What are prion diseases?: more detail

How are prion diseases grouped?

Three routes of origin are used in practice.

Sporadic disease arises when prion protein misfolds without an inherited change or an identified exposure. Sporadic CJD is the commonest form, and the group also contains sporadic fatal insomnia and variably protease-sensitive prionopathy.

Genetic disease follows a pathogenic variant in PRNP, inherited in an autosomal dominant pattern. The recognised phenotypes are genetic CJD, Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia. A family history may be absent where penetrance is incomplete, where a relative died before onset or where a variant has arisen de novo.

Acquired disease follows exposure to prions from outside the body. This includes iatrogenic cases from dura mater grafts, corneal grafts, contaminated neurosurgical instruments and cadaveric pituitary growth hormone given before synthetic preparations replaced it, along with variant CJD, which is linked to bovine spongiform encephalopathy, and kuru.

The proportions differ between surveillance systems. The CDC puts sporadic cases at about 85 percent, familial at 5 to 15 percent and iatrogenic at under 1 percent. MedlinePlus Genetics gives 85 to 90 percent sporadic or acquired, 10 to 15 percent familial and 1 to 2 percent iatrogenic. The Canadian CJD Surveillance System reports about 93 percent sporadic, about 6 percent inherited and under 1 percent acquired. The differences come from ascertainment and from how mixed categories are assigned, so a range is the fair thing to quote when speaking to a family.

What do the molecular subtypes mean?

Sporadic CJD is subtyped by the codon 129 genotype of PRNP, which can be methionine homozygous, valine homozygous or heterozygous, combined with the type of protease-resistant prion protein found on Western blot. This yields the familiar labels MM1, MV1, VV1, MM2, MV2 and VV2, which were all represented in the 2026 Annals of Neurology diagnostic series by Myskiw and colleagues. Subtype tracks with clinical course, so a VV2 case may present with ataxia and run longer than a classic MM1 case. Genetic cases are named by variant instead, such as E200K, V210I, V180I, D178N, P102L, P105S and A117V, with D178N producing either genetic CJD or fatal familial insomnia depending on the codon 129 allele carried in cis.

For counselling purposes, the practical point is that subtype is a laboratory description of a case, usually established late or only after death, and it carries little predictive weight for one person.

How is a diagnosis reached in life?

CDC criteria describe three levels of certainty. Definite sporadic CJD rests on neuropathology, immunocytochemistry, a Western blot showing protease-resistant prion protein or the presence of scrapie-associated fibrils, which means brain tissue from biopsy or autopsy. Probable sporadic CJD can be reached in two ways: a neuropsychiatric disorder with a positive real-time quaking-induced conversion assay, usually called RT-QuIC, in cerebrospinal fluid or other tissue, or a rapidly progressive dementia with at least two of myoclonus, visual or cerebellar signs, pyramidal or extrapyramidal signs and akinetic mutism, together with at least one supportive investigation and no routine test pointing elsewhere. Possible sporadic CJD covers a progressive dementia with two of those four features, an illness shorter than two years and no positive confirmatory test.

The supportive investigations are a 14-3-3 assay in cerebrospinal fluid when the illness has lasted under two years, periodic sharp wave complexes on EEG at any stage, and high signal on diffusion weighted or FLAIR MRI in the caudate and putamen or in at least two cortical regions among temporal, parietal and occipital. Variant CJD has its own criteria, where bilateral pulvinar high signal on MRI is reported in more than 75 percent of cases and is highly specific in the right clinical setting.

Assay development continues. Myskiw and colleagues reported an end-point QuIC method using a deer mouse recombinant substrate with 96.6 percent sensitivity, 111 of 116 samples, and 100 percent specificity, 35 of 35, against 87.1 percent for the earlier end-point format in the same work. They are explicit that independent laboratories, inter-laboratory reproducibility, substrate standardisation and prospective longitudinal samples are all still needed, so a clinician should treat this as a promising assay under validation and not as a replacement for current testing.

More on the sequence of tests is on how it is diagnosed.

Who keeps count?

National surveillance is how rare prion disease is tracked and how iatrogenic clusters have been detected. Annual incidence is about 1 to 2 cases per million in many countries. The CDC reports about 500 to 600 cases a year in the United States, MedlinePlus Genetics gives about 350 new cases a year there, and the Canadian system recorded 90 diagnoses in 2022, with about 90 percent of people aged 45 to 85.

In Canada, health care professionals must inform their local public health authority of a suspected case and are strongly encouraged to notify the CJD Surveillance System as well, which can be reached on 1-888-489-2999 or at cjdsurveillance@phac-aspc.gc.ca. Clinicians elsewhere should use their own national unit, and in the United Kingdom suspected prion disease is referred to the National Prion Clinic.

What can be offered now?

Treatment is supportive. The 2026 multidisciplinary palliative and supportive care recommendations in Age and Ageing set out an approach that fits the speed of these illnesses: early palliative involvement, treatment of myoclonus when it interferes with daily function or causes distress, with levetiracetam as a first-line option and clonazepam reserved for the more advanced non-ambulant stage, and management of neuropsychiatric symptoms that starts from the view that so-called challenging behaviour is usually the communication of an unmet need. Because symptoms can arise and settle quickly, the authors note that a watch-and-wait approach to troubling symptoms such as delusional ideas is often justified. Decisions about clinically assisted nutrition and hydration are made individually and reviewed at every care review.

Practical guidance for families is on what to expect.

What is in development?

Nothing has yet changed the course of human prion disease. Completed trials up to 2013 covered flupirtine, pentosan polysulphate, quinacrine and doxycycline, and none established benefit in a controlled design.

Current work aims at lowering prion protein before or early in illness. A 2025 Nature Medicine report from the Broad Institute describes dual-AAV base editing installing a PRNP R37X change, with 37 percent average installation of the desired edit, a 50 percent reduction of prion protein in the mouse brain and a 52 percent extension of lifespan in transgenic human PRNP mice given human prion isolates. A related epigenetic editor, CHARM, removed more than 80 percent of prion protein in mouse brain, against earlier work indicating that as little as 21 percent lowering can improve symptoms. Both are mouse work. The MIT account of CHARM states plainly that these tools have many hurdles to pass before anyone knows whether they work as therapeutics.

Trials open to people are listed on current trials, and the research-facing account of mechanism is in our mechanisms overview. The plain version of this page is what are prion diseases.