Ulofe Uduokhai
University of Lethbridge
25/9/26
Atypical bovine spongiform encephalopathy (BSE) is classified as a sporadic disease of old cattle. The classification rests on two observations: cases occur in old animals, and the disease is detected at a low, apparently uniform rate. The 2021 identification of a germline E211K mutation in a Canadian H-type case is difficult to reconcile with a purely sporadic origin, because a heritable variant implies further carriers in the population. This synthesis asks whether the two observations are sufficient to exclude a genetic origin, and finds that neither is: age at onset does not separate sporadic from genetic prion disease, and the prevalence of atypical BSE is not uniform between countries. Atypical BSE is better read as a mixture of a heritable fraction, concentrated in the H-type form, and a spontaneous age-related background. The associated research programme, a population screen for E211K in cattle and a genotype-defined transmission study in sheep, is a single test of whether host genotype governs both the origin of the disease and its transmission.
Bovine spongiform encephalopathy is a fatal neurodegenerative disease of cattle and one of the transmissible spongiform encephalopathies (TSEs), in which the host cellular prion protein (PrPC) is converted into a misfolded isoform (PrPSc) that accumulates in the central nervous system. BSE occurs as classical BSE (C-BSE) and two atypical forms, H-type and L-type, distinguished by the biochemical properties of PrPSc. Classical BSE is linked epidemiologically to feed contaminated with the TSE agent; the atypical forms were recognised later, through active surveillance, and were defined on molecular grounds (Casalone et al., 2004; Biacabé et al., 2008).
Atypical BSE is described as sporadic and attributed to the age of affected cattle. Two observations support this. Atypical cases are almost always found in old animals, by analogy with sporadic Creutzfeldt-Jakob disease in humans, an age-related stochastic event. And atypical BSE is detected at a low, relatively constant rate wherever cattle are tested in sufficient numbers, read as a background occurrence rather than an epidemic (Biacabé et al., 2008; Sala et al., 2012). On this basis the atypical forms are treated, for surveillance and trade, as spontaneous events expected in any herd.
This classification is complicated by a specific PRNP mutation. An H-type case in the United States in 2006 carried an E211K substitution (Richt & Hall, 2008; Nicholson et al., 2008), and a Canadian case in 2021 carried the same substitution in the germline (Tahir et al., 2025). Bovine codon 211 is homologous to human codon 200, where E200K is the most frequent cause of genetic Creutzfeldt-Jakob disease (Kovacs et al., 2005). A germline E211K variant therefore raises the possibility that part of atypical BSE is heritable rather than sporadic, and that further carriers exist. The remainder of this synthesis asks whether the evidence for the sporadic classification can withstand this finding.
The occurrence of atypical BSE in old cattle is treated as evidence against a genetic origin. It is not, because age at onset does not separate sporadic from genetic prion disease. Carriers of the human E200K mutation, the homologue of bovine E211K, typically develop disease in the sixth or seventh decade rather than in early adulthood, yet the disease is unambiguously heritable (Kovacs et al., 2005; Minikel et al., 2016). Late, age-dependent onset is a recognised feature of genetic prion disease and reflects incomplete, age-related penetrance, not a spontaneous origin. The advanced age of affected cattle is therefore equally consistent with a mutation of age-dependent penetrance, and cannot on its own establish that atypical BSE is spontaneous. Whether the age distribution of cases fits stochastic misfolding or mutation-driven penetrance has not, to the author's knowledge, been tested.
The second argument, uniform low prevalence, does not hold either. A heritable germline variant would produce a prevalence that tracks the frequency of the variant, which differs among herds according to breeding history and founder composition. Uniform prevalence is therefore not what a genetic model predicts.
The surveillance data are not uniform. In the case counts reported through the European Food Safety Authority, the ratio of H-type to L-type cases varies markedly between countries, and several national series consist almost entirely of one form: the Portuguese and Brazilian series are entirely H-type and the Irish series predominantly so, while the Polish and Italian series are predominantly L-type (EFSA, 2025). Such variation is difficult to reconcile with a single spatially uniform spontaneous process, and is more readily explained if a heritable or population-structured factor contributes to the H-type form. The countries whose series are dominated by H-type BSE are also those whose cases have not had PRNP sequenced, so whether a heritable variant underlies these clusters is unknown (Clawson et al., 2008; Orge et al., 2015).
A genetic origin cannot, however, account for all atypical BSE. An individual-level analysis of French cases found no birth-cohort effect for either form, inconsistent with feed-borne transmission and consistent with an age-related process (Sala et al., 2012). The European atypical cases that have been sequenced, including the French cases, carried neither E211K nor any other consistent PRNP mutation (Clawson et al., 2008), and no causative mutation has been identified for L-type BSE.
Atypical BSE is therefore best read not as genetic but as a mixture: a heritable fraction, concentrated in the H-type form and associated with E211K and possibly other unscreened PRNP variants, on a spontaneous age-related background that predominates in the L-type form. The size of the heritable fraction is unknown, because PRNP is rarely sequenced in atypical cases and the H-type-dominant series have not been examined at all.
The two components of the research programme correspond to the two stages at which host PRNP genotype may act. Screening 1,000 to 1,200 cattle for E211K addresses origin: a population estimate of E211K frequency would show whether the germline case of Tahir et al. (2025) reflects a real pool of carriers or an isolated event, and would give a first estimate of the heritable fraction of a disease currently called sporadic.
Challenging sheep of defined PRNP genotype and examining their tissues by immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay addresses transmission. Genotype control of prion susceptibility in sheep is established: susceptibility to classical and atypical scrapie depends strongly on PRNP genotype (Moum et al., 2005), and the ability of atypical bovine prions to propagate in a new host depends on the prion protein sequence of the recipient (Béringué et al., 2008; Marín-Moreno et al., 2020). The sheep component tests whether recipient genotype gates the transmission of atypical BSE.
Together the two components ask whether host genotype determines both whether atypical BSE arises in cattle and whether it can cross the species barrier. If it governs both, the sporadic, age-related classification is inadequate, and atypical BSE is better described as a low-penetrance heritable prion disease of cattle whose emergence and transmission are each under genetic control.
The sporadic, age-related classification of atypical BSE is an assumption made before it could be tested, not a conclusion drawn from evidence. Neither observation supporting it excludes a genetic origin: age at onset does not distinguish sporadic from genetic prion disease, and prevalence is not uniform across populations. The germline E211K mutation, together with the absence of PRNP data for the series in which H-type BSE predominates, leaves the relative contributions of heritable and spontaneous mechanisms undetermined. The programme combining an E211K screen in cattle with a genotype-defined transmission study in sheep is an appropriate framework for resolving this, provided the two components are read as one investigation of host genetic control over the origin and transmission of the disease.
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