Aleutian Disease in Ferrets

by Dr Adrian Deeney

History of Aleutian Disease

Aleutian Disease (AD) has been considered to be a disease of ranch mink, and is named after the highly susceptible Aleutian mink, which carry recessive genes for the dilute coat colour, producing a gun-metal grey pelt. This is also associated with Chediak-Higashi syndrome, an inherited disorder of the immune system. For a long time, it was assumed that the disease was a result of the genetic disorder, associated with this mutation, but it was later found that mink heterozygous for the mutation, and even homozygous for the dominant coat colours also were susceptible to the disease - but tend to have a lower morbidity and mortablity compared with Aleutian mink (McCrackin Stevenson and Murray, 2001).

AD was recognised as a disease syndrome in 1946 when mink ranchers realised the economic potential of the grey pelts and began actively breeding Aleutian mink for their desirable coat colour. Harborough and Goram first described AD in mink in1956.

In the USA, many ferrets were probably naturally exposed to AD on mink ranches because some farmers raised mink and ferrets on the same property. Ferrets were also experimentally infected with AD during the 1960's because researchers felt that AD could be developed as an animal model for human immune-mediated diseases but sought an animal that was easier to handle than the ferocious mink. Ferrets were injected with tissue homogenates from infected mink, or were closely housed with infected mink and ferrets.

Although the ferrets did not develop clinical signs, they did develop some of the antibody responses and pathological changes that are the hallmarks of Aleutian Disease (Kenyon et al, 1966; Kenyon et al, 1967).

The overall conclusions of studies conducted before 1985 were that there were distinct mink and ferret strains of AD virus, that the disease progressed more slowly in ferrets than in mink, and that the disease and microscopic changes were less severe in ferrets than in mink.

Aleutian Disease was first reported in domestic ferrets in the UK by Oxenham in 1990. It has been suggested that the disease in UK ferrets may have its origins in feral mink, and that it may have been introduced 40 years ago with the importation of ranch mink. There is a suspicion that the mink that have either escaped or been released into the wild may be responsible for infecting the domestic ferret.

The Causative Agent

AD is now known to be caused by a PARVOVIRUS. In the 1960's, it was common practice for mink ranchers to make their own distemper vaccines by homogenising from distemper-infected mink, making suspensions, and injecting all the mink on their ranch. This practice led to a severe outbreak of AD on a Connecticut ranch, with a mortality of almost 100% in less than 6 months. Over the following few years, suspicions arose that AD was caused by a 'filterable agent' (i.e. a virus).

AD virus was isolated and studied during the early 1970's, particularly by Kenyon's group, but was not correctly characterised as a parvovirus by Bloom until 1980.

The parvoviruses are a large family of physically similar viruses infecting animals as diverse as man and moth. The virus causing disease in the ferret and mink is similar to, but not the same as, canine parvovirus, feline panleukpaenia, mink enteritis, and human parvovirus (Fifth's disease).

There are at least 4 strains that affect mink - Utah 1, Ontario, Montana, and Pullman; there may also be a ferret strain.

Parvoviruses are characteristically hardy agents. That is, they can withstand temperatures of up to 80C for half an hour and can take an acid pH of around 2, to an alkaline pH of around 9, and solvents such as ether.

With experience of parvoviruses in other situations and in other species, we have known rat populations to become re-infected with rat parvoviruses several months after moving in to decomtaminated facilities. The source of the re-infection has been dust lodged above the ceiling space that was dislodged by electricians rewiring above the false ceiling. Thus, parvoviruses can remain in the environment for significant lengths of time.

The Disease

Basically, the virus interferes with the immune system, which is why it was long thought that the disease in Aleutian ferrets was a genetic characteristic of this mutation, rather than being caused by an infectious agent.

Manifestations of clinical disease are likely to be determined by virus strain, host genotype and immune status. Thus, there is a wide range of clinical signs - from clinically normal to non-specific signs (eg lethargy and anorexia) to specific problems (eg uraemia, neurological dysfunction, frank haemorrhage of the digestive tract, including the mucosa of the oral cavity and intestines (see McCrackin Stevenson and Murray, 2001).

The mink, the disease was first manifested as a chronic wasting disease of adult Aleutian mink. Weight loss, poor pelts, lethargy, anorexia, polydipsia, anaemia, melaena (black tarry stools) were common clinical signs in infected mink.

Infertility, small litters and high stillbirth rates were also noted.

On necropsy, infected animals typically showed small, shrivelled kidneys, splenomegaly, mesenteric lymphadenopathy, hepatomegaly and blood in the intestinal tract.

In summary, the mode of action of this virus can be contrasted to the animal's response to a fast virus such as distemper. Shortly after exposure to the distemper virus, the virus multiplies in the host. The virus reaches a peak about a week after exposure. Antibodies against the virus begin to appear and combine with the virus. These virus-antibody complexes are of such a size that they are easily destroyed by the white cells, and the animal (theoretically) recovers.

The AD virus stimulates the antibody producing cells so vigorously that the animal's tissues become packed with them and produce an enormous amount of antibody (gammaglobulin). It would normally be assumed that the antibody would neutralise the AD virus, but this is not the case, and the antibody itself kills the animal.

What happens is that the virus rises rapidly as in a conventional virus infection, but it does not decline. Neither is the virus effectively neutralised. It combines with antibody, but the virus-antibody complexes are of such a size that they cannot be handled effectively by the white cells and they begin to accumulate in the blood.

In the kidneys, blood is usually filtered and water and dissolved substances are removed and excreted as urine. In the mink, the immune complexes clog up the filter, and the urea, which is normally filtered does not pass in to the urine, but backs-up into the blood causing uraemia.

In ferrets, the disease was originally considered to be a subclinical problem. However, one report in 1978 (Daoust and others) and all studies of AD in ferrets published since 1990 have described clinical overt disease (Welchman and Oxenham, 1993; Rozengurt, 1995; and Palley and others, 1992).

Clinical syndromes include chronic wasting disease and neurological disease consisting of posterior paresis or paralysis.

There have been DNA sequence studies carried out on virus isolated from the spleen of an infected ferret. It was shown that the sequence for this so-called ADV-F was 88-89% similar to the sequences obtained from some pathogenic mink strains. These differences are sufficient to confirm that the ADV-F was dissimilar to isolates identified in mink.

Clinical signs seen during a 1998 outbreak in San Antonio Texas included generalised wasting and respiratory, neurological and cardiac forms of the disease in ADV-positive ferrets.

Ferrets with chronic wasting disease had small kidneys on necropsy and glomerulonephritis on microscopic examination.

Respiratory disease in affected ferrets included severe coughing, lung lobe consolidation, and collapse, and serosanguinous pleural effusion.

Microscopic examination of necropsy tissue samples revealed interstitial pneumonia. Neurological signs usually followed respiratory signs by several weeks, but occurred alone in some ferrets. Neurological dysfunction started as posterior paresis and either remained stable or progressed to posterior paralysis accompanied by urinary and faecal incontinence.

A few ferrets developed cardiac disease which on necropsy was shown to be arteritis in the cardiac muscle - suspected to have resulted from immune complex deposition.

All of the diseased ferrets tested positive for AD by CEP testing and viral DNA was amplified by PCR using tissue from some of these ferrets. The DNA sequence analysis of these PCR products was identical to that previously reported for ADV-F. To date ADV-F is the only isolate of ADV in ferrets with published DNA sequence data (Saifuddin and Fox, 1996).

Disease Transmission

Natural horizontal transmission of ADV among mink is likely to occur either by the oral or the aerosol route. AD has been experimentally transmitted between mink by inoculation of whole blood, serum, urine, faeces, saliva and bone marrow from infected mink.

Vertical transmission of ADV has also been shown to occur in mink. Dams with either progressive or non-progressive subclinical infections were shown to have high numbers of infected kits. The risk for ADV infection in kits born to dams with non-progressive subclinical infections was less than that for kits with progressive AD. Dams infected with AD prior to mating had a higher percentage of dead and resorbed foetuses compared with dams infected after expected embryo implantation.

Although it must be assumed that the mode of transmission in ferrets is the same as for mink, the dearth of research into this disease in ferrets means that the natural route of transmission of AD between ferrets is at present unknown. Horizontal transmission is suspected but whether infectious ADV is present in urine, faeces, or saliva of infected ferrets is unknown. Clearly, this information is critical to help companion ferret owners prevent transmission of the virus from infected to non-infected ferrets in their homes. It is likewise important for ferret clubs in establishing rules regarding the admission of infected ferrets in ferret shows.

Vertical transmission in ferrets is suspected because this phenomenon occurs in mink, but it has not been studied. Knowledge of the mechanisms for horizontal and vertical transmission is crucial for ferret breeders to be able to make decisions about acquiring new ferrets for breeding programmes, and monitoring breeding ferrets.

Disease transmission is an area that requires further research, and until such time as the results of such research are available, then there is little alternative than to assume that transmission in ferrets is the same as in mink (McCrackin Stevenson and Murray, 2001; Nye and Brown, 2000).


Counterimmunoelectrophoresis (CEP) is the standard for detecting anti-ADV antibodies in mink and ferrets.

The principle of the CEP test is that antigen, which has a negative charge, is placed in a small circular well cut into a thin layer of gel.

Another well contains the test serum and buffer.

An electric field is placed across the agar gel. The negatively-charged antigen migrates towards the positive electrode, and enters a 'zone of reaction' between the two wells. The buffer and plasma/serum in the test well begins to move in the opposite direction because of the normal flow of the buffer from the positive to the negative electrode. It, too, enters the zone of reaction

When specific antigen and antibody complex in the proper proportions, a precipitin line forms between the two wells.

A true precipitin line is usually straight, or only slightly arced, and is located between the antigen and corresponding antibody well.

In some cases, substances in a specimen or in the antiserum may form a hazy zone or highly curved precipitin arc around the antigen or antibody well. True positive reactions are NOT highly curved.

A final test may be made by dilution of the specimen, in which case the non-specific precipitin arc is usually unaffected, whereas specific reactions will become less intense and may form nearer the antigen well.

It is also important to evaluate the purity, potency, sensitivity and specificity of the antigen used.

This test establishes whether or not antibody to AD is present in the test sample and therefore gives a simple positive or negative result.

The currently supplied test is reliable and does not give false-positive results due to vaccines against mink enteritis or other viruses.

It is clear, however, that CEP reactions in individual animals can fluctuate, and reversion from positive to negative results is certainly not uncommon. Interpretation of these findings is a particular challenge. I was interested to learn from the Internet of various cases of ferrets that had given a positive result, only to test negative on numerous subsequent occasions. In one case, it was assumed that the initial result was a false positive. However, the animal reverted to seropositive and now has clinical Aleutian Disease.

If nothing else, these illustrate the need for frequent testing - or at least testing carried out more than annually.

It is also clear that in ferrets the occurrence of positive CEP results does not mean that the animal will go on to develop the disease. Indeed, in ferrets, the number of CEP positive animals that develop the disease is low compared to mink.

United Vaccines inform me that kits born to females infected with AD prior to whelp will test CEP positive, but they may not show positive reactions for possibly 5 months. Adult ferrets can be tested at any time and should be retested as frequently as they are put into a potentially infected situation. If they are housed as pets that never get outside, or never have contact with other ferrets, then CEP testing once per lifetime may be sufficient.

An ELISA test has recently been developed by Avecon Laboratories in the USA which is directed against the non-structural proteins of ADV.

The ELISA test works in the following way.

The wells of a polycarbonate plate are coated with the antigen, in this case ADV. Test serum, plasma is added to the well; if antibody is present, then it will bind to the antigen coating the plate and form a virus-antibody complex.

The plate is washed and a second antibody that is directed against globulins produced by the animal species is added. In this case, the second antibody is an anti-ferret antibody. This second antibody carries a label, which in most cases is an enzyme, such as horse-radish peroxidase. A substrate for the enzyme, hydrogen peroxide, is added together with a colour marker. If ADV antibody is present in the test sample, the reaction occurs, eliciting a colour response that can be measured using a spectrophotometer.

The new test has the stated advantage that it will only detect antibody against virus that has replicated. However, McCrackin-Stevenson and others, in a recent review have noted that because the vast majority of mink and ferrets infected with ADV produce antibodies against both capsid and non-structural proteins, the lack of non-structural protein detection has not been a problem. Furthermore, to date I have found no published reports of the assay protocol or the sensitivity and specificity of the test.

Whilst the manufacturers claim no false positives occur due to reactivity with other ADV proteins, or from vaccine derived cellular debris, it is widely accepted that up to 10% of ELISA positive tests will be false positives

The test is much more expensive than the CEP test, and has not been tested widely. I understand that United Vaccines are currently running a project to compare the Avecon kit with the CEP test by running ranges of known positive and negative samples.

Hypergammaglobulinaemia is a characteristic of the disease in mink, and can develop in infected ferrets. For those ferrets exhibiting clinical signs and testing positive by CEP testing, a serum test for gamma-globulin would support a diagnosis of AD.

The use of molecular biology in testing for animals and humans has advanced significantly in recent years. In particular, the polymerase chain reaction (PCR) has become widely used diagnostic tool.

PCR has been described as being to genes what Guttenberg's printing press was to the written word. PCR can amplify a desired DNA sequence of any origin (virus, bacteria, plant or human) hundred of millions of times in a matter of hours.

PCR is especially valuable because the reaction is highly specific, easily automated, and capable of amplifying minute amounts of sample. For these reasons, PCR has also had a major impact on clinical medicine, genetic disease diagnostic, forensic science and evolutionary biology.

PCR is a process based on a specialised polymerase enzyme, which can synthesise a complementary strand to a given DNA strand in a mixture containing the 4 DNA bases and 2 DNA fragments flanking the target sequence. The mixture is heated to denature - or separate - the strands of double stranded DNA containing the target sequence. It is then cooled to allow the primers to find and bind to new complementary strands. Repeated heating and cooling cycles multiply the target DNA exponentially, since each new double strand separates to become two templates for further synthesis. In about 1 hour, 20 PCR cycles can amplify the target by a millionfold.

PCR is very sensitive and has proved to be extremely valuable in animal diagnostics. However, Richard Nye and Susan Brown, in their excellent review written last year, state that this test may not be practicable at this time in ferrets, because of the antigenic diversity of ADV. PCR is generally used to support evidence gained by using other tests; for examply, to confirm the results of a serological test or histopathological finding. It depends entirely on viral DNA being present in the sample taken for analysis. This may not always be the case.

What to do with the Results of Testing

Serological testing for antibodies is still the best means of testing. However, what is serology telling us?

Serology identifies the presence of specific antibody against the antigen being tested. This means that the animal either is infected with, or has been exposed to, the antigen being tested.

It also should be remembered that infection is not synonymous with disease.

There is no information available at this time on the incubation period of AD, nor the period of shedding of ADV.

However, as the antibodies do not neutralise the virus, it must be assumed that parvovirus in ferrets is persistent, even though they may vary from CEP positive to CEP negative and back again over their lifetime. Given that the infection is persistent in the animal, then it must also be assumed that CEP positive animals will shed virus, probably for some period of time - possible when stressed.

Many CEP positive ferrets appear normal, whilst others have serious identifiable health problems. Much of the fear surrounding AD, in addition to being the result of observations of severe disease in mink and in some ferrets, is also due to the fact that AD is currently untreatable. Therefore, prevention of infection appears to be the best approach at this time.

Mink breeders have been successful in controlling the disease by means of culling positive reactors. Many ferret breeders also follow this course in order to be sure that animals that have previously tested positive, but which have more recently tested negative, do not inadvertently attend shows or other activities where they may come into contact with other ferrets. Pet owners are advised to isolate CEP positive pets from other ferrets and do not attend ferrets shows or club meetings with their pets or cohorts of their infected pets. Culling of CEP positive animals may be the best way of guaranteeing control of the infection among the general ferret population.

The results of serological testing in ferrets may be unpredictable, and negative results can follow positive findings. Therefore, if a ferret has had a positive result on CEP testing, it must be considered a risk to allow that ferret in to shows or other events, even if it has had subsequent negative tests.

The bottom line is that isolation, culling and pursuance of strict hygienic controls are the best means of control, until such time as research provides more information on the pathogenesis of this potentially severe disease.


1. Aleutian Disease has been recognised for over 50 years in mink, but is a more recent phenomenon in ferrets.

2. As a consequence the disease in ferrets has not been fully studied, and assumptions are only possibly on, for example, the mode of transmission of the disease.

3. The effects of the disease in ferrets are more variable than in mink, but overt disease has been described.

4. It is likely that a ferret strain of the causative parvovirus exists.

5. It is assumed that, like in mink, the virus infection is persistent, as antibody does not neutralise the virus.

6. The best means of diagnosis of the infection is still the counterimmunoelectrophoresis test (CEP)

7. CEP reactions in individual animals can fluctuate, but once an animal tests positive, it should be regarded as positive, regardless of the number of subsequent negative tests.

8. An ELISA test has been developed, but the efficacy in the field is as yet unknown.

9. PCR tests are useful, but should be used as an adjunct to existing tests.

10. Isolation, culling and pursuance of strict hygiene measures are the best means of control, until such time as research provides more information on this disease in ferrets.


McCrackin Stevenson MA and Murray J (2001). Aleutian mink disease parvovirus: implications for companion ferrets. Small Animal Exotics 23, 178-185.

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Kenyon AJ, Howard E and Buko L (1967). Hypergammaglobulinaemia in ferrets with lymphoproligerative lesions (Aleutian disease). American Journal of Veterinary Research 28, 1167-1172.

Kenyon AJ, Magnano T, Helmbold CF etal (1966). Aleutian disease in the ferret. JAVMA 149, 920-923.

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Bloom ME, Race RE and Wolfenbarger JB (1980). Characterisation of Aleutian disease virus as a parvovirus. Journal of Virology 35. 836-843.

Welchman D, Oxenham M and Done SH (1993). Aleutian disease in domestic ferrets: Diagnostic findings and survey results. Veterinary Record 132, 479-484.

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Saifuddin M and Fox JG (1996). Identification of a DNA segment in ferret Aleutian disease virus similar to a hypervariable capsid region of mink Aleutian disease parvovirus. Arch Virol. 141, 1329-1336.

Nye RR and Brown SA (2000). Aleutian disease in ferrets.

(First published in the April 2002 Issue No. 60 NFWS News)

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