disorders resemble the clinical syndrome (Table 29–1). Prion diseases result from accumulation in the brain of an abnormal conformation of the cellular protein called prion protein (PrP). Prion diseases are unusual among neurodegenerative disorders in that in addition to having sporadic and inherited forms, they also can rarely be transmissible through infection by iatrogenic or, in the case of variant CJD, by oral intake exposures.

Table 29–1.Differential diagnoses of rapidly progressive dementia with abnormal movements.

PrP is encoded by the prion gene (PRNP) on chromosome 20 and is a cell-surface glycoprotein of unclear function. It is expressed in various cell types throughout the body, but is principally expressed in the brain. Normal cellular PrP (called PrPc) is found in neurons and may be involved in copper transportation and synaptic signaling. In the disease state, PrP undergoes an abnormal post-translational change to produce a pathogenic conformation called PrPsc (scrapie inducing) or PrPres (resistant to protease), which differs from PrPc not in its amino acid sequence but rather in its physical properties: the pathologic form includes a greater proportion of β-pleated sheet conformation, rendering the protein relatively insoluble, protease-resistant, and liable to the formation of protein deposits. What initiates a conformational shift from PrPc to PrPres is not understood; however, once present, PrPres self-propagates by recruiting and converting the nonpathologic PrPc to the PrPres form. An additional molecular form of prion disease has been described in about 1% of cases of Creutzfeldt-Jakob disease (CJD), in which an abnormal form of prion protein is variably sensitive, rather than resistant, to proteases.

Prion disease is responsible for several clinically recognized human disorders besides CJD; these include variant Creutzfeldt-Jakob disease (vCJD), Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, and kuru. Prion diseases may have sporadic, inherited, or transmissible pathogenesis.

CREUTZFELDT-JAKOB DISEASE

ESSENTIALS OF DIAGNOSIS

  • Clinical triad of rapidly progressive dementia, myoclonus, and gait disorder—often accompanied by focal neurologic deficits

  • Cerebrospinal fluid (CSF) profile is acellular, but total protein, 14-3-3 protein, and tau may be elevated and the RT-QuIC test may be positive

  • Magnetic resonance imaging (MRI) may show characteristic abnormalities on diffusion-weighted (DWI) and T2-weighted fluid-attenuated inversion recovery (FLAIR) images

  • Brain biopsy provides definitive diagnosis

General Considerations

The most common of the prion diseases, CJD, can be subclassified as sporadic ...

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