• Symptoms
• Cause
• Diagnosis
• Risk factors
• Approach

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Symptoms

The symptoms of scrapie generally appear from the age of one and a half years old. Clinical cases from ten months old and sometimes even younger have been described, but these are exceptions. Usually the animals are older than two years and show the following symptoms:

• abnormal behaviour;
• itching, chafing;
• neurological signs:
  • tremors at the head;
  • startle behaviour;
• ill-thrift.

Deviant behaviour

The first symptoms of scrapie often consist of changes in behaviour. Sometimes the animals can stare 'dreamily' for a long time with their head slightly lowered. While at another time, the animal shows no symptoms. In a flock of sheep where scrapie occurs, an owner can sometimes recognize a sick animal at a very early stage, because it no longer shows similar behaviour with the group. For example, if the rest of the animals are grazing, the scrapie affected sheep is either lying down or walking alone in another corner of the pasture.

Itching

Initially, sometimes only symptoms of itching occur. Affected animals chafe at anything, which can cause changes to wool or skin. Chafing is also often done on wool-less parts of the body. When rubbing the lumbar region, the animals often start smacking. It is estimated that about sixty percent of sheep with scrapie show itching.

Neurological signs

Sheep suffering from scrapie may, among other neurological symptoms, be restless and jumpy. Sometimes they tremble all over the body. The trembling is often only visible at the head. The animal's movements have also changed. Especially if the animal moves a little faster, the movements are reminiscent of those of a trotter.

Ill-thrift

In addition to the above symptoms, the animals eventually lose weight and the fur becomes dry and gray. A treatment is not available. All affected animals eventually die. At autopsy, the cadaver is often thin; sometimes skin and coat changes are present.

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Cause

Scrapie belongs to the TSEs (transmissible spongiform encephalopathies: transmissible brain abnormalities associated with sponge formation). On microscopic examination, the brains of animals with a TSE show spongy structural changes. The causative agent of scrapie is referred to as 'prion' (proteinaceous infectious particle).

The susceptibility to scrapie is genetically determined and, as far as is known, this is controlled by a single gene, the PrP gene. This PrP gene determines the production and characteristics of the normally occurring prion protein (PrP = prion protein). This normal prion protein is indicated as PrPC (c stands for cellular). An altered form of the PrP occurs in animals with a prion disease such as scrapie; this altered form is indicated by PrPSc (scrapie protein; is identical to scrapie pathogen). When sheep or goats come into contact with the PrPSc, depending on their susceptibility to the disease, they are prone to developing scrapie. The animal's own PrPC is converted into PrPSc after infection and this happens faster and more efficiently in animals with a susceptible genotype. The aberrant PrPSc protein is not soluble and resistant to degradation by enzymes. Due to reduced degradation, an accumulation of PrPSc takes place in nerve cells, causing cells to damage, break and dissolve. This results in cavities in the nervous tissue, creating the typical spongy structure characteristic for this disease.

For both sheep and goats, the PrP gene is known to consist of 256 codons. Each codon codes for an amino acid, a building block for proteins. Mutations can occur on this PrP gene that cause another amino acid to be incorporated into the prion protein. Depending on the location of this mutation, this can affect the susceptibility to scrapie.

The codons concerned are well known in sheep, namely codons 136, 154 and 171. Changes to these codons mainly affect scrapie sensitivity. In sheep, codon 136 may contain A (alanine) and V (valine); codon 154 may contain R (arginine) and H (histidine), and at codon 171 especially R (arginine) and Q (glutamine) can occur.

Four variants of the PrP gene are of interest: VRQ (136 V, 154 R, and 171 Q), ARQ, AHQ and ARR. The wild type is ARQ, the genotype originally found in sheep. The other three variants are mutations of ARQ, normally only one of the three codons can be mutated relative to ARQ. Of these four variants, VRQ is the most sensitive to scrapie and ARR is the least sensitive. In descending susceptibility to scrapie, the order is as stated above: VRQ, ARQ, AHQ and ARR. Sheep with genotype VRQ/VRQ are most susceptible to scrapie and sheep with genotype ARR/ARR are most refractory. Broadly speaking, the same applies to BSE in sheep. Sheep with genotype ARQ/ARQ are most susceptible to BSE. Sheep with genotype ARR/ARR are insensitive to BSE. Based on the above, a total of ten combinations (genotypes) are possible, which determine the susceptibility to scrapie.

For goats it has long been unclear which genotype should be selected order to breed for scrapie resistance. Research has shown that a number of codons influence scrapie sensitivity, but the degree of influence differs per codon. The influence on resistance is most certain for codons 146 and 222. At codon 146 it is a mutation to serine (S) or aspartic acid (D) instead of asparagine (N), and at codon 222 it is a mutation to lysine (K) instead of glutamine (Q). Goats carrying at least one of the favourable variants of a gene, 146S, 146D or 222K, are considered to be insensitive to scrapie.
Previous research has shown that only a small percentage of the Dutch goat population carries the resistant genotype. It is striking that 222K carriers are found relatively often in the Toggenburger and 146S carriers in Boer goats.

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Diagnosis of Scrapie

In an advanced and typical case of scrapie, an experienced person can diagnose the live animal with a high degree of certainty after intensive observation. 

However, microscopic examination of the brain is needed to confirm the diagnosis. This examination finds, among other things, vacuoles or cavities in the brain. With a special stain it is possible to make the PrPSc visible under the microscope. As a result, a more specific diagnosis can be made, also the diagnosis can be made at an earlier stage. With this technique, diagnosis is even possible in the live animal by removing a piece of the tonsil (so-called tonsil biopsy) and staining with this special stain. It has been shown that VRQ/VRQ animals can be positive in the tonsil biopsy from the age of four months; animals with more resistant genotypes may become positive later or not at all.

Electron-microscopic examination of the brain also reveals certain fibrils (SAFs: scrapie associated fibrils).

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Risk Factors for Scrapie

Under natural circumstances, infection usually occurs after ingestion through the mouth. The immune system of the intestinal mucosa is most likely involved in the uptake of PrPSc by the intestinal wall. In susceptible animals, compared to less sensitive animals, the uptake of PrPSc takes place more efficiently or there is more effective accumulation in the immune cells of the intestinal mucosa. 

In VRQ/VRQ animals, after ingestion of PrPSc, infection first occurs in the tonsils and Peyer’s patches, tissue with a immune function in the intestinal wall, and from there further spread takes place, first to the lymph nodes that receive the lymph from the tonsils and the Peyer’s patches. Multiplication of PrPSc in the immune system is slower and more limited in distribution in animals with a less sensitive genotype. In animals with a scrapie-resistant genotype, this way of spreading does not occur or hardly occurs. This is also consistent with the experiences of Dutch research performed in the context of the scrapie control programme. Heterozygous ARR animals were negative in the tonsil biopsy even if they were found to be infected on microscopic examination of the brain.

Infection of the nervous system occurs at a later stage than infection of the immune system and possibly even caused by the immune system. The infection starts in gut nervous tissue and from there further spread takes place. At a later stage, PrPSc occurs in the spinal cord of thoracic and lumbar vertebrae and in the medulla oblongata of the brain via nerve pathways in the abdominal and thoracic cavities. From there, PrPSc spreads further through the nervous system. It has been found that at equal time points after infection, there was always less PrPSc in the less susceptible animals compared to susceptible VRQ/VRQ animals.
Distribution of PrPSc can also occur through the bloodstream. Experimental blood transfusions from sheep infected with scrapie or with BSE succeed in transmitting an infection.

A Norwegian research group confirms that the multiplication of PrPSc is slower, and the spread less progressive, in animals with a more resistant genotype. In this experiment, the first clinical symptoms in a VRQ/VRQ animal occurred at seven months of age. The extensive follow-up study showed PrPSc in the cornea of the eye in one animal and it was found in the placenta of two animals. The placenta of scrapie-infected animals is thought to play a significant role in the transmission of infection in a flock. In humans, cases of Creutzfeldt-Jakob disease, also a TSE, have been described following corneal transplantation. 

The above applies to classic scrapie. Much less is known about the NOR98 variant found in 1998 and the atypical scrapie found afterwards. Research considering these forms of scrapie is performed in a number of places and the latest information on this indicates that this atypical scrapie is transmissible under experimental conditions but is not contagious under natural conditions. 

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Approach to Scrapie in goats

Scrapie genotyping goats

In July 2019, an amendment was made to European Regulation 999/2001. This amendment complements the current Regulation and states that goats carrying at least one of the favourable alleles, 146S, 146D or 222K, will be considered scrapie resistant.