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  Home > VBS Faculty > James R. Mickelson > Canine And Equine Genetics Laboratory > Leonberger Polyneuropathy > LPN Project Update
 

LPN Project Update

Summary of the original presentation by Dr. Kari Ekenstedt at the Leonberger Club of America National Specialty in Sacramento, CA, on April 14, 2010. 

 

Some Leonberger dogs suffer from a neuromuscular disease called Leonberger polyneuropathy (LPN). This disease, in its classical presentation, sets in 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 as well. 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.

LPN appears to be inherited, although the mode of inheritance (dominant, recessive, X-linked) is still unclear. The Canine Genetics Laboratories of Drs. James Mickelson and Ned Patterson at the University of Minnesota’s College of Veterinary Medicine, in collaboration with Drs. Tosso Leeb and Cord Drögemüller at the University of Bern, in Switzerland, have been investigating the genetic basis of LPN and have recently made some exciting breakthroughs. Blood samples of affected and unaffected dogs were submitted by owners and DNA was isolated from the blood. Using the latest canine genetic research technology, single nucleotide polymorphism (SNP) arrays containing 170,000 SNPs (each a unique DNA marker in the genome) are being used to look across the entire canine genome for a link between some of the SNP markers and the occurrence of LPN disease.

A very highly significantly associated set of SNPs was observed on canine chromosome (CFA) 16, and a second, slightly less significant set of SNPs, was observed on CFA7. This enabled a narrowing of the search down to a very small interval on each of these two chromosomes, containing only a handful of genes.

Some interesting points became apparent when the data was examined further:

· The CFA16 segment that was associated with affected dogs was often present on both chromosomes (two copies) in the dogs which were affected more severely and at a very young age.

· The CFA16 segment was often present on only one chromosome (one copy) in the dogs which were mildy affected at an older age; in other words, they probably have the same disease as those dogs affected at a very young age – they just have much milder symptoms. However, some of the older-onset dogs probably have a different disease.

· A very few of the control dogs had a single copy of the CFA16 segment. It is known that these dogs did not have any LPN-like problems, but none of them were biopsied so the actual status of their nerves is not known.

· All of this SUGGESTS dominant inheritance, with a dose-dependent nature to the disease (more copies = worse disease).

· Some of the affected dogs did not have the CFA16 segment at all. These dogs could have disease originating from the CFA7 segment or could have an entirely different disease, such as hypothyroidism.

· The CFA7 segment could be a different disease that is indistinguishable from LPN; in other words, there may be two different genetic mutations causing diseases that look identical in the dog and on a biopsy. Or, the CFA7 segment could also be modifying the affect of the CFA16 segment – either dampening or increasing its influence on LPN severity. This remains to be determined with additional work.

The Leonberger breed is a small breed and already has a limited gene pool. Once a test is available, it will be prudent to test breeding dogs and at least avoid producing the severely affected, young-onset dogs. Until then, it is probably wisest to not repeat a breeding that produced severely affected, young-onset dogs and to not breed the severely affected young-onset dogs at all.

Although great strides have been made in determining the cause of LPN, the work is by no means finished! A mutation has not yet been found at either CFA16 or CFA7, and a “marker test” is not yet available. Much work remains to be done to determine exact DNA sequence alterations occurring on these two chromosomes to cause disease. This work is underway, including looking at some potential causative genes. Hopefully rapid progress can be made and complete answers will soon be available.

Because this work is ongoing, there are still ways you can help!

· First, blood samples, particularly from affected dogs and old-aged dogs clear of any symptoms (unaffected dogs), are still gratefully accepted at the University of Minnesota.

· Second, biopsies of nerve and muscle should still be sent to Dr. Diane Shelton, at the University of California – San Diego. Biopsies can be sent from affected dog for diagnosis, as well as from any dog after its death for a post-mortem diagnosis.

· Third, annual updates from owners on how their dogs are doing are also vital. Simple questionnaires for updates are available and can be submitted electronically or in hard copy.

· Fourth, as a very special case, the laboratory at Minnesota is looking to acquire one or two fresh nerve/muscle biopsy specimens that are to be handled in a unique way. If a Leonberger owner is planning to get their affected dog biopsied for a diagnosis from Dr. Shelton, and would be willing to send an additional sample to Minnesota, please contact us for special handling and shipping instructions.

· Because these findings are still preliminary, we are not releasing individual dog’s results to owners at this time.

CVM VBS Mickelson Lab_Tree Climber


 

Additional questions can be directed to:

Katie Minor by email at minork@umn.edu or by telephone at 612-624-5322.

The website for Drs. Leeb and Drögemüller (Switzerland) is:

http://www.genetics.unibe.ch/content/e2353/e2783/index_eng.html

 

This work was made possible by the generous support of the Leonberger Health Foundation (USA), the Schweizerischer (Swiss) Leonberger Club, and the Deutscher Club Für Leonberger Hunde e.V. (German Leonberger Club).




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