Leonberger Health Panel

Laryngeal Paralysis - Polyneuropathy (LPN1, LPN2, & LPPN3)

LeonbergerLeonberger dogs may suffer from neuromuscular disease collectively termed Laryngeal Paralysis - Polyneuropathy (LPPN). Many LPPN affected dogs suffers from laryngeal paralysis; clinical signs include noisy breathing, a change in their bark, or even difficulty breathing due to involvement of the larynx and laryngeal folds in the throat. Additionally, dogs may show signs of 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. Eventually the disease may progress to the point where surgical intervention for laryngeal paralysis is required or 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. 

Dogs with LPPN may show only signs of laryngeal paralysis or only gait abnormalities at the onset of disease.

Research carried out at the University of Minnesota, the University of Bern, and the University of California, San Diego - Comparative Neuromuscular Laboratory indicates that polyneuropathy / laryngeal paralysis within the Leonberger breed is a group of several genetically distinct, but clinically similar diseases. We have mapped three major genetic risk loci and identified the causative mutations that we now term LPN1, LPN2, and LPPN3.

Leukoencephalomyelopathy (LEMP)

Leonberger on the beach

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 gene NAPEPLD, one in the Leonberger and the other in Rottweilers.  The Rottweiler mutation has also been observed in Great Danes.

LPPN3 - CNTNAP1

LPPN3 is a form of laryngeal paralysis and polyneuropahty results from amino acid change within the gene CNTNAP1. It is inherited in an autosomal recessive manner, meaning that two copies of the mutation are required to show signs of disease (LPPN3-D/D).  LPPN3 affected Leonberger dogs typically develop severe laryngeal paralysis at a young age, with most affected dogs requiring laryngeal tieback surgery. Additional clinical signs, which were noted variably among the dogs, included difficulty swallowing, changes in barking frequency and quality, high-stepping and uncoordinated gait, stumbling and tripping, exercise intolerance, and muscle atrophy. Like many neurological diseases, there is no effective treatment for LPN. Since in most cases the dog is not in pain but is strongly restricted in its quality of life, especially due to the frequent loss of normal function of the larynx, owners are encouraged to ask a veterinarian for advice.

  • This mutation explains ~3% of all diagnosed cases of laryngeal paralysis-polyneuropathy in Leonbergers (average onset 3.5 years); population testing of >2,700 Leonbergers indicates that the carrier rate is ~11%.
  • This mutation explains ~40% of young onset laryngeal paralysis-polyneuropathy within the Saint Bernard (average onset 2 years); population testing of >300 Saint Berndards indicates that the carrier rate is ~20%.
  • This mutation has also been found to be a rare cause of laryngeal paralysis-polyneuropathy in Labrador retrievers (especially younger Labradors, average onset 7.5 years); population testing of >1,500 Labrador retrievers indicates that the carrier rate is ~10%.
  • We have also identified LPPN3-D/D affected mixed breed dogs, and the mutation is present in several breeds.

LPN1 - ARHGEF10

LPN1 is a polyneuropathy resulting from a 10 base pair deletion within the gene ARHGEF10; dogs homozygous (LPN1-D/D) for the LPN1 mutation typically develop clinical signs of disease (including severe laryngeal paralysis) 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 Saint Bernards 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 - GJA9

LPN2 is a partially penetrant autosomal dominant polyneuropathy resulting from a 2 base pair deletion within the gene GJA9; 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.


Age on Onset Graph LPN2

LEMP - NAPEPLD

LEMP in Leonbergers is a partially penetrant autosomal recessive central neverous system disease resulting from an amino acid change within the gene NAPEPLD.  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 clinical signs of disease within their lifetime.   Clinical signs may develop as early as 1 year of age.

  • Population testing of >7,000 Leonbergers indicates that the carrier rate of this mutation is ~15%.

Ongoing Laryngeal Paralysis - Polyneuropathy Research

Leonberger Chewing on a Stick

The tests for LPN1, LPN2, and LPPN3 do not account for all confirmed or suspected cases of laryngeal paralysis and polyneuropathy. Until additional DNA-based test(s) are developed, the only way to confirm a suspected diagnosis of laryngeal paralysis is via laryngoscopy and/or nerve conduction study; polyneuropathy is diagnosed via a nerve and muscle biopsy.

Dogs showing clinical signs of polyneuropathy may qualify for free LPN1, LPN2, and LPPN3 testing.  Special forms and instructions, as well as pre-approval, are required for free testing.  Please e-mail [email protected] to see if your dog may be eligible.  

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Funding

main headerThis work is generously supported by the Leonberger Health Foundation International, the Schweizerischer (Swiss) Leonberger Club, and the Deutscher Club Für Leonberger Hunde e.V. (German Leonberger Club), as well as from the proceeds of LPN & LEMP genetic testing.


Scientific References

A CNTNAP1 Missense Variant Is Associated with Canine Laryngeal Paralysis and Polyneuropathy
Letko A, Minor KM, Friedenberg SG, et al. (2020)
Genes 2020, 11, 1426. doi:10.3390/genes11121426

Letko A, Minor KM, Jagannathan V, et al. Genet Sel Evol 52, 61 (2020). doi: 10.1186/s12711-020-00581-3
 
Minor KMLetko ABecker Det al. (2018)
Scientific Reports volume 8, Article number: 5818 (2018doi:10.1038/s41598-018-23938-7
 
Becker D, Minor KM, Letko A, et al. (2017)  
BMC Genomics (2017) 18:662. doi: 10.1186/s12864-017-4081-z
 
Ekenstedt KJ, Becker D, Minor KM, Shelton GD, Patterson EE, Bley T, et al. (2014)  
PLoS Genet 10(10): e1004635. doi:10.1371/journal.pgen.1004635
 
Oevermann A, Bley T, Konar M, Lang J, and Vandevelde M. (2008)
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)  
Muscle Nerve 27: 471–477. doi: 10.1002/mus.10350 doi:10.1002/mus.10350

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      University of Minnesota
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