Health

Mandiger update on Polymyositis summer 2019
November 2020 – Update polymyositis research and improvement in the treatment of polymyositis:
Mutation found

It is assumed to be an autoimmune disease that causes chronic inflammation of one or more muscle groups resulting in loss of functionality and muscle weakness in the affected areas. Myositis is a progressive form of the disease with a very poor prognosis. We see two groups. The first  group consists of relatively young dogs with swallowing or eating problems. The second group consists of dogs that are young to middle aged and have more musculoskeletal problems and sometimes a combination with swallowing problems.  Depending on the location , the most common symptoms are:

• reduced endurance
• muscle weakness
• swallowing problems
• fever
• general fatigue
• lack of drive to play or walk
• lameness
• stiffness
• walking with curved back
• salivation
• vomiting
• poor appetite.

Because many symptoms are also features of other disorders, this condition is often difficult to recognize. If left undiagnosed, Myositis is lethal; if diagnosed early, available treatments are immunosuppression and management with steroids. Kooikers with Myositis seem to pass away at  3 or 4 years  after being diagnosed. Myositis in general can be hereditary or caused by infections, autoimmune diseases and toxins. It can be misdiagnosed as Myasthenia Gravis, for example, by veterinarians. In order to  make a definitive diagnosis, a muscle biopsy by a qualified veterinarian is required. This tricky disease has been found more often in the Kooikerhondje population in recent years. We hope that current research in the Netherlands will give us a better understanding of the disease in the near future.

Professor Paul J.J. Mandigers from the Veterinary Faculty at the University in Utrecht gave a lecture about polymyositis during the Symposium of the VHNK. Here is the summary:

VHNK Health Symposium Nov 2017:

Polymyositis (and HNM) in

“Het Nederlandse Kooikerhondje”

By Dr. Paul Mandigers

Dr. Paul Mandigers discussed the relevance of HMN ( hereditary necrotizing myelopathy) and polymyositis (PMN) to breed health.   

His colleagues of ECGC (Expertise Centre Genetics Companion Animals) conceptualize development of a breeding app.  This app would utilize various resources such as pedigree, molecular markers, health data, show results etc to support estimated breeding values.  

Contrasting the differences in research cost and details between HMN and PMN, funding is needed to continue the more elusive search for PMN carrier testing.   

Clinically dogs with PMN may present with problems swallowing ( eating, drinking, salivation) and/ or locomotion.  Presentation is varied from mild to severe with progression ranging from resolution to reoccurrence to demise.  Relying on reported data from the Dutch club registration, approximately 2% of dogs are affected with a carrier rate of 20-30%.  Roughly 17% present under 1 year of age; 25% between 1-2 years or age; 11% between 2-3 years of age; 11% between 3-4 years of age and 36% are greater than 4 years of age at time of presentation.  

In muscle biopsies (the current goldstandard to diagnose), variants of lymphocytic polymyositis, eosinophilic (lymphocytic) polymyositis and granulomatous histiocytic polymyositis and various combinations exist with mild to severe symptoms.  Recognition of mild cases can be difficult with elevation of CK (creatine kinase) suggestive but not diagnostic of disease.  Due to differing presenting phenotype so, treatment has ranged from supplements to corticosteroids to spontaneous resolution with varying responses.  

No genetic test has been developed yet. 

Research has identified a region with 4 important genes.  Use of genetic sequencing has shown 2 of the genes to be abnormally up-regulated in PMN.  However, it is complex, as heterozygous dogs can get sick while a few homozygous dogs remain healthy.  Ideally, research would allow for identification of either phenotypic mutations or variance by expanding the genetic sequencing or affected homozygous dogs, heterozygous dogs and controls.   

The anticipated cost is 10,000 to 20,000 Euros with already 50,000 Euros expended.   Continued funding and support is needed to solve this complex genetic issue.

End of symposium summary.

The medical work-up includes a muscle biopsy (tissue sample taken from the affected muscle group). If the dog has difficulty swallowing, a bronchoscopy (internal exam with a camera visualising the lungs and bronchial tree) as well. Before starting steroid therapy, the diagnosis of Polymyositis needs to be confirmed because steroids can alter test results. Professor Mandigers thinks that Polymyositis in the Kooiker is a breed specific disease that is familial and hereditary. There is most likely a trigger that causes Polymyositis to break out.

This disease has appeared lately with a certain frequency and is hard to deal with for both the dog and the owner. If you have further questions, feel free to contact us. There is more information on Polymyositis at http://www.kooikerhondje.nl – see under „Gezondheit“.

We hope to have a blood test soon that can screen for carrier status. We will keep you posted.

Polymyositis in the Kooikerhondje - facts and case report

The patella, or kneecap, is part of the stifle joint (knee). In patella luxation, the kneecap luxates, or pops out of place, either in a medial or lateral position. This can be a hereditary defect, it can also be caused by malnutrition and over-exercise. Kooikerhondjes, as well as all mixed dogs or purebred, are susceptible to this structural defect. It is prevented through selective breeding and by use of a licensed canine orthopedic specialist’s diagnosis. The official evaluation normally occurs after 12 months, once most of the growing of the dog is done. However you may have your dog inspected earlier by a veterinarian for symptoms. Find out more on the Orthopedic Foundation for Animals’ (OFA) website. Dogs used for breeding should be free or only minimally affected with patella luxation and should carry a valid OFA certificate.

Prevalence and genetics of patellar luxation in Kooiker dogs

ABSTRACT The prevalence of patellar luxation (PL) and genetic factors potentially involved in the disorder were investigated in Dutch Kooiker dogs. A cohort of 842 Kooiker dogs, the offspring of 195 sires and 318 dams, was screened for PL from 1994 to 2011. The cohort was included in a pedigree of 1737 Kooiker dogs comprising nine generations. PL was present in 24% of screened dogs, with unilateral and bilateral luxation being observed equally frequently. Medial PL was more common (61%) than lateral PL (32%) or bidirectional PL (7%). The frequency of PL was similar in male and female dogs, with a female:male relative risk of 1.15 (95% confidence interval, CI, 0.90-1.48). The heritability of PL in the screened population was 0.27 ± 0.07. Since the start of the screening programme, the prevalence of PL decreased from 28% to 19%. A genome-wide association study of PL with 48 cases and 42 controls suggested the possible involvement of a region on chromosome 3 (Praw = 1.32 x 10-5, Pgenome = 0.142), but the involvement of this region could not be confirmed in a validation group. Breeding programmes for complex diseases, such as PL, would benefit from combining pedigrees, phenotypes and genotypes, i.e. from genomic selection, as is currently the method of choice for breeding of production animals. The Veterinary Journal, 01/2014, C. Wangdee, P.A.J. Leegwater, H.C.M. Heuven, F.G. van Steenbeek, F.J. Meutstege, B.P. Meij, H.A.W. Hazewinkel

Renal dysplasia is defined as disorganized development of renal parenchyma that is due to abnormal differentiation. For definitive diagnosis of this category of conditions, microscopic observation of structures in the kidney that are inappropriate for the stage of development of the animal is required. The presence of immature glomeruli and tubules usually within radial bands adjacent to more normally developed tissue (i.e., asynchronous differentiation of nephrons) is the most consistent feature. Other findings indicative of renal dysplasia include persistent immature mesenchyme, persistent metanephric ducts, atypical tubular epithelial proliferation, and (albeit rare in dogs) dysontogenic metaplasia. Secondary changes that are commonly observed include compensatory hypertrophy and hyperplasia of glomerular tufts and tubules, interstitial fibrosis, tubulointerstititial nephritis, pyelonephritis, dystrophic mineralization, cystic glomerular atrophy, microcystic tubules, retention cysts, and glomerular lipidosis.

Renal dysplasia is reported in Kooikerhondjes . Additionally, juvenile nephropathies with microscopic features of renal dysplasia have been reported in one or more unrelated dogs of so many different breeds that it seems likely that the disorder occurs at least sporadically in all breeds. The causes and pathogenesis of canine renal dysplasia are unknown. To date, data documenting the validity of genetic testing for renal dysplasia have not been published for any breed.

A condition of the hip join in which the bones are not properly formed, resulting in a loose hip socket the thighbone connection. This can cause pain and lameness that can range from mild to crippling. This can be caused by and inherited structural defect or environmental variables such as obesity and physical over-exertion. Like patella luxation, hip dysplaysia can be screened for. Ask a qualified veterinarian to x-ray your dog and submit results to OFA. Although hip dysplaysia is no a prevalent problem in the breed, it is always good to test for and to avoid mating Kooikers that have both poor hip testing results. Comparison to other countries:

Like patella luxation all dogs, mixed or purebred are susceptible to hereditary eye abnormalities and deformations such as cataracts, retinal dysplasia or distichiasis (where the eye lash grows towards the lens). It is important to have Kooikers examined by a board certified Veterinary Ophthalmologist and registered with CERF, the Canine Eye Registration Foundation. Dogs used for breeding should carry a valid CERF certificate. A dog should be checked at age 12 months and then again before being bred if there is a time difference of more than 2 years. The guidelines are currently a little loose regarding retesting.

Epilepsy is a brain disorder in which a dog has repeated seizures (convulsions) over time. Seizures are episodes of disturbed brain activity that cause changes in attention or behavior.

There are several types of seizures that are seen, and many times the owner isn’t even aware of the problem. An epileptic seizure is the clinical manifestation of abnormal brain activity in the cerebral cortex. These abnormalities can create seizures that vary from the mild “petit mal” to the generalized, full body “grand mal.” Epilepsy in canines is classified into two types: Idiopathic (also known as Primary) and Secondary. In Secondary epilepsy, a specific cause for the seizures is discovered, such as ingesting toxins or hypoglycemia.

Idiopathic epilepsy, which is diagnosed when there is no known cause for the condition, and is assumed to be inherited. This disease can only be avoided by careful selective breeding. A new research project has started in the Netherlands in order to find a gene marker for epilepsy but there are currently not enough cases and blood samples collected. Every breeder should follow breeding rules established by the Dutch Kooiker Club when breeding with lines affected with epilepsy.

This project was discontinued in 2013.

An important gene cluster, called “major histocompatibility complex (MHC) at the canine chromosome 12, has been found in the dog’s genome. MHC complex is the home for genes that are responsible for the recognition of the individual’s own tissues and separating the foreign material. The ability is related to the genetic diversity of the individual’s MHC complex. It is very important that this area maintains as diverse as possible within a single dog breed to ensure the health and vitality of the breed. The narrowing down the genetic variance on the MHC complex alters the individual, and the whole breed in general to increased susceptibility to autoimmune diseases (e.g. diabetes, atophy, hypothyroiditis, a number of inflammatory disorders). It could be assumed that autoimmune disorders on kooikerhondje are associated with homozygosity on the haplotypes located at the MHC-area, since many canine autoimmune disorders have already been found to have a connection to that. The MHC-area includes two clusters of genestrings called the DLA, that are always inherited as a whole string, not as separate genes. The individual inherits the clusters from the parentdogs, one DLA cluster (genestring) from the sire, and one DLA cluster (genestring) from the dame. If the inherited DLA clusters are identical, the individual will have homozygote haplotypes whereas if they are different, the indivual will have heterozygote haplotypes. At the wild animal poplulations heterozygosity is preferred, and that should be the aim for breeding a healthy dogbreed as well.The Finnish Kooikerhondje Association started a research on the Kooikerhondje MHC complex (DLA-typing) during 2011 which is currently put on hold. If we are able to maintain heterozygosity of the MHC region as vast as possible in the breeding lines of the Kooikerhondje, we should be able to reduce the risk for autoimmune or other diseases associated with the area.

VWD is a hereditary clotting disorder caused by a defect or deficiency of a blood clotting protein, called von Willebrand Factor, a protein that is required for platelet adhesion. This condition makes those afflicted likely to bleed abnormally and severely. This can lead to potentially life threatening consequences in situations such as accidental injuries, spaying, or neutering. Testing is available through Utrecht University of Veterinary Medicine in the Netherlands by blood sample. All breeding stock is required to be tested for the carrier status.

Also called Kooiker Paralysis or Leukodystrophy. It affects currently only 0.2% of the population approximately. The carrier status is most likely as high as 25% of the Kooiker population world wide. A dog that is a carrier will not show any symptoms during his lifetime. ENM is a devastating disease that is still undergoing intense study. It is thought to be a recessive degenerative spinal disease.

The disease usually breaks out between the 3rd and 12th month of life. Noticeable is a change in movement and muscle weakness that starts in the hind legs and progresses to the front legs until there is a complete paralysis of the body. Affected dogs die of asphyxiation if they are not euthanized. ENM is not painful and is not treatable. ENM is always lethal. After the first physical signs have started, Kooikers will die within 2 weeks to 11 months.

The cause is a destruction of the spinal cord. Post mortem examination has revealed a symmetrical bilateral necrotizing myelopathy with malacia in the ventral and dorsal white matter. The disease resembles the hereditary myelopathy seen in Afghan Hounds and the leucoencephalomyelopathy in Rottweilers. A research article from 1993 has concluded that it is an autosomal recessive disease. Currently, the only way to effectively eliminate ENM is to use preventative selection when choosing a sire and dam to breed. Your breeder should know about ENM!

A DNA blood test is available to screen for carrier status of ENM. The first analysis were performed beginning of July 2012 at the University of Utrecht. A dog that has been identified as carrying ENM does not mean that it is unhealthy. However the result does help with the selection of sire and dam. A carrier can be mated with a non-carrier or two non-carriers can be mated. Two carrier should NEVER be mated since their offspring can get the disease. Carriers should be INCLUDED with breeding stock since the gene pool is limited as is.

Please follow this link (ENM test) to learn more about the test and research that has been done in the Netherlands.