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  Home > Services and Fees > Canine Neuromuscular Testing > Leonberger Polyneuropathy (LPN1) > LPN1 FAQ
 

LPN1 FAQ

1. What is Leonberger Polyneuropathy (LPN)?
2. Does this test identify all dogs affected by or carriers for polyneuropathy?
3. Is LPN1 only found in Leonbergers?
4. What is the mode of inheritance of LPN1?
5. How prevalent is the LPN1 mutation in Leonbergers?

6. How many dogs that test clear (N/N) have been diagnosed as polyneuropathy affected or presumed?

7. Should we only use clear (N/N) dogs for breeding? Are there any other breeding recommendations?

8. Is the test 100% accurate? Have you had any evidence of false positives?
9. What sample types are accepted for LPN1 testing?
10. If DNA is already available in the DNA bank, will the test fee be reduced?

11. Is research still ongoing to find the marker(s) for the other version(s) of the disease?
12. Are there any associated illnesses?
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1. What is Leonberger Polyneuropathy (LPN)?

Leonberger Polyneuropathy (LPN) is a neuromuscular disease. In its classical presentation, clinical signs begin before three years of age. The dog suffers from slowly worsening exercise intolerance and may develop gait abnormalities, such as an exaggerated “hitched” step, especially in the hind limbs. There is often wasting of the hind limb muscles. Additionally, these dogs may have noisy breathing, a change in their bark, or even difficulty breathing due to involvement of the larynx and laryngeal folds in the throat. Eventually the disease may progress to the point where the dog cannot support its own weight. Biopsies of nerve from affected dogs show degradation of the nerve fibers and loss of myelin, the insulating material that normally helps speed messages along nerves. Muscle biopsies show atrophy resulting from nerve loss. It is important to note that older dogs can also display some or all of these signs and suffer from disease, although typically when dogs are affected at an older age, the disease is less severe. 

Click here for a video of affected dogs.

 

2. Does this test identify all dogs affected by or carriers for polyneuropathy?

No. Similar to Charcot-Marie-Tooth (CMT) disorders in people, it is possible for multiple mutations to present with extremely similar neurological signs and histopathogical changes. As of early 2010, mutations in >35 different genes have been identified as causes of CMT. Histopathological changes in CMT are usually classified as affecting the myelin or the axons of the nerve cells, or, in the case of intermediate forms of CMT, both the myelin and the axons. It is important to obtain a nerve biopsy to confirm that a polyneuropathy truly exists, and that the clinical signs that a dog is presenting with are not being caused by other disease processes, such as spinal disc disease, heart failure, hypothyroidism, etc. Even in families with a history of LPN, other causes of clinical signs need to be ruled out. Finally, while histopathological examination of a nerve biopsy will indeed demonstrate characteristic changes of LPN (or CMT in humans), there are a very limited number of ways in which nervous tissue will respond to insult/injury. Therefore, several neurological diseases may look quite similar or even indistinguishable on a nerve biopsy. This is why it is vital to pair the nerve biopsy with as much additional information about the patient as possible (including clinical signs, any other tests that were performed, etc.)

In the case of the Leonbergers, indeed, it does appear that at least two independent genetic mutations have occurred, and that they do lead to similar neurological illnesses. Although this may sound like a bizarre coincidence, one has to also keep in mind that neurons are probably the most sensitive cells in the body. Therefore many disturbances of general physiological processes can manifest as neurological disease, because the neurons are the first cells that start dying in the body. This reality is confirmed by the dozens of known mutated genes for CMT in human patients.

We have identified the causative mutation in one of these genes that we now term LPN1, This genetic test does NOT test for other forms (with as yet undiscovered genetic mutations) of LPN.

 

3. Is LPN1 only found in Leonbergers?

No. Although first described and researched in the Leonberger breed, we have since identified three St. Bernards that are homozygous mutant (two copies of the LPN1 mutation).  All three of these dogs displayed the clinical signs of polyneuropathy, and were confirmed via muscle/nerve biopsies. Therefore, we know that the St. Bernard breed has the identical mutation and it can cause clinical neuropathy in this population. The frequency of this mutation in the St. Bernard breed is yet undetermined and will require an unbiased genetic survey of many St. Bernards.

The full extent of other breeds affected by the LPN1 mutation is unknown.

 

4. What is the mode of inheritance of LPN1?

Dogs that are homozygous mutant (two copies of the LPN1 mutation) will typically develop neuropathy before they reach 3 years of age.  Dogs heterozygous for this mutation (one copy of the mutation) might also develop mild clinical signs late in life, but they will most likely not develop severe disease.  The identified LPN1 mutation appears to be responsible for approximately one third of the cases of polyneuropathy in Leonbergers. The other two thirds of cases are apparently caused by different genetic mutations.

 

5. How prevalent is the LPN1 mutation in Leonbergers?

Combining data from both the University of Bern and the University of Minnesota, we have found these relative frequencies of the affected, heterozygous and clear state in Leonbergers:

Affected (D/D) 2.3%
At Risk/Heterozygous/Carrier (D/N) 15.4%
Clear (N/N) 82.3%

The LPN1 mutation frequency is not known in the Saint Bernard or other breeds

 

6. How many dogs that test clear (N/N), have been diagnosed as polyneuropathy affected or presumed?

We have identified over 1500 N/N Leonbergers to date.  Within that group, we have 44 positive or probable biopsy confirmed cases (~3%).  We have an additional 128 dogs (~8%) with either breathing and/or gait abnormalities that may or may not be attributable to polyneuropathy. The LPN cases amongst this group are caused by another, as yet unknown, genetic mutation.

However, it must be remembered that this sample population includes many dogs submitted for LPN research studies, and it is heavily biased toward those dogs that have disease. Therefore, it is not a  random sampling and does not accurately reflect the Leonberger population as a whole.

 

7. Should we only use clear (N/N) dogs for breeding? Are there any other breeding recommendations?

We don’t yet have enough data to answer this extremely important question. Until other potential disease-causing mutations are discovered, it is impossible for us to determine why some D/N dogs develop mild disease later in life. It could be due to the single copy of the LPN1 deletion, or it could be due to another form of disease (yet to be elucidated), or even a combination of the two.

As long as it is not absolutely clear that D/N dogs will all develop neurological disease, we recommend keeping them in the breeding pool for at least one generation. Litters of D/N x N/N matings should be tested and preferentially the N/N pups (50%) should be kept for future breeding.

Immediately eliminating all D/N dogs from breeding may have negative consequences for the genetic diversity of the breed.  Important lines within the breed should be maintained, for example, if an important line is about to vanish, limited use of D/N animals may be used to preserve them.  In other cases, it may be appropriate not to use any D/N dogs for breeding, if you “only” lose 15% of your population.  This is not an overly dramatic loss of genetic diversity.

We were originally more cautious last summer (2010), because we did not know the exact frequency of carrier animals.  As the predicted carrier rate has dropped from 25% to the more current estimate of 15%, this presents a good scenario for the sustainable eradication of LPN1.

We suggest a mid-term goal of reduction of the LPN1 allele from the breeding population. If eradication of LPN1 is desirous for a breed club, a complete ban of D/N animals starting in several years would represent a sensible measure in our opinion.

One final word of caution: we do not yet know what other specific genes and mutations are causing polyneuropathy in Leonbergers, and this will make exclusion based on LPN1 alone far less clear. 

See Implications for Breeding for diagrams of the different possible mating combinations.

 

8. Is the test 100% accurate? Have you had any evidence of false positives?

This is a 100% specific test for a DNA segment deletion and the test is 100% accurate for detecting this specific DNA segment deletion. There has been no evidence of a false positive to date.

So far, we have identified 41 D/D Leonbergers.  Of those at least three years of age, only 1 of 39 dogs was not showing clinical signs of polyneuropathy.  We have also identified three D/D St. Bernards, all showing clinical signs of polyneuropathy before age three years.

 

9. What sample types are accepted for LPN1 testing?

At the University of Bern, only blood samples are accepted for genetic testing. A turn around time of three months is guaranteed, but in general the clients get the results faster than that.

At the University of Minnesota: dew claws from the removed tissue of newly whelped pups can be tested, and, after a pup has been weaned for at least 24 hours,  cheek swab samples can be accepted. Ideally, pups should be isolated from the dam and littermates for 1 hour before swabbing.

For blood sample testing, the dog should be old enough to have 1-3 ml of blood drawn by a veterinarian. Click here for instructions on submitting these samples.

 

10. If DNA is already available in the DNA bank, will the test fee be reduced?

The University of Bern and the University of Minnesota will provide LPN1 test results free of charge to all owners who donated samples for research before the 15th of June, 2010. If you have submitted a sample for research before this date and not yet received your free test result, please contact Prof. Cord Drögemüller at Cord.Droegemueller@itz.unibe.ch for the University of Bern or Katie Minor at lpninfo@umn.edu for the University of Minnesota.

We will continue to give free LPN1 tests to submitters of blood samples from affected dogs, if they also send us a copy of a qualified abnormal neurological exam together with normal thyroid blood test results, OR if they also send us the positive result of the histopathological examination of a muscle/nerve biopsy. For the University of Minnesota, if you are interested in submitting your dog’s sample for this free testing, please contact us at lpninfo@umn.edu for special shipping instructions.

Should a second “LPN2” test become available, this will be cheaper for dogs which already have DNA banked at the University of Bern. This will likely also be the case at the University of Minnesota.

 

11. Is research still ongoing to find the marker(s) for the other version(s) of the disease?

The search for additional LPN mutations is underway and we have strong indications for at least one additional locus on a different chromosome. However, in contrast to the LPN1 gene this second locus is at the stage of identifying potential “LPN2” gene(s) and these genes have not been well characterized in the literature. Therefore, it may still take some time until genetic testing will become available. It is of utmost importance that we continue to receive samples from Leonbergers for our research at both the University of Bern and the University of Minnesota, especially from affected Leonbergers that have a biopsy confirmed diagnosis and are N/N at the LPN1 gene.

At the University of Bern and the University of Minnesota, samples submitted from affected Leonbergers that have undergone a neurological examination (which was abnormal) and testing to rule out thyroid disease are candidates for free LPN1 testing. If you have an affected dog that fits these requirements, please email Cord.Droegemueller@itz.unibe.ch in Berne or lpninfo@umn.edu in Minnesota for special shipping instructions.

At the University of Minnesota, we are not actively seeking samples from elderly Leos clear of neurological signs unless you are also planning to obtain a nerve and muscle biopsy from this dog at post-mortem (to definitively show that the dog’s nerve was normal). These samples will not receive free LPN1 testing.

 

12. Are there any associated illnesses?

We have seen what appears to be an above average pattern of cruciate ligament injuries occurring early on in the lives of Leonbergers, who then go on to develop LPN. We have also seen an apparently above average incidence of digestive issues occurring in LPN dogs. Is it possible that both of these conditions are connected with, or are perhaps exacerbated by, LPN? Does degeneration of the peripheral nerves in the hind legs make it more likely that a dog will damage its cruciate ligament? Does the laryngeal nerve have any association with the vagus nerve that could account for these reported episodes of reflux and dry vomiting?

A paper in The Veterinary Journal by Nicolas Granger entitled “Canine inherited motor and sensory neuropathies: An updated classification in 22 breeds and comparison to Charcot-Marie-Tooth disease” states the following: “Orthopaedic lesions can worsen the locomotor deficits and are sometimes considered as primary injuries, whereas they are in fact secondary to the neuropathy (e.g. due to lack of muscle support to the joints).”This seems to suggest exactly what has been suspected: the atrophy of the pelvic musculature or the degeneration of nervous stimulation to the muscles, may, in fact, predispose the dogs to cruciate rupture and perhaps other orthopedic injuries as well.

Gastrointestinal problems have been reported in CMT cases, so it is possible that similar problems could be occurring in Leonbergers with LPN. It is impossible for us to know at this time if the neuropathy extends to the vagal nerve. Historically, the laryngeal nerve(s) were presumed to be involved earlier in the disease process due to the extreme length of the nerve. Similarly, the nerves in the hindlimbs are quite long. It is within the realm of possibility that all nerves in the body are affected to some degree, including the vagus.

We cannot, however, comment specifically on these problems as there is not extensive recorded data to match with dogs’ genotypes. The LPN1 gene has no known specific role in either orthopedic or gastrointestinal processes. However, we cannot rule out that there may be links between the other unknown LPN gene(s) and cruciate ligament injuries or digestive issues.

 

Contact Us

For questions concerning LPN please email us at: lpninfo@umn.edu.

 

For additional questions and answers, please see the Leonberger Breeder’s Q & A.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


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