Cns Prion

Transmissible Spongiform Encephalopathies (Prion Diseases) Jeffrey W. Oliver

Learning Objectives • Explain the pathophysiology common to the transmissible spongiform encephalopathies. • List risk factors for these diseases and their implications in the donation of blood products. • Recognize the clinical and morphologic features of the human prionopathies.

Prion Diseases • Due to abnormal form of prion protein (PrP) • Infectious, transmissible, and can be familial • Human diseases: Creutzfeld-Jakob disease (CJD), variant-CJD, Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia, kuru • Animal diseases: bovine spongiform encephalopathy (mad cow disease), scrapie, mink transmissible encephalopathy, elk wasting disease

Pathogenesis • PrP is a normal cellular protein found in neurons • Disease occurs when the normal α-helix conformation (PrPc) changes to a β-pleated sheet isoform (PrPsc or PrPres), which is protease resistant • PrPsc then facilitates conversion of other PrPc molecules to PrPsc, accounting for its transmissibility

Pathogenesis • PrPc is coded for by the PRNP gene on chromosome 20 • Mutations in this gene can make it more susceptible to the conformational change to Prpsc, accounting for the familial forms • How accumulation of PrPsc causes the morphologic changes and neuron loss is unknown

Morphology • Similar for most prionopathies • Usually little gross evidence of atrophy • Microscopic vacuolar change in the neuropil and neuron cytoplasm (spongiform change), primarily in cortex and basal ganglia, without significant inflammation • Severe neuron loss, often gliosis • Kuru plaques: extracellular aggregates of PrPsc, Congo Red and PAS positive

Kuru • First described in the aboriginal Fore tribe in New Guinea in 1957 • Probably began as a sporadic case of CJD, then passed by ritualistic cannibalism • Women and children would eat brains (and had highest incidence of disease), men only ate muscle • Cannibalism is no longer practiced by this people, and kuru is very rare today

Kuru • Patients primarily had ataxia and tremor, dementia is an occasional late finding • Loss of Purkinje and granular cells of cerebellum • Mild spongiform change, especially cerebral cortex and basal ganglia • Kuru plaques mainly in cerebellum

Creutzfeldt-Jakob Disease (CJD) • Rare (global annual incidence 1 per million) • 85% sporadic, but familial forms exist • Iatrogenic causes: corneal or dural transplants, deep electrodes, HGH • Anyone with any of these risk factors is prohibited by law from ever donating blood or blood products • Average age = 7th decade

Creutzfeldt-Jakob Disease (CJD) • Initial subtle memory and behavior changes, followed by rapidly progressive dementia, and startle myoclonus, sometimes with ataxia • Uniformly fatal, with average duration of 7 months

Variant Creutzfeldt-Jakob Disease (vCJD) • First discovered in 1995 • Young adults, more pronounced behavioral changes, slower progression • Morphologic features identical to CJD • Associated with eating beef from cows with BSE

Gerstmann-Straussler-Scheinker Syndrome (GSS) • Autosomal dominant disease with mutations of PRNP gene; very rare – only 32 known families (incidence 2-5 per 100 million) • Usually begins with ataxia followed by progressive dementia • Slower course than CJD, with death after average of 6 years • Kuru plaques prominent in cerebellum

Fatal Familial Insomnia • Autosomal dominant disease with mutation of PRNP • Age of onset 35-60 • Insomnia usually initial complaint, then ataxia, autonomic signs, stupor & coma • Usually fatal within 3 years • Little to no spongiform change or kuru plaques, but severe neuron loss and gliosis in thalamus and inferior olives