Leonberger Polyneuropathy & Leukoencephalomyelopathy
The neurological disorder leukoencephalomyelopathy (LEMP) is a recessively inherited neurodegenerative disorder that affects the white matter of the central nervous system (CNS). Canine LEMP is characterized by slowly worsening gait abnormalities, especially spontaneous knuckling, dragging of the paws and hypermetria of the thoracic limbs, and a characteristic pattern on magnetic resonance imaging (MRI). Affected dogs show corresponding gross lesions in the cervical spinal cord white matter that may extend to the thoracic spinal cord, as well as to the brain; peripheral nerve and muscle biopsies are unremarkable. Canine LEMP often shows a juvenile onset and is characterized by a generalized progressive ataxia. Spinal reflexes of affected dogs are mostly normal. In the progressive clinical course of the disease, affected dogs may become increasingly immobile within a few months. Like many diseases of the CNS, there is no effective treatment for LEMP. Since in most cases the dog is not in pain, but is strongly restricted in its quality of life, owners are encouraged to ask a veterinarian for advice.
Research carried out at the University of Minnesota, the University of Bern, and Utrecht University has identified two LEMP mutations within the same gene, one in the Leonberger and the other in Rottweilers. The Rottweiler mutation has also been observed in Great Danes.
Leonberger Polyneuropathy (LPN)
Leonberger dogs may suffer from neuromuscular disease collectively termed Leonberger Polyneuropathy (LPN). LPN affected dogs may suffers from slowly worsening exercise intolerance and 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 and surgical intervention for laryngeal paralysis may be required. 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.
Research carried out at the University of Minnesota, the University of Bern, and the University of California San Diego, indicates that polyneuropathy within the Leonberger breed is a group of several genetically distinct, but clinically similar diseases. We have mapped two major genetic risk loci and identified the causative mutations that we now term LPN1 and LPN2.
in Leonbergers is a partially penetrant autosomal recessive central neverous system disease resulting from an amino acid change within the LEMP gene. All Leonbergers with confirmed LEMP have tested homozygous affected (D/D) for this LEMP mutation; however, not all dog that are homozygous for this mutation may show obvious clincial signs of disease within their lifetime. Clincal signs may develop as early as 1 year of age.
- Population testing of >5,000 Leonbergers indicates that the carrier rate of this muation is ~14%.
is a polyneuropathy resulting from a 10 base pair deletion within the gene ARHGEF10; dogs homozygous (D/D) for the LPN1 mutation typically develop clinical signs of disease before they reach 3 years of age.
At present, LPN1 D/D dogs represent ~11% of all diagnosed cases of Leonberger polyneuropathy; a further 24% of dogs in our research population with a phenotype consistent with or diagnosis of unexplained polyneuropathy have the LPN1-D/N genotype (compared to 12.5% of healthy control dogs). The average age that clinical signs are first noted in these LPN1-D/N dogs, if they develop at all, is 6 years. Due to other causes of neuropathy in Leonbergers, the exact mode of inheritance of the LPN1 form of neuropathy cannot yet be stated for certain.
We have also identified LPN1 homozygous affected with a biopsy confirmed polyneuropathy and clinical signs consistent with the disease. The LPN1 test can also be used in the Saint Bernard breed to aid in the diagnosis of polyneuropathy and to identify carriers in the breeding population.
- Population testing of >7,000 Leonbergers indicates that the carrier/at risk rate of this muation is ~12%.
- Population testing of >350 Saint Bernards indicates that the carrier rate of this mutation is ~2%
LPN2 is a partially penetrant autosomal dominant polyneuropathy; dogs heterozygous (D/N) and homozygous (D/D) for the LPN2 mutation may begin to show signs of disease as young as age 1, but may not show signs of disease until later in life or never at all. The average age of onset is 6 years.
The identified LPN2 mutation appears to be responsible for approximately 20-25% of the cases of polyneuropathy in Leonbergers,
- Population testing of >7,000 Leonbergers indicates that ~6% are LPN2 affected/susceptible.
Ongoing Polyneuropathy Research
The tests forand do not account for all confirmed or suspected cases of polyneuropathy. Until additional DNA-base test(s) are developed, the only way to confirm a suspected diagnosis of LPN in dogs that test free of the LPN1 and LPN2 mutations is via a nerve and muscle biopsy.
Dogs showing clinical signs of polyneuropathy may qualify for free LPN1 and LPN2 testing. Special forms and instructions, as well as pre-approval, are required for free testing. Please e-mail email@example.com to see if your dog may be eligible.
This work is generously supported by 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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Ekenstedt KJ, Becker D, Minor KM, Shelton GD, Patterson EE, Bley T, et al. (2014) An ARHGEF10 Deletion Is Highly Associated with a Juvenile-Onset Inherited Polyneuropathy in Leonberger and Saint Bernard Dogs. PLoS Genet 10(10): e1004635. doi:10.1371/journal.pgen.1004635
Oevermann, A., Bley, T., Konar, M., Lang, J. and Vandevelde, M. (2008), A Novel Leukoencephalomyelopathy of Leonberger Dogs. Journal of Veterinary Internal Medicine, 22: 467–471. doi:10.1111/j.1939-1676.2008.0068.x
Shelton GD, Podell M, Poncelet L, Schatzberg S, Patterson E, et al. (2003) Inherited polyneuropathy in leonberger dogs: A mixed or intermediate form of charcot-marie-tooth disease? Muscle Nerve 27: 471–477. doi: 10.1002/mus.10350 doi:10.1002/mus.10350