prion

**Pathophysiology** - The normal prion protein (PrP^C) is encoded by the PRNP gene on chromosome 20. It is a membrane-bound, GPI-anchored protein, mostly alpha-helical, protease-sensitive, and expressed mainly in neurons. - The pathologic isoform (PrP^Sc, "scrapie") has the same amino acid sequence but a different conformation, rich in beta-pleated sheets. It is protease-resistant (PK-resistant) and aggregates into amyloid-like deposits. - PrP^Sc acts as a template. It converts PrP^C to PrP^Sc in a self-propagating chain reaction. There is no replication of nucleic acid. - The result is neuronal vacuolization ("spongiform change"), neuronal loss, and gliosis. There is characteristically NO inflammatory infiltrate, so no fever and no CSF pleocytosis.

**Modes of acquisition** - Sporadic (~85% of CJD): spontaneous misfolding, peak age ~60s. - Genetic/familial (~10–15%): autosomal dominant PRNP mutations (familial CJD, GSS, FFI). - Acquired/infectious: iatrogenic (contaminated neurosurgical instruments, dura mater or corneal transplants, cadaveric human growth hormone), dietary (kuru from ritualistic cannibalism in Papua New Guinea; variant CJD from BSE-contaminated beef).

**Clinical syndromes** - **Sporadic CJD:** rapidly progressive dementia, myoclonus (startle myoclonus), ataxia, and akinetic mutism, with death usually within about 1 year. - EEG: periodic sharp-wave complexes (triphasic, ~1 Hz). - MRI: cortical ribboning and basal ganglia hyperintensity on DWI/FLAIR. - CSF: positive 14-3-3 protein (less specific), elevated tau, and positive RT-QuIC (highly sensitive and specific, now the preferred test). - **Variant CJD:** younger patients, prominent psychiatric/behavioral symptoms first, painful sensory symptoms, later dementia. Longer course. MRI shows the "pulvinar sign." It is linked to BSE and can be found in tonsil/lymphoid tissue. - **Kuru:** cerebellar ataxia and tremor ("laughing death"). - **GSS:** ataxia with later dementia, with PrP plaques in the cerebellum. - **FFI:** intractable insomnia, autonomic dysfunction, and thalamic degeneration. Mutation at codon 178 with methionine at codon 129.

**Diagnosis** - Definitive diagnosis is by brain biopsy or autopsy. It shows spongiform change, with PrP^Sc detected by immunohistochemistry or Western blot (protease-resistant bands). - Clinical diagnosis relies on the MRI, EEG, and RT-QuIC findings above.

**Treatment and prevention** - No effective treatment. Care is supportive and the disease is uniformly fatal. - Decontamination: autoclave at a higher temperature/longer duration than usual, along with sodium hydroxide or bleach (sodium hypochlorite). Routine sterilization methods are inadequate. - Exclude people at risk from blood and organ donation. Use single-use instruments where possible.

**High-yield associations** - A protein that is infectious without DNA/RNA. - A beta-sheet conformational change is the key concept (shared in principle with amyloidoses and some neurodegenerative diseases). - Homozygosity at PRNP codon 129 (Met/Met or Val/Val) increases susceptibility to CJD. Heterozygosity is protective. - Differential for rapidly progressive dementia: autoimmune encephalitis, paraneoplastic syndromes, CNS infection, and Hashimoto encephalopathy (all potentially treatable, so exclude them). - Histology: "swiss cheese" vacuolated brain tissue without inflammation.