What causes prion disease?: more detail

How are the categories defined, and how large is each?

Sporadic disease is defined by exclusion: no pathogenic PRNP variant and no identified exposure. Surveillance figures put it at about 85 percent of reported CJD. Genetic disease accounts for 10 to 15 percent and is defined by a pathogenic variant in PRNP, with CDC giving a range of 5 to 15 percent for CJD specifically. Acquired disease, which includes iatrogenic cases and variant CJD, is 1 to 2 percent of all prion disease.

Those denominators differ between sources because some count CJD and others count all human prion disease, and because ascertainment depends on whether a country runs active surveillance with autopsy. The figures are best read as the shape of the distribution rather than as precise shares.

What is actually proposed as the cause of sporadic disease?

No exposure has been established. The 2022 review by Appleby and colleagues sets out two mechanistic proposals and one modifier.

The first is stochastic conversion. Incidence rises steeply with age, so sporadic disease could follow from the chance production of misfolded prion protein combined with reduced clearance in an ageing brain. The second is somatic mutation, in which a PRNP change arising in a cell lineage rather than the germline initiates conversion locally. The review also notes preliminary work on epigenetic contributions. None of the three has been demonstrated as the initiating event in a human case.

The modifier is the codon 129 methionine or valine polymorphism, which is common in the general population. Homozygosity at that position is associated with sporadic CJD risk, which the review attributes to sequence homogeneity among expressed prion proteins. Genome-wide work has additionally implicated loci outside PRNP, including STX6 and GAL3ST1.

Clinically, the relevant point for families is that a sporadic diagnosis in a relative carries no implication for their own PRNP status, and that no lifestyle, dietary, occupational or geographic exposure has been identified for them to act on.

Does the epidemiology point anywhere?

It raises questions without answering them. The French age-period-cohort analysis published in 2023 examined 2,510 probable and definite sporadic CJD deaths recorded by the national surveillance network between 1992 and 2016, with 2,475 cases aged 45 to 89. Mortality peaked at 75 to 79 years and declined after that, and the authors reported an interaction between sex and age, with higher rates in women at younger ages and in men at older ages, which they described as a first report.

Two systematic effects emerged. A period effect concentrated in the early years was attributed by the authors to the surveillance network itself and improving case identification, after which rates were stable. A cohort effect persisted: people born in 1962 had a 1.65-fold risk relative to the 1937 reference cohort, with a 95 percent confidence interval of 1.19 to 2.27, and the 1922 cohort had 0.60-fold risk.

The authors read the cohort gradient as a signal that environmental exposures may contribute, and tested none. The candidate exposures they discussed, including sheep scrapie, L-type BSE, rising consumption of animal products, mechanically separated meat, pesticides and antibiotics, were raised as possibilities. Pesticides and antibiotics were introduced by analogy with other brain proteinopathies rather than from any prion finding. Reporting this study to a family requires saying both parts: a reproducible birth-cohort pattern, and no identified cause.

The zoonotic question has evidence on both sides. L-type BSE, the atypical strain found in older cattle, transmits more readily than classical BSE to mice expressing human prion protein, and in those mice its biochemical properties resemble the MM2-cortical sporadic CJD subtype, which is why the hypothesis was raised. A 2016 strain-typing study in human PrP transgenic mice compared L-BSE against a panel of sporadic CJD subtypes and found no evidence that L-BSE causes a known form of sporadic CJD. Those authors noted that the agent could still circulate in humans as an unrecognised phenotype, and argued for keeping such agents out of the food chain and for active surveillance of CJD phenotypes. The honest summary is a negative result against a specific hypothesis, not a closed question.

What determines whether a PRNP variant causes disease?

Variant identity, principally. Four variants, E200K, D178N, P102L and A117V, account for more than half of genetic prion disease, and E200K is the most common worldwide. D178N and P102L are described as nearly completely penetrant. E200K shows incomplete, age-associated penetrance. V180I is put near 1 percent and V210I near 10 percent lifetime risk.

Codon 129 determines phenotype as well as risk. For D178N, the polymorphism on the mutated allele decides the clinical syndrome: 129M in cis typically produces fatal familial insomnia and 129V typically genetic CJD. The variant is the same in both.

Inheritance is autosomal dominant, and most carriers inherit from an affected parent, though a new variant can arise during formation of reproductive cells or in early embryonic development. Absence of family history does not exclude a genetic cause, and the 2022 review lists the usual explanations: low penetrance, misdiagnosis in earlier generations, death from other causes before onset, misattributed parentage and incomplete family knowledge.

Variant-level interpretation for a specific family belongs with the reporting laboratory and a genetic counsellor. Genetic counselling comes first sets out the published sequence, and PRNP variants collects what is known variant by variant.

What are the acquired routes, and are they still open?

The iatrogenic routes are historical in most countries, which is relevant when a patient asks whether a past operation could be responsible.

Contaminated surgical or neurosurgical instruments account for six known CJD cases, with none reported since 1976 after decontamination procedures changed. Pituitary-derived human growth hormone, given in the UK between 1958 and 1985 and in the US before 1978, produced cases that are still being identified roughly 50 years after exposure, which is the clearest illustration of how long incubation can be. Dura mater grafts and corneal transplants from donors with undetected disease are the other recognised routes. Variant CJD arose through dietary exposure to BSE, and in the UK it has also been transmitted by blood transfusion on five occasions.

There is no evidence of transmission by everyday contact, droplets, ordinary blood contact or sexual contact. That reassurance is one of the most useful things to offer a household early. Iatrogenic CJD covers the acquired routes in detail and myths and facts is the page to give a worried family.

What should be documented at diagnosis?

Three things make later counselling possible: a PRNP result or, where testing was not done, stored DNA; a structured three-generation family history, since absent history is weak evidence against a genetic cause; and any history of neurosurgery, dura mater or corneal grafting, or pituitary-derived hormone treatment. National registries ask for DNA storage from suspected cases for exactly this reason.

Genetic prion disease: more detail carries the inherited forms further, and prion diseases lists the individual conditions.

This page summarises published literature and is not clinical or genetic advice. No proportion or penetrance figure here describes the position of any particular person.