Australian Shepherd

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Australian Shepherds & Health

The MDR-1 Multi Drug Resistance

In the normal healthy dog, the brain tissue and central nervous system are protected from the high concentrations of toxic substances (such as drugs) circulating in the bloodstream.

The "Multidrug Resistance gene 1" (the MDR1 gene) has an important function in the barrier between blood vessels and brain tissue.

It encodes the protein P-glycoprotein, which is part of the membrane of the blood-brain barrier. P-glycoprotein ensures that various toxic substances (including drugs like ivermectin) are transported from brain cells back into the bloodstream.

In the scientific literature, a number of medications have been reported to cause hypersensitivity reactions in dogs, particularly in Collies and Collie-related breeds. Whenever a dog known or suspected to have such hypersensitivity requires medication, it is advisable to consult the most up-to-date version of the list of “risk medications.” This list is expected to expand as further research becomes available. Biochemical research has shown that the MDR1 gene plays a role in sensitivity to at least fifty different medications.

Hypersensitivity to certain drugs was first identified and described in Collies (Scottish Shepherd Dogs). Initially, this condition was referred to as “ivermectin sensitivity.” Research over recent years has demonstrated that ivermectin is only one of several medications that may cause adverse effects. It has also become clear that this inherited condition does not occur exclusively in Collies, but is present in a wide range of Collie-related breeds.

Dr. Mark Neff and his colleagues have demonstrated that the mutant mdr1- allele likely originated in a dog belonging to the earliest English herding breeds (the so-called working sheepdogs), prior to the establishment of official studbooks around 1873. From these foundation populations, the defective allele was introduced into most modern Collie breeds and into several other breeds as well.

In the past, during the formation of dog breeds, animals from other breeds were often used to enhance certain desired traits. In this process of introducing “desirable genes,” it was inevitable that unwanted genes were also transferred from one breed to another. We must therefore consider the possibility that the defective Multidrug Resistance (mdr1) allele may also be found in other, sometimes unexpected, breeds.

Once it becomes clear that a hereditary condition occurs within a breed, some people advocate for the immediate exclusion of all animals carrying the “undesirable” genetic trait.

This approach is not always wise. In the past, we have repeatedly seen that excluding too many dogs — and sometimes entire bloodlines — has led to new problems, such as increased inbreeding and the emergence of other hereditary disorders.

MDR1 – Risk and problem medications

The list dated 1 December 2005 includes the so-called “Problem Drugs” — medications that have been proven to cause adverse reactions in dogs carrying the MDR1 mutation:

Problem Drugs:

Acepromazine – sedative
Butorphanol – pain relief
Cyclosporine – immunosuppressive medication
Digoxin – enhances heart function
Doxorubicin – cell growth inhibitor, used in cancer treatment
Ivermectin – used against parasites such as lice, mites and worms
Loperamide – used to treat diarrhoea
Vinblastine – cell growth inhibitor, used in cancer treatment
Vincristine – cell growth inhibitor, used in cancer treatment

The list also includes “Potential Problem Drugs” — medications strongly suspected of causing adverse reactions in dogs with the MDR1 mutation:

Potential Problem Drugs:

Domperidone – for nausea and gastrointestinal complaints
Etoposide – cell growth inhibitor, used in cancer treatment
Mitoxantrone – cell growth inhibitor, used in cancer treatment
Morphine – analgesic, primarily for pain relief
Ondansetron – for nausea and vomiting
Paclitaxel – cell growth inhibitor, used in cancer treatment
Quinidine – used for heart rhythm disorders
Rifampicin – antibiotic

In European literature, additional medications are included in the list of Problem Drugs:

Quinidine – for heart rhythm disorders
Dexamethasone – anti-inflammatory and anti-allergic medication
Ebastine – antihistamine for allergic reactions
Grepafloxacin – antibiotic used to treat infections
Sparfloxacin – antibiotic used to treat infections

CEA – Collie Eye Anomaly

Collie Eye Anomaly (CEA), also referred to as Sheltie Eye Anomaly (SEA), is caused by a defect during eye development.
It is therefore a congenital developmental disorder, present from birth.

CEA is very common in both rough and smooth Collies and in the Shetland Sheepdog, less common in the Border Collie, and occasionally observed in non-Collie breeds, including the Australian Shepherd.
The first report of CEA in Australian Shepherds dates back to 1985 in the United States.

Most affected dogs show no noticeable loss of vision.

Eye abnormalities associated with CEA

By definition, all dogs with CEA have at least choroidal hypoplasia (CH) in the lateral or dorsolateral area of the fundus near the optic disc.
In this area, retinal and choroidal pigmentation is partially or completely absent, and the tapetum is poorly developed or missing.
Choroidal blood vessels in the same area may also be abnormal in thickness, number or position.
If a white sheen is visible between these vessels, this represents the underlying sclera.

The condition is usually bilateral, though not necessarily symmetrical.

Diagnosing CEA in merle-coloured dogs can be challenging, especially when only choroidal hypoplasia is present, as these dogs naturally have reduced pigmentation in the fundus.
In such cases, diagnosis is based on the appearance of the choroidal blood vessels and the possible presence of colobomas.

Inheritance of CEA

In most breeds affected by CEA, inheritance is considered autosomal recessive.
This means that affected dogs are homozygous for the same mutant gene (two copies), regardless of whether only CH is present or additional abnormalities occur.

Dogs that are heterozygous carriers (one mutant gene) will never show eye abnormalities and cannot be distinguished from genetically normal dogs by eye examination alone.

At present, it is not fully understood why some dogs show only CH while others develop additional abnormalities such as colobomas.
This is believed to be due to variable expression of the same genotype (cea/cea).

Pleiotropy refers to the phenomenon where one gene causes multiple phenotypic effects — meaning different manifestations from a single genotype.

Simplified, assuming only two alleles:

mutant allele: cea
normal allele (wild type): +

GenotypeDescriptionPhenotype

+/+Homozygous normalUnaffected

-/-Homozygous mutantAffected

+/-Heterozygous (carrier)Unaffected

PRA – Progressive Retinal Atrophy

Progressive Retinal Atrophy (PRA), also called Progressive Retinal Degeneration (PRD), refers to inherited retinal diseases leading to blindness.

Some breeds develop blindness due to abnormal retinal development (retinal dysplasia – RD), while others suffer from a slow degeneration of retinal tissue.
These conditions are generally hereditary, but inheritance patterns vary by breed.

The key to successfully eliminating autosomal recessive PRA is the reliable identification of dogs free of the prcd gene.

Using the OptiGen prcd test, dogs can be identified with 100% certainty as:

genetically clear (free)
non-carriers
homozygous normal

Such dogs can only pass on the normal gene to their offspring.

Homozygous means both gene copies are identical (both normal or both prcd).
A carrier has one normal gene and one prcd gene.

The OptiGen prcd test is a marker test, based on a genetic “fingerprint” on chromosome 9 near the prcd locus, rather than direct mutation detection.

Possible test results:

Pattern Risk group Breeding relevance Risk of prcd

A I Normal (clear) – always suitable for breeding Will never develop prcd

B II Carrier – unaffected Will never develop prcd

C III High risk (affected) Likely to develop prcd

HD – Hip Dysplasia

Possible results:

HD A (negative) – no radiographic signs of HD
HD B (transitional) – minor changes
HD C (mild) or HD D (positive) – clear HD changes
HD E (severe) – severely malformed hip joints

An HD A result does not guarantee the dog will never develop symptoms.
Likewise, severe malformations do not always result in clinical problems.

HD has a multifactorial polygenic inheritance.
Recommended breeding combinations according to KMSH guidelines:
A×A, A×B, B×B

ED – Elbow Dysplasia

Possible results:

Free (0)
Borderline
Grade 1
Grade 2
Grade 3

Radiographs alone cannot predict whether dogs without clinical symptoms will develop problems later in life.

Degenerative Myelopathy (DM)

Degenerative Myelopathy is a progressive neurological disease of the spinal cord, comparable to MS/ALS in humans.
Onset typically occurs between 6 and 10 years of age, with progression lasting 6 to 18 months.

Initial signs include loss of coordination in the hind limbs, stumbling or dragging of the rear legs, often starting on one side.
Incontinence is common. Eventually, vital functions may be affected.

Despite its devastating appearance, DM is not painful.

Cause:
The disease affects the white matter of the spinal cord, where nerve fibres lose their myelin insulation, leading to nerve degeneration and progressive muscle control loss.

Recent research suggests that environmental factors and gut microbiota, particularly segmented filamentous bacteria found in soil, may influence disease development in genetically predisposed individuals.

Recent research into MS/ALS (including studies in the Netherlands) has suggested that a possible infection of the nerves may also play a role, or that there may be a combination of degeneration of nerve pathways and an infection affecting the nerves — as Jean-Martin Charcot, the discoverer of MS in 1880, already suspected.

New environmental factors may also have been identified that could contribute to the development of MS (and possibly DM). This was mentioned in the science supplement of the Dutch newspaper NRC on 24 July 2010.

By chance, researchers at the California Institute of Technology discovered that, when a genetic predisposition is present, the actual development of MS/ALS (and possibly DM) may depend on the composition of the gut microbiome, particularly on the presence of so-called “segmented filamentous bacteria.” These bacteria occur in soil — so it is very likely that many dogs come into contact with them.

The bacteria may cause small inflammatory reactions, which stimulate immune cells. Those immune responses can then trigger inflammatory processes in the central nervous system, which may contribute to the development of MS/ALS (DM). This knowledge may, in the long term, be useful in the search for possible solutions to this disease.