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CMR2 – Canine multifocal retinopathy type 2

Canine multifocal retinopathy (CMR) is a hereditary disease. Most often affected dog breeds are: Great Pyrenees, English Mastiffs, Bullmastiffs, Coton de Tulear and related breeds.

CMR symptoms are very similar to Best macular dystrophy disease (BMD) in humans. BMD and CMR are retinal disorders caused by mutation in VMD2 gene (Vitelliform Macular Dystrophy 2 Gene). VMD2 gene is coding a protein bestrophin which is responsible for right forming of pigment epithelium in retina. Mutations in VMAD2 gene cause pigment epithelium athrophy which is leading to serious damage of sight.

Two VMD2 gene mutations responsible for CMR in dogs were identified:

• Mutation C73T in exon 2 causing CMR1 in Great Pyrenees, English Mastiffs, Bullmastiffs and related breeds. This mutation causes forming of premature stop codon in positi on 25 ( R25X) of VMD2 gene.

• Mutation G482A in exon 5 causing CMR2 in Coton de Tulear. That leads to glycine to aspartic acid change in position 161 of protein sequence (G161D).

CMR disease usually arises before 4th month of age in an affected puppy. Clinically, rose-grey coloured lesions are remarkable in retina. These lesions are of different size and shape and are occured in both eyes of affected individual. Total blindness usually comes in higher age.

CMR is an autosomal recessive disorder. The disease affects dogs with P/P (positive / positive) genotype only. Dogs with P/N (positive /negative) genotype are clinically without any symptoms. They are genetically considered carriers of the disease (heterozygotes). In offspring of two heterozygous animals following genotype distribution can be expected: 25 % N/N (healthy non-carriers), 25 % P/P (affected), and 50 % N/P (healthy carriers). Because of high risk of producing affected offspring, mating of two N/P animals (carriers) can not be recommended.

BNAt Neonatal ataxia

Ataxia is a neurological symptom consisting of a lack of normal coordination of movements. In case of neonatal ataxia the lack of normal coordination becomes evident soon after birth.

Neonatal ataxia was (BNAt – Bandera´s neonatal ataxia) originally called Bandera´s syndrome after the first puppy of Coton de Tulear breed affected, in which the clinical signs of this disease were described.

All affected pups showed similar clinical signs. They nursed well and grew adequately, but have difficulties from the time they became active. The affected pups are unable to stand and walk. Despite all their efforts, they move uncoordinatedly all four limbs and these movements are often compared with “swimmer” movements. When attempting to move, they will frequently push themselves forward, but fall immediately to one side or the other in an attempt to get up. After the fall they often continue to paddle by their limbs.

Another common sign is a tremor or bobbing of the head that are most dramatic when the pup is trying hardest to hold the head steady, for example, when the pup is trying to eat or sniff an object and is referred to as an intention tremor. There may also be a tremor or jerking of the eyes.

The study by Zeng et al. 2011 has described the insertion of retrotransposon in GRM1 gene that disrupts the GRM1 coding sequence in exon 8. Retrotransposons are sequences in the genome that can move or transpose themselves to new positions within the genome. For their „jumping“ in the genome they need RNA polymerases that can transcribe them into RNA. By reverse transcription, the copy of RNA is transcribed into DNA that can be inserted in the genome of the organism in a new position.

The GRM1-gene encodes metabotropic glutamate receptor (mGluR1) which belongs to the group of transmembrane receptors also called receptors coupled with G proteins. The ligand binding induces activation of signalling cascades mediated by G-protein.

In a 4-month old affected puppy, no macroscopic or microscopic abnormalities in the brain anatomy were identified. There were observed only minor ultrastructural abnormalities in the molecular layer of the cerebellum. In the affected pups, the important biochemical pathways are disrupted and therefore the dogs affected with BNAt are not able to walk normally.

Further study of dogs affected with BNAt may clarify the possible role of mGluR1 in learning and memory (Zeng et al. 2011).

Neonatal ataxia in Coton de Tulear is inherited as an autosomal recessive trait. That means the disease affects dogs with P/P (positive / positive) genotype only. The dogs with P/N (positive /negative) genotype are clinically without any symptom. They are genetically considered carriers of the disease (heterozygotes). In offspring of two heterozygous animals following genotype distribution can be expected: 25 % N/N (healthy non-carriers), 25 % P/P (affected), and 50 % N/P (healthy carriers). Because of high risk of producing affected offspring, mating of two N/P animals (carriers) can not be recommended.

PH1 

Primary hyperoxaluria type I (PH I)

Primary hyperoxaluria (PH) is a rare autosomal recessive disorder of glyoxylate metabolism in humans that was also described in dogs (Jansen &Arnesen 1990; Danpure et al. 1991, Vidgren et al. 2012) and cats (Goldstein et al. 2009).  It is characterized by the accumulation of oxalate and subsequent precipitation of calcium oxalate crystals, primarily in the kidneys, leading to progressive kidney failure. If the storage capacity of the kidneys is exhausted, the crystals are accumulated in other tissues, for example in bones, joints, cartilages, retina and muscles.

The PH disease is caused by insufficient function of a liver-specific enzyme alanine -glyoxalate aminotransferase (AGT, AGXT) or an enzyme possessing both glyoxalate reductase and hydroxyl-pyruvate reductase activities (GRHPR). Lack of these enzymes occurs in 95% of animals affected with PH.  Lack of AGXT results in more serious form of the disease with earlier disease onset designated as PH I and the lack of GRHPR-enzyme causes the PH II-form.

In connection with PH I-disease in Coton de Tulear breed, a mutation c.996G>A in AGXT gene was found. At the protein level, the glycine amino acid is substituted with serine in position 102 (Vidgren et al. 2012). The presence of mutation c.996G>A was tested in 118 Finnish dogs of Coton de Tulear breed. A heterozygous mutation was found in 8.5 % animals, i.e. carriers of PH-disease without clinical signs. This preliminary study reported PH as a cause of neonatal death in Coton de Tulear puppies and recommended genetic testing of breeding dogs before mating to prevent the birth of puppies affected with PH I (Vidgren et al. 2012).

The PH I disease in Coton de Tulear is inherited as an autosomal recessive trait. That means the disease affects dogs with P/P (positive / positive) genotype only. The dogs with P/N (positive /negative) genotype are clinically without any symptom. They are genetically considered carriers of the disease (heterozygotes). In offspring of two heterozygous animals following genotype distribution can be expected: 25 % N/N (healthy non-carriers), 25 % P/P (affected), and 50 % N/P (healthy carriers). Because of high risk of producing affected offspring, mating of two N/P animals (carriers) can not be recommended.

von Willebrand disease type 1(vWD type1)

Von Willebrand disease (vWD) is caused by plasmatic von Willebrand factor (vWF) insufficiency. VWF is a blood glycoprotein (not enzyme) important for blood coagulability.

Its primary function is to bind itself to other proteins (for example it stabilizes Factor VIII), and also facilitates aggregation and adhesion of the trombocytes to wound site. The deficiency or failure of vWF function causes bleeding which is most apparent in tissues having high blood flow shear in narrow vessels. VWD manifests oneself as a tendency to bleeding from skin and tissues. The disease can be inheritable or acquired.

In dogs (as well as in people), there were identified three types of vWD. Finally, there were identified five different mutations causing vWDs in dogs. Genetic tests  have been already developed for all the mutations.

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vWD type I

VWD type I is the most often and simultaneously the least serious form of mammalian vWD. It is inherited autosomal recessively. The disease is characteristic by low plasma vWF concentration and normal vWF protein structure.

Individu als suffered wi th vWD have serious bleeding problems. vWD type I occurs, for example, in dog breeds:

• Bernese mountain dog
• Doberman pinscher
• Manchester terrier
• Kerry blue terrier
• Welsh Corgi Pembroke
• Poodle
• Golden retriever
• Labradoodle
• Goldendoodle
• Miniature Schnauzer
• Basethound
• German Shepherd
• Rotttweiler
• Keeshound
• Dachshund (standard, mini)
• Coton de Tulear
• Drentsche Patrijschond
• Papillion
• Stabyhoun

Causal mutation in mentioned breeds is G>A substitution in exon 43 of vWF gene. The mutation is of a type such that completely normal von Willebrand’s factor (vWf) is made about 5-10% of the time. Technically, the mutation is called a splice site mutation, with alternative splicing occurring about 90-95% of the time (Brewer 2006). So, even in affected dogs, there is 5-10% of normal vWF produced. This low concentration of normal vWF prevents excessive bleeding.

The mutation is inherited autosomal recessively, which means that the disease occurs only in individuals, who inherit mutation from both biological parents. The individuals with one mutated allele are disease carriers without any clinical symptoms.

In the Doberman pinscher population in the USA there is about 36% vWD affected dogs and about 48% of carriers. The frequency of mutated gene in the whole population is estimated on a level of 60% (Brewer 2006).

Degenerative Myelopathy – Disease Basics

What is Degenerative Myelopathy?

Degenerative myelopathy is a progressive disease of the spinal cord in older dogs. The disease has an insidious onset typically between 8 and 14 years of age. It begins with a loss of coordination (ataxia) in the hind limbs. The affected dog will wobble when walking, knuckle over or drag the feet. This can first occur in one hind limb and then affect the other. As the disease progresses, the limbs become weak and the dog begins to buckle and has difficulty standing. The weakness gets progressively worse until the dog is unable to walk. The clinical course can range from 6 months to 1 year before dogs become paraplegic. If signs progress for a longer period of time, loss of urinary and fecal continence may occur and eventually weakness will develop in the front limbs. Another key feature of DM is that it is not a painful disease

What causes Degenerative Myelopathy?

Degenerative myelopathy begins with the spinal cord in the thoracic (chest) region. If we look under the microscope at that area of the cord from a dog that has died from DM, we see degeneration of the white matter of the spinal cord. The white matter contains fibers that transmit movement commands from the brain to the limbs and sensory information from the limbs to the brain.

This degeneration consists of both demyelination (stripping away the insulation of these fibers) and axonal loss (loss of the actual fibers), and interferes with the communication between the

brain and limbs. Recent research has identified a mutation in a gene that confers a greatly increased risk of developing the disease.

How is degenerative myelopathy clinically diagnosed?

Degenerative myelopathy is a diagnosis of elimination. We look for other causes of the weakness using diagnostic tests like myelography and MRI. When we have ruled them out,

we end up with a presumptive diagnosis of DM. The only way to confirm the diagnosis is to examine the spinal cord under the microscope when a necropsy (autopsy) is performed.

There are degenerative changes in the spinal cord characteristic for DM and not typical for some other spinal cord disease.

What else can look like degenerative myelopathy?

Any disease that affects the dog’s spinal cord can cause similar signs of loss of coordination and weakness. Since many of these diseases can be treated effectively, it is important to

pursue the necessary tests to be sure that the dog doesn’t have one of these diseases. The most common cause of hind limb weakness is herniated intervertebral disks.

The disks are shock absorbers between the vertebrae in the back. When herniated, they can cause pressure on the spinal cord and weakness or paralysis. Short-legged, long back dogs

are prone to slipped disks. A herniated disk can usually be detected with X-rays of the spine and myelogram or by using more advanced imaging such as CT scan or MRI. Other diseases

we should consider include tumors, cysts, infections, injuries and stroke. Similar diagnostic procedures will help to diagnose most of these diseases. If necessary, your veterinarian can

refer you to a board certified neurologist who can aid in diagnosing degenerative myelopathy. A directory to a neurologist near you can be found at

American College of Veterinary Internal Medicine website under the “Find a Specialist Near You” link.

How do we treat degenerative myelopathy?

There are no treatments that have been clearly shown to stop or slow progression of DM. Although there are a number of approaches that have been tried or recommended on the

internet, no scientific evidence exists that they work. The outlook for a dog with DM is still grave. The discovery of a gene that identifies dogs at risk for developing degenerative myelopathy

could pave the way for therapeutic trials to prevent the disease from developing. Meanwhile, the quality of life of an affected dog can be improved by measures such as good nursing care,

physical rehabilitation, pressure sore prevention, monitoring for urinary infections, and ways to  increase mobility through use of harnesses and carts.

Lidt på DANSK

Ud over de af DKK anbefalede fysiske tests (PL og PRA) er det muligt at lade Coton de Tulear DNA-teste for yderligere 6 sygdomme.

Sygdommene er ikke særlig udbredt, men for at undgå det sker, er der alt mulig grund til at foretage de tilgængelige tests. Men fordi de ikke er så udbredte, er der ingen avlsrestriktioner, men udelukkende en anbefaling.  Alle hunde er bærere af et eller andet, , og det er ikke alt vi kan teste for. Men at være bærer af  en sygdom, betyder bare at den bærer et defekt gen, ikke at den nogensinde får sygdommen. Men ved at man ved at en hund er bærer af en sygdom, kan man bruge det i avlen til at undgå at hundene bliver syge, ved altid at parer en fri med fri, eller en bærer med en fri.