Scrapie is the one sheep disease that probably every veterinarian can vaguely remember learning about (before promptly forgetting). It is not, however, a disease many practitioners expect to encounter in practice, even those in food animal medicine, over the course of their careers. Yet, with the current rise in popularity of backyard sheep and goats and the ongoing economic impact scrapie has domestically and internationally, revisiting this disease is prudent for large and small animal veterinarians.
What is scrapie?
Scrapie is the prototypical transmissible spongiform encephalopathy (TSE). Similar to other TSEs such as chronic wasting disease and bovine spongiform encephalopathy (BSE or “mad cow disease”), scrapie is an incurable, progressive, degenerative and fatal disease of the central nervous system.
It has been described in Europe since the 18th century, and prior to the late 20th century, scrapie was believed to exist as a single phenotype, now called classical scrapie. In 1998, a novel phenotype of the disease was discovered in Norway. This phenotype, named “atypical scrapie” or “Nor98”, appears to occur spontaneously in populations but is not considered contagious in a natural setting. Recently, a third phenotype, CH1641, has been described in sheep and goats. (This phenotype has more BSE-like properties but will not be further discussed in this article because it is extremely rare and needs additional characterisation.)
Distribution
Nowadays, classical and atypical scrapie are found throughout the world. Atypical scrapie alone has been found in domesticated sheep and goats around the world, including in the US, UK, Australia and New Zealand.
Transmission
Classical scrapie naturally infects all breeds of domestic sheep and goats as well as mouflon (Ovis musimon). It may naturally infect other closely related species, but to date, no evidence of such infection has been found.
Early laboratory studies of classical scrapie using an oral transmission model demonstrated that cattle, swine and some non-human primates were resistant to infection via this route (Comoy et al., 2015; Gibbs et al., 1980; Greenlee, 2018; Konold et al., 2013; Safar et al., 2008). However, more recent studies involving pigs suggest transmission following ingestion of the scrapie-infected tissue is possible (Gallardo and Delgado, 2021). Pigs, however, do not show clinical signs of the disease, and it cannot be detected by traditional testing methods. Hamsters have also proven to be susceptible to scrapie via oral transmission (Prusiner et al., 1985).
In other studies, various animal species, including voles, mink, rats, mice, cattle and non-human primates, could be infected with the disease, but only if transmitted by intracranial inoculation (Carlson et al., 2015; Hamir et al., 2011; Tyler, 2004). Surprisingly (or perhaps not, knowing felines), cats were resistant to classical scrapie infection even after intracranial inoculation (Hamir et al., 2002).
In scientific studies, many animal species sensitive to classical scrapie by intracerebral inoculation, eg voles, have proven resistant to atypical scrapie (Carlson et al., 2015).
Of note, though, is the fact that recent studies demonstrated the production of classical BSE prions in transgenic mice expressing bovine proteins and pigs when either species was inoculated with atypical scrapie intracranially (Marín et al., 2021).
Is scrapie zoonotic?
The World Organization for Animal Health does not consider scrapie a risk to human health. Further, no connection between classical scrapie and human TSEs has been established, although speculation about its zoonotic potential still exists. Like classical scrapie, atypical scrapie is not considered a risk to humans, and no direct association with human disease has been found.
The scrapie disease agent: prions
Prions, the abnormally folded neurotoxic versions of naturally occurring proteins, are the disease agent of any TSE. The scrapie prion (PrPsc) is an aberrantly folded isoform of a glycoprotein found in the cell membranes of neurons (PrPc). Upon contact with normal proteins, prions induce secondary structural changes that convert the normal proteins into the toxic, infectious prion version of the protein. These prions induce changes in additional copies of the normal protein and build up in the cells causing cell death.
Classical scrapie prions remain infective in an environment kept free of sheep and goats for over a decade and a half
Prions are incredibly hardy. They resist degradation by cold, high heat (including sterilisation temperatures), disinfectants, ultraviolet light and microwaves. They can tightly bind to metals and plastics and can be carried on fomites, including “sterilised” surgical instruments. Organic material can also protect scrapie prions from decontamination or degradation. They can persist in aldehyde-fixed samples and soil for years.
As a failed attempt at eradication in Iceland demonstrated, classical scrapie prions remain infective in an environment kept free of sheep and goats for over a decade and a half (Georgsson et al., 2006). One environmental study in the United Kingdom revealed that infective classical scrapie prions carried on dust could travel, airborne, between 30 and 60m from the source of contamination (Gough et al., 2015). These sources of contamination are most often birth fluids and tissues; however, colostrum, milk, urine, saliva and faeces have all been shown to carry infectious prions.
Pathophysiology
Classical scrapie is most easily transmitted when animals are young but is considered a disease of older small ruminants because it takes, on average, two to seven years for clinical signs to appear. Young animals ingest the prions, which then enter the body through the Peyer’s patches, gut-associated lymph tissue and the enteric ganglia. From there, the prions travel throughout the lymph and peripheral nervous tissue until they reach the central nervous system (CNS).
Classical scrapie is most easily transmitted when animals are young but is considered a disease of older small ruminants because it takes, on average, two to seven years for clinical signs to appear
Classical scrapie prions commonly appear in the obex and midbrain, while atypical scrapie prions home to more rostral portions of the brain, such as the cerebellar cortex. Once prions enter the central nervous system, tissue death due to the accumulation of prions triggers the clinical signs associated with scrapie.
Clinical signs
The eponymous clinical sign of classical scrapie is incessant scratching, chewing and/or scraping of the skin by afflicted sheep. Weight loss, skin or fibre damage due to trauma, abnormal gait, ataxia, tremors, convulsions, behaviour changes, bruxism and hypersensitivity to stimuli are also reported (Table 1). Blindness is not a common sign, but a staring fixed gaze can occur.
Atypical scrapie does not manifest as commonly with pruritus but rather ataxia with hypermetria, absent menace response, circling and head tremors. This may reflect more damage to and dysfunction of the cerebellar tissue where those prions are found frequently. Goats also do not demonstrate as much pruritus as sheep, but nibbling of their bodies rather than scratching on objects can be seen.
Clinical signs are progressive, and death occurs within weeks or months after the first appearance.
| Clinical signs of classical and atypical scrapie in sheep and goats |
|---|
| Pruritus (more commonly in classical scrapie) Circling (more common in atypical scrapie) Weakness/ataxia Nibbling or licking Weight loss Tremors Excitability Behaviour changes Bruxism Absent menace response |
Since any abnormality of the CNS can mimic either variant of scrapie, differential diagnoses (Table 2) should include:
- Rabies
- Polioencephalomalacia
- Meningitis
- Infectious diseases (bacterial and viral)
- CNS abscess
- Toxins
Likewise, any disease that can cause weakness or ataxia (such as pregnancy toxaemia or hypocalcaemia) and any disease that causes itching (such as lice or mite infestations) should also be considered.
| Differential diagnoses for classical and atypical scrapie |
|---|
| Rabies Trauma Polioencephalomalacia CNS abscess Infectious disease/meningitis (bacterial and viral) Pregnancy toxaemia Hypocalcaemia Toxins/poisons Ectoparasites (eg lice and mites) |
Diagnosis
Definitive pre-mortem diagnosis of scrapie is difficult – prions do not generate an antibody response, so serological tests cannot be used for diagnosis. Biopsies of the third eyelid and rectal mucosa have been approved by the United States Department of Agriculture (USDA) for disease detection in live animals. However, the challenges involved in sample collection and low test sensitivity make their application rare.
In the US and the UK, a presumptive diagnosis in live animals is often based solely on clinical signs with post-mortem confirmation. Therefore, any sheep or goat that dies with undiagnosed CNS signs should be tested for scrapie. Post-mortem testing is done using molecular and microscopic techniques such as immunohistochemistry and immunoblotting. No gross lesions specific to the disease are found on general necropsy.
Prevention: selecting for genetic resistance
Sheep
Because the environmental eradication of, and testing for, prions is so difficult, selecting sheep with genetic resistance to classical scrapie has become the focus of many producers and regulatory bodies.
Because the environmental eradication of, and testing for, prions is so difficult, selecting sheep with genetic resistance to classical scrapie has become the focus of many producers and regulatory bodies
Genetic resistance to classical scrapie in sheep is well established and has been used in the US and the UK since the turn of the century to help select for scrapie-resistant sheep. Amino acid changes to the PRNP gene (which codes for the PrPc protein) at codons 136, 154 and 171 influence resistance or susceptibility to classical scrapie in sheep. Within the US, codons 136 and 171 are considered the most important for determining resistance and thus are the most commonly screened. In other parts of the world, all three codons are assessed.
Codon 136 can code for either valine (V) or alanine (A), and codon 154 can code for either histidine (H) or arginine (R). Codon 171 can code for one of four amino acids: glutamine (Q), arginine (R), lysine (K) or histidine (H). One copy of each codon is inherited from each parent. So, the degrees of resistance are generated by the various possible combinations of inherited codons.
Sheep that inherit alanine at codon 136 and arginine at codons 154 and 171 (A136 R154R171 or ARR/ARR) from both parents are considered the most resistant to classical scrapie
Sheep that inherit alanine at codon 136 and arginine at codons 154 and 171 (A136 R154R171 or ARR/ARR) from both parents are considered the most resistant to classical scrapie. Sheep with valine at codon 136, an arginine at codon 154 and a glutamine at codon 171 (V136R154Q171 or VRQ/VRQ) are considered the most susceptible to classical scrapie (Table 3). Sheep with other combinations of codons show varying degrees of resistance or susceptibility.
| Genetic resistance/susceptibility to classical scrapie (US notations) | |||
|---|---|---|---|
| Sheep (codons 136 and 171) | Goat (codons 146 and 222) | ||
| A/A R/R | Nearly completely resistant to classical scrapie | N/N Q/Q | No protective variants: susceptible to classical scrapie |
| A/A Q*/R | Rarely susceptible to classical scrapie | N/N Q/K | At least one protective S146 or K222 variant: increased resistance to classical scrapie |
| A/V Q/R | Somewhat susceptible to classical scrapie | N/N K/K | |
| A/A Q/Q | Susceptible to scrapie and can transmit disease | N/S Q/Q | |
| A/V Q/Q | S/S Q/Q | ||
| V/V Q/Q | N/S Q/K | ||
| S/S K/K | All protective variants: increased resistance to classical scrapie | ||
Atypical scrapie resistance does not have the same genetic determinants. Sheep with the ARR and AHQ genotypes, some of the most resistant to classical scrapie, are more susceptible to atypical scrapie. Codon 141, which is not routinely screened in the US, may also play a role in atypical scrapie susceptibility.
| Genetic resistance/susceptibility to classical scrapie (UK notations) codons 136, 154, 171 | |||
|---|---|---|---|
| Resistant | Susceptible | ||
| Type 1 (highly resistant) | ARR/ARR | Type 4 (susceptible) | ARR/VRQ |
| Type 2 (resistant) | ARR/AHQ | Type 5 (highly susceptible) | AHQ/VRQ |
| ARR/ARH | ARH/VRQ | ||
| ARR/ARQ | ARQ/VRQ | ||
| Type 3 (little resistance) | AHQ/AHQ | VRQ/VRQ | |
| AHQ/ARH | |||
| AHQ/ARQ | |||
| ARH/ARH | |||
| ARH/ARQ | |||
| ARQ/ARQ | |||
Goats
In 2017, the European Food Safety Authority concluded that breeding programmes for goats based on genetic resistance to scrapie should be implemented. Genetic testing for resistance to classical scrapie in goats became commercially available in the US in 2018.
Over 50 changes to the PRNP gene in goats have been discovered. However, only a handful appear to play a major role in conferring resistance to classical scrapie (Konold et al., 2020a; Konold et al., 2020b; Madsen-Bouterse et al., 2021). In goats, serine (S) at codon 146 in place of an asparagine (N) and/or a lysine (K) at codon 222 instead of a glutamine (Q) confer greater resistance to classical scrapie.
Changes to codons 142 and 211 may also influence resistance to classical scrapie in goats. Indeed, in an outbreak of classical scrapie in a goat herd in the UK in 2016, which led to the culling of 2,500 goats, no goat found to carry a single allele associated with resistance (S146, Q211 or K222) was positive for scrapie.
Goats, as with sheep, appear to be more at risk for atypical scrapie if they have histidine at codon 154.
Final thoughts
Scrapie, with its long incubation period, infective prions that are resistant to decontamination and a dearth of pre-mortem testing, is a difficult disease to eradicate. But progress is being made. The US reported no incidences of classical scrapie in fiscal year 2022, and models suggest the UK may have only three more cases of classical scrapie before 2030.
To continue this progress, veterinarians with sheep and goats as patients will be well-served revisiting this disease over the course of their careers as scientific understanding of it continues to grow. Being well informed about scrapie will not only allow veterinarians to help survey for and identify rare cases of this neurological disease but also allow them to provide their clients with valuable information to help them make educated decisions regarding the health of their sheep and goats.
