GENETIC DISORDERS - in general

What is a genetic disorder?

Most diseases are affected to some extent by both genes and the environment. A genetic disorder is one in which an abnormality in the genetic make-up (the genome) of the individual plays a significant role in causing the condition. Although some disorders occur because of spontaneous mutation, many genetic disorders are inherited. These conditions are seen quite often in dogs, mostly but not exclusively in purebreds. These situations are often heart-breaking because the dog is generally a well-loved family member by the time the condition is  apparent and has been diagnosed by a veterinarian.

The role of genes in disease

The role played by genes in disease is becoming better understood. Genetic factors are involved to a greater or lesser extent in congenital malformations (conditions with which an animal is born), metabolic disorders, disorders of immune function, disorders associated with aging, and cancer. These categories of disease have become relatively more important as infectious, parasitic, and nutritional diseases have become less common due to vaccination programmes and advancing knowledge about nutrition, treatments and diagnostic methods.

How to reduce inherited disorders

The frequency of inherited conditions can be reduced through good breeding practices. For this to occur, we need to know how the disease is inherited (the mode of inheritance), how to identify the condition as early as possible, and ways to recognize carriers of the disease who, except in the case of autosomal dominant traits, are not clinically affected. For many of the disorders that are believed to be inherited, the specific pattern of inheritance has not been established. Breeds that have an increased risk for a condition, relative to other dog breeds, are said to have a breed predisposition. Preferably, affected dogs and their close relatives should not be used in breeding programmes.

How are defects inherited?

DNA, chromosomes, genes All animals are made up of billions of tiny cells. The nucleus of these cells contains all the information to regulate the activity of the cell and therefore the form and function of the particular body tissue, and ultimately to form the individual animal. This information originally comes from the parents of the animal, with approximately one half  from the mother and one half from the father. This information from which all life develops is in the form of DNA (deoxyribonucleic acid). A gene is a portion of a DNA molecule, carried on a chromosome. Think of a chromosome as a long string of genes. Hundreds and even thousands of genes may be carried on a particular chromosome. Chromosomes occur in pairs in the cell nucleus, except in the egg and sperm where they occur in half pairs. When an egg is fertilized by the sperm, the resulting cell from which the animal will develop has complete pairs again. This is the way in which one half of the genetic information comes from each parent. The dog has 78 chromosomes, in 39 pairs, on which approximately 100,000 genes are located. This makes up the animal's genotype. The phenotype is what you actually see in the animal, and this can be influenced by both environmental and developmental factors. For example, a dog's size as an adult is determined partly by his or her genes, but is also influenced by environmental factors such as its health as a puppy and the food it eats.

Each gene in a chromosome pair has a partner at the same position (or locus) on the matching chromosome. Each member of a gene pair is called an allele. A gene can have many alleles within a population but an individual animal will have only 2 alleles which influence a particular trait. If the 2 alleles are identical (AA or aa for example), the individual is homozygous at that locus; if the alleles are different (Aa), then heterozygous.

If the allele is dominant, only 1 copy is required to express the trait; if recessive then 2 copies. Upper case letters are traditionally used to represent dominant traits, lower case letters for recessive traits. Thus for a dominant trait, either AA or Aa will express the particular characteristic, while for a recessive trait only aa will express the characteristic. The heterozygote (Aa) will be a carrier - clinically unaffected but able to pass the harmful allele to the offspring.

Defects: inherited or not? 

A disease condition or abnormality may be caused by many factors. Some of these are genetic; that is the disorder is a result of a mutation in a gene that carries particular information. Some mutations are spontaneous, such as a mutation caused by toxins consumed by the mother during pregnancy. An inherited defect is one in which the defective gene has been inherited from one or both of the parents.

Many conditions that have a well-documented hereditary basis may also have other causes. For example, there are several forms of hereditary cataracts, but cataracts may also occur as a result of injury, toxins, or a disease such as diabetes.  In trying to determine whether a disorder is inherited, your veterinarian will look at many factors, including the age the disorder becomes evident, whether littermates or other relatives are affected, and whether the defect  is known to occur in that breed. It is very important that inherited disorders be identified so that information can be relayed back to the breeder, and on a larger scale, so that breeding programmes can be designed to reduce or eliminate these debilitating conditions in dogs.

Patterns of inheritance

The specific pattern of inheritance has not been established for many of the disorders that are believed to be inherited. Where the mode of inheritance is not known, breeds that have an increased risk relative to other dog breeds are said to have a breed predisposition for a particular condition.

The following describes known patterns of inheritance.

Autosomal dominant

Only 1 copy of the gene, which may be inherited from either parent, is required to produce the trait. The parent with the dominant trait will pass the affected gene to approximately half its offspring, and the trait will be apparent in both the parent and the affected progeny. These conditions are uncommon because, as long as it is of early onset (ie becomes apparent before breeding age is reached), the disorder can be readily eliminated by avoiding the breeding of affected individuals.

In many instances however, there is incomplete dominance. The trait may be dominant with variable expressivity, which means that if either parent is affected, all puppies have a susceptibility to the disorder but not all will be affected equally. Alternately, a dominant trait may have incomplete penetrance. If penetrance is 75% for example, only about 3 quarters of the pups who inherit the trait will express it.

Autosomal recessive  

This is the most common mode of inheritance for genetic conditions in dogs. Progressive retinal atrophy (PRA), which causes blindness in many breeds, is such a trait. To be affected, the animal must inherit 2 copies of the gene (genotype pp), 1 from each parent. Dogs with the genotype PP (normal) or Pp (carrier) will be clinically normal but the carrier will pass the affected gene to approximately half the offspring. As long as carriers (Pp) are mated to normal animals (PP), the offspring will be unaffected but some will remain carriers. If 2 carriers are mated, some of the offspring (approximately 25%) will be affected.  

Because the recessive gene is carried in the population in outwardly normal animals, it is very difficult to eradicate these traits. However the incidence can be reduced by identification of carriers through test matings or through various tests that have been developed, and the conscientious use of this information in breeding programmes. Veterinarians, dog breeders, and breed associations must all work together for substantial progress to be achieved.

In these traits, the gene is located on the X chromosome. Males have 1 X chromosome from their mother, and 1 Y chromosome from their father, which carries little information other than maleness. Females have 2 X chromosomes, 1 each from their mother and father. So if a mother who is a carrier for a harmful recessive gene (Xx) passes the recessive gene (x) to her daughter, the daughter will be an unaffected carrier, but her sons who receive that gene will be affected.

The bleeding disorder hemophilia is the best known of the X-linked traits, which are uncommon in the dog. Control programmes are possible because carrier females can be identified through blood screening. The above-mentioned traits are inherited in a straightforward manner. Many others are inherited in a more complex fashion. In fact, most traits that are selected for in the dog are the result of the interaction of many genes. Modifying genes may influence how other genes are expressed. As mentioned above, a trait may be dominant, but with incomplete penetrance so that it is not always expressed. Epistaxis occurs when alleles at one locus mask the action of another pair of alleles.

Polygenic inheritance

Polygenic traits are controlled by an unknown number of genes. The gene expression is influenced by a variety of factors including gender, nutrition, breed, rate of growth, and amount of exercise. These traits are quantitative traits - that is, there is a wide range within the population. Such traits include height, weight, character, working abilities, and some genetic defects. Heritability varies within different breeds and within different populations of a particular breed.

Because it is virtually impossible to determine the exact genotype for such traits, it is difficult to control defects with a polygenic mode of inheritance. The best attempts at control are based on a grading scheme for identification of the defect and a breed policy of recording and publishing the results for as many dogs as possible. 

Canine hip dysplasia is a polygenic trait that remains a problem in most large breeds of dog.  


Hip Dysplasia:




 Affects bone in the hip ball and socket. The mode of inheritance is polygenic (controlled by a number of genes) and can skip several generations without showing up. Environmental factors also influence the soundness of the hip joint. Controlled breeding programs offer the only means by which the incidence can be reduced. Only dogs with good hips as determined by hip x-ray should be bred from, however, pups from x-ray cleared parents can still be affected, although the likelihood is reduced. Relief can be provided to affected dogs by medication or surgery. Prospective buyers should make certain both parents of the pup have been x-rayed and passed for hip dysplasia before choosing a pup.

Hypothyroidism:

A hormonal disorder arising from deficient production of metabolic hormones by the Thyroid Gland. The most common sign is lethargy, but symptoms may also include dry, coarse and sparse coat and obesity. Diagnosis is made by a blood test. Successful treatment of this condition requires an adequate level of hormone to be given each day to compensate for the deficiency in secretion.

Epilepsy:



A functional disorder of the brain characterised by symptoms related to the nervous system including convulsions, hysteria and unusual behaviour patterns. Epilepsy can be due to parasites, exposure to toxic chemicals or hereditary factors. The clinical signs may include the dog convulsing, with or without loss of consciousness, and may be followed by drowsiness and disorientation for several minutes after the attack. Dogs which have suffered an attack will appear very tired afterward and will need to be rested. Medication can be dispensed during stressful times to help prevent an attack. Dogs with a history of epilepsy should not be bred, and owners of related animals should be notified.

Gastric Torsion & Dilatation: (Bloat)




This condition can occur in any breed of dog at any age, but is more prevalent amongst large, deep chested breeds such as the Alaskan Malamute. Bloat results from the dog’s inability to pass food through the stomach into the lower intestines and, in cases of torsion (twisting) of the stomach, inability to vomit. The symptoms appear shortly after the dog has eaten and may include distension of the abdomen, restlessness, excessive salivation, unproductive attempts to vomit and reluctance to move or lie down. The situation worsens rapidly with the dog going into shock, indicated by pale mucous membranes, rapid heartbeat and weak pulse. Death is rapid and painful. Suspected cases must be taken immediately to a veterinarian for urgent treatment. Studies have indicated that overeating, swallowing large amounts of air whilst eating (gulping) and exercising shortly before or after eating may predispose a dog to this condition.

 

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