Scrapie (from English scrape Scrapie is a transmissible, slowly fatal disease of the brain ( encephalopathy ) in sheep and, to a lesser extent, goats. It is most likely caused by malformed proteins (prions). Scrapie is associated with the formation of cavities (vacuolisation) in the nerve cells and manifests itself in behavioural and gait disorders. The English name comes from the fact that the diseased sheep have a tendency to rub off their wool as a result of severe itching. Like Creutzfeldt-Jakob disease and Kuru in humans, it belongs to the transmissible spongiform encephalopathies (TSEs). Like all TSEs, scrapie is a notifiable animal disease. The transfer of the pathogen to cattle is considered to be the cause of the occurrence of BSE. In 2015, there were eleven confirmed scrapie cases in Germany, the highest number of cases (n=43) since 1990 was observed in 2004.
The infectious agent (scrapie agent) is considered to be a pathologically altered protein, a prion. The normal prion protein (PrPC, “c” stands for cell ) in sheep consists of 256 amino acids (in mammals the number varies between 253 and 273 amino acids). Its C-terminal (that end where the carboxy group is not involved in a peptide bond) domain consists of three α-helices and contains two antiparallel β-sheets. It is a component of almost all cells, in the nervous system mainly of nerve contact sites (synapses), its function is unknown so far. The PrP gene is located on chromosome 20.
The pathologically altered prion protein (PrPRES or PrPSc, from resistant or scrapie, respectively) differs only in having a higher proportion of β-sheet structures. This makes it insoluble and no longer degradable by protein-cleaving enzymes (proteases) (amyloidosis). The molar mass of the fragment of PrPSc produced by treatment with proteinase K is 33 to 35 kilodaltons. The pathologically altered prion proteins accumulate and form 500 to 1000 nm long fibrils (scrapie-associated fibrils, SAF) within the nerve cells. Different subforms of the PrPSc (pathogen strains) exist, which differ in terms of their protease sensitivity and pathogenic effect in the mouse model.
According to the prion theory, once altered prion proteins also elicit a change in healthy PrPC. The exact mechanism of this process is not yet known and host factors and copper ions probably also play a role and copper ions play a role in the development. The PrPSc from sheep, like that from BSE-infected cattle, can cause such a change in humans, but the pathogenic effect of the sheep PrPSc for humans is many times less than that of Creutzfeldt-Jakob disease. The risk of infection for humans is therefore low, and so far there have been no confirmed transmissions from sheep to humans, but a classification as potentially dangerous seems justified.
The PrPSc is not only largely insensitive to degradation by cellular processes, but also to chemical and physical effects. It is largely resistant to many disinfectants, ionizing and UV radiation. Moist heat (131 °C) in autoclaves used for sterilization in medicine destroys the PrPSc only after two hours, so that medical instruments must be autoclaved four times in succession. In dry heat at 200 °C, the prion is inactivated only after 60 minutes. Effective disinfectants include sodium hydroxide, guanidinium thiocyanate and sodium hypochlorite.
Another hypothesis, but one that is now held by only a few scientists, assumes an unknown virus or virus-like virion as the cause of the disease, and the prion protein is thought to play only a role as a receptor on the cell surface.
The pathological prion is found in the central nervous system, cerebrospinal fluid, tonsils, lymph nodes and spleen. It is excreted through the afterbirth and amniotic fluid. Surfaces contaminated with the scrapie agent can be a source of infection for years.
Natural transmission is mostly by oral ingestion of afterbirth and amniotic fluid or water or feed contaminated with it, and licking of the lamb by the ewe. The ewe may transmit the disease to the fetus. Apparently, transmission by contact is also possible, and transmission by mites (hay mite) is also being discussed. Experimental evidence has also shown transmission of infection via the conjunctiva and minute injuries to the mucous membrane of the mouth, as well as via blood transfusions. Contaminated vaccines have also been identified as a trigger. Likewise, transmission through the consumption of milk and milk products from small ruminants cannot be ruled out.
The pathogen enters the spinal cord via the enteric nervous system and the visceral nerves and from there ascends to the brain. In sheep, dissemination via the lymphatic system also plays a role.
In principle, all breeds of sheep are susceptible. Apart from sheep and (to a lesser extent) goats, minks, mice, rats, hamsters, European mouflons, monkeys and humans are also susceptible. The transition of the agent to cattle (BSE) is considered a TSE in its own right.
Susceptibility in sheep varies depending on genetic variation in the amino acid sequence of the prion protein. For example, sheep with a homozygous hereditary predisposition for alanine (A) at position 136, arginine (R) at position 154 and arginine at position 171 (AA136, RR154, RR171) are almost resistant. However, in the meantime atypical scrapie cases have also been reported with this genotype and this genotype is in principle also susceptible to the BSE agent, so that the animals can be silent carriers of BSE.
|Genotype class||Genotype *||Hazard|
|G1||AA, RR, RR||extremely low (“resistant”)|
|G2||AA, RH, RQ
AA, RR, RH
AA, RR, RQ
|low risk if mated with G1 or G2|
|G3||AA, HH, QQ
AA, HR, QH
AA, HR, QQ
AA, RR, HH
AA, RR, HQ
AA, RR, QQ
|increased risk for the individual animal, most common affected genotype in Germany is ARQ|
|G4||AV RR, RQ||high risk for the individual animal and half of the offspring|
|G5||AV, HR, QQ
AV, RR, HQ
AV, RR, QQ
VV, RR, QQ
|very high risk|
|*Amino acid 136, 154 and 171 of both sets of chromosomes; A=alanine, R=arginine, V=valine, H=histidine, Q=glutamine; pairs of same letters indicate homozygosity. (Source: NSP Genotypes Table of DEFRA)|
In the EU, member states have been obliged since 2003 to set up programmes for breeding sheep for resistance to TSE. In goats, this genetic dependency is not present, so that breeding for scrapie-resistant animals is not possible.
According to the prion theory, the incubation period should be several (usually three to four) years. In experimental infections, incubation periods of 180 to 900 days have been determined. Such long periods until the formation of the first symptoms are otherwise only known in chronic diseases, for example of the immune system, chronic poisoning or hereditary diseases. Scrapie is one of the so-called slow infections. The disease appears clinically at the earliest at the age of 18 months, most frequently it appears at the age of three years. Scrapie is a disease of individual animals, affecting up to 1 % of the animals in a herd.
Clinically, the disease initially manifests itself in behavioural changes such as jumpiness, restlessness, changes in lip (“gnubbing”) and ear play as well as nodding and sideways movements of the head. When seized, diseased animals suddenly collapse. Increased salivation is also frequently observed. Another characteristic feature is disturbances in locomotion such as a trotter-like movement of the forelimbs (“trotter’s disease”), a cock-step-like gait or weakness of the hind limbs, dragging of the toes across the ground, swaying gait, and buckling in the limbs. Galloping and jumping are no longer possible for the animals. Another frequently observed feature is itching, which causes the animals to stomp their limbs, gnaw or rub against objects (hence the English name scrapie), resulting in damage to the fleece. As a rule, the disease is accompanied by emaciation.
After the first symptoms of the disease, the affected sheep survive only one to six months (in extreme cases two weeks to six months), after which death inevitably occurs.
With the naked eye (macroscopically), no changes can be seen in dead animals, apart from possible skin and fleece damage as a result of scouring.
The brain tissue histologically shows a cell proliferation of astroglia and subsequently a vacuolization and degeneration of the neurons in the brainstem and cerebellum. In some cases, eosinophilic granules and shrunken (pyknotic) cell nuclei can be detected in the nerve cells. Vacuolization also occurs in the white matter. The scrapie-associated fibrils can be detected by electron microscopy, and the pathological prion proteins can also be detected by immunohistochemistry.
Diagnosis and differential diagnosis
The diagnosis can be made with certainty only on the basis of biopsies of the lymph nodes with detection of PrPSc by ELISA or Western blot and after death by pathohistological examination. Recently, PrPSc detection methods have also been developed in the live animal prior to the appearance of clinical signs, although these are still at the experimental stage. The diagnosis may only be made by an official veterinarian. After a positive result in an approved testing facility, a second verification examination of the sample is carried out at the Friedrich-Loeffler-Institute. Various genetic tests exist for genotyping and thus risk assessment.
Differential diagnosis must exclude other central nervous diseases of sheep such as Borna’s disease, rabies, visna, listeriosis, coenurosis, enzootic ataxia and cerebrocortical necrosis, as well as metabolic diseases associated with neurological symptoms such as ketosis and hypocalcaemia(See also VETAMIN D). With regard to the pruritus, Psoroptes mange should also be considered.
As scrapie is not treatable, control is directed towards the killing and destruction of affected animals, breeding for genetically resistant sheep and quarantine measures. The specific control measures vary internationally.
In the European Union, control is governed by Regulation (EC) No 999/2001, as last amended by Regulation (EC) No 339/2006, and national animal disease law (in Germany: Tierseuchengesetz, Viehverkehrsverordnung, VO über anzeigepflichtige T ierseuchen and the TSE-Überwachungsverordnung; in Austria: Scrapie Surveillance Ordinance) are regulated. All deaths of sheep over 18 months of age must be examined for scrapie, as must all animals slaughtered from this age onwards on a random basis. As scrapie is notifiable, the appropriate measures are determined by the official veterinarian. The current regulations allow that not whole herds but only genetic risk groups (rams G2-G5, female sheep G3-G5) are killed in affected herds. Flocks may only be replenished after culls with homozygous ARH animals or heterozygous ARH combinations with other genotypes except VRQ. Purchases should only be made from herds in which no scrapie cases have occurred for at least 5, preferably 8 years. If no such animals are available, the veterinary office may grant exemptions. However, the breeding of “genetically resistant” sheep has recently become questionable again due to the atypical scrapie cases. Through consistent hygiene measures, scrapie-free flocks can also be produced with genetically susceptible genotype classes.
The first published case of scrapie dates back to 1732 in Great Britain. The number of animals affected annually is estimated at around 10,000 there alone. The disease has also occurred in Germany and the rest of Europe since the middle of the 18th century. It was probably introduced via imports of breeding sheep. Today, with the exception of Australia and New Zealand, scrapie is widespread worldwide and occurs most frequently in Great Britain and Cyprus.
The number of clinical diseases has decreased significantly in Germany since 1945, also due to the change in the utilization concept (meat production instead of wool production), as sheep today rarely live longer than five years.
In 1947, the first deaths also occurred in mink in the United States after feeding sheep slaughterhouse waste, and from 1967 also in Europe. In 1967, it was recognized that the pathogen does not contain nucleic acid due to its resistance to radiation and it was suspected that an infectious protein was involved. In 1982, Stanley Prusiner hypothesized the sole protein cause of TSE, he also coined the term “prion” from proteinaceous infectious particle.
The 1985 outbreak of BSE in the United Kingdom has been attributed to the feeding of sheep-derived meat-and-bone meal to cattle.
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