Types of Genetic Diseases

Genetic Diseases Affecting Immune System

Primary immune deficiencies are genetic defects that compromise the immune response and thereby render affected individuals highly susceptible to infection. White blood cells, or leukocytes, are the work horses of the immune system. Their constituents, including B and T lymphocytes, monocytes and neutrophils, course through the peripheral circulation. Leukocytes develop from stem cells and are renewed throughout life.

The major function of B lymphocytes is to produce antibodies (humoral immunity) that confer protection against bacterial infection. T lymphocytes, which direct cell-mediated immunity, fend off intracellular invaders, such as fungi, protozoa and viruses; a subset of T lymphocytes, helper T cells, regulate and enhance humoral immunity. Monocytes and neutrophils, the "garbage collectors" of the immune system, phagocytize foreign invaders. Complement - enzymatic proteins in the serum, combines with the antigen-antibody complex to stimulate lysis of potentially pathogenic antigen. A flaw in any of these immune components can cause an immunodeficiency syndrome. Where the genetic defect is in the development of the immune system determines how severe the immune deficiency is.

Some 50 heritable immune deficiencies have been identified in humans. In the dog, only a few have been documented. These same 50 disorders should also be seen in the dog, and in higher incidence because of inbreeding.

The clinical features of immune incompetence in the dog include recurrent, chronic infections that are refractory to treatment; chronic diarrhea; growth retardation; and adverse reactions to modified live vaccines. Several simple tests are used to diagnose canine immune deficiencies. They include quantification of antibodies or complement, measurement of B- and T-lymphocyte maturity through analysis of cell surface markers, and challenge assays to assess the competence of both the T lymphocytes (lymphocyte transformation test [LTT]) and the phagocytic system.

Among the significant primary immune deficiencies that have been reported in the dog are XSCID, selective IgA deficiency and leukocyte adhesion deficiency (LAD). Afflicted dogs experience chronic infections that typically begin at a few months of age. These infections, usually bacterial, are generally unresponsive to antibiotic therapy. Affected dogs are smaller than their litter mates and exhibit marked failure to thrive.

Selective IgA deficiency, which leads to less severe recurrent infections, occurs quite commonly in dogs. It can be diagnosed with LTT or by measurement of the serum IgA concentration, which is profoundly depressed in affected dogs.

LAD is caused by defective integrins, proteins that enable phagocytes to bind to microorganisms. Signs of LAD, which occur at a few weeks of age, include recurrent pus-forming infections and poor wound healing. LAD is often diagnosed using flow cytometry to discern the presence of normal adhesion molecules.

Heritable Kidney Diseases

A variety of serious kidney (renal) disorders are encoded by genes. The kidney plays several important roles. It filters the blood through its glomeruli -- small tufts of capillaries, and excretes toxic waste products. The renal tubules resorb substances from the glomerular filtrate -- such as amino acids, sugars, water and a electrolytes, in amounts necessary to maintain hydration, acid-base balance, blood pressure and other normal parameters. Also, the kidney manufactures important vitamins and hormones.

The kidney is so efficient that it can serve all of the body's functions with just a portion of its nephrons, or functional renal units. The dog, for example, can lose one of its two kidneys and remain healthy. With a 67 percent loss of kidney mass, it might show signs of kidney failure, but blood measures of renal function, such as creatinine and blood urea nitrogen (BUN), are not affected. In fact, renal failure does not typically occur until about three-quarters of the kidney is destroyed.

Signs of renal failure include increased thirst and urination, dehydration, loss of appetite, vomiting, weight loss, anemia, hypertension and ascites.

Several inherited renal defects, such as renal dysplasia, glomerular diseases, tubular diseases and structural abnormalities, can lead to renal failure Yet when they occur, these problems should not be assumed to be genetic; infectious and metabolic mechanisms, for example, may be the cause. In assessing their etiology, it is important to survey the affected dog's pedigree and consider whether a breed predisposition exists for the disorder.

Renal dysplasia is a congenital or neonatal disorder that results in maldevelopment of the kidneys predisposing the dog to progressive kidney failure. Renal dysplasia is thought to be familial in the Lhasa Apso, Shih Tzu, Miniature Schnauzer, Doberman Pinscher, Chow Chow, Soft-coated Wheaten Terrier, Golden Retriever, and Standard Poodle breeds.

Clinical signs of renal dysplasia include poor growth, pu/pd, cachexia and "rubber jaw." Renal dysplasia is thought to be an autosomal recessive trait, but no carrier tests have yet been developed.

Unlike renal dysplasia, which usually presents in young dogs, glomerulopathies may emerge clinically at any age. They are characterized by protein-losing nephropathy, which leads to edema/ascites, hypertension and thromboembolism. Like renal dysplasia, glomerulopathies seem to gravitate toward certain breeds of dogs, including Beagle, Basenji, Samoyed, Labrador and Golden Retrievers, Soft-coated Wheaten Terrier, Bernese Mountain Dog, Doberman Pinscher, Bullmastiff, Bull Terrier, English Cocker Spaniel, Rottweiler, and Shar-Pei. Likewise, Dr. Littman cautioned, the pathogenesis of these disorders may vary from breed to breed.

Certain dog breeds are also predisposed to tubular diseases and structural anomalies. Telangiectasia occurs in some Pembroke Welsh corgi dogs. The Siberian husky appears prone to ectopic ureter and subsequent hydronephrosis.

The genetic defects inherent in most inherited kidney disorders have not yet been identified, she added. But once these modes of inheritance are worked out, special breeding strategies may be devised to reduce the occurrence of these often-debilitating maladies.

Genetic Basis of Hip Dysplasia

Sound imaging techniques for diagnosing the presence of hip dysplasia are currently available. Hip dysplasia is the most common heritable orthopedic disease of the dog. Due to a misshapen femoral head (ball) or shallow acetabulum (socket), the ball-and-socket hip joint does not form a tight union in dysplastic dogs. Consequently, these individuals have lax, or loose-fitting, hips. Joint laxity may, depending upon the severity, over time lead to degenerative joint disease (DJD), or arthritis.

Hip dysplasia in the dog was first described in the 1930s. After decades of research on the disorder, why are there still so many dogs walking around on bad hips? For one thing, little is known about the genetic scheme and molecular patterns of hip dysplasia. What is understood, however, is that hip dysplasia arises from a complex form of inheritance. Its expression is polygenic and multifactorial; in other words, many genes, as well as environmental factors, influence its development.

The other reason hip dysplasia is ubiquitous is that dysplastic dogs have not been kept out of the breeding pool because, until recently, their disorder was not accurately diagnosed. In 1983, Dr. Smith developed the PennHIP® program, which utilizes a highly reliable method for diagnosing hip dysplasia. By the PennHIP® method, radiographs are taken when the dog's hips are in the neutral (standing) position, which allows maximum laxity. (The traditional position used for evaluating hip status was legs fully extended.) The femoral heads are then manually pushed laterally out of the acetabula as far as they will easily go. A distraction index (DI), which measures the distance the heads can be pushed out of the joint, is then calculated. The DI is numbered 0 (no laxity) through 1 (complete laxity). A DI of .75, for example, indicates that the hips can be translated 75 percent from the congruent position.

Ongoing research indicates that hip laxity is the most important factor in predicting DJD. Arthritis susceptibility is also highly breed dependent. In other words, different breeds of dogs have different degrees of tolerance of laxity in their hip joints; for example, German shepherd dogs are more likely to develop arthritis, given the same amount of laxity, than are Rottweilers. Environmental factors can also dramatically influence the expression of arthritis in an arthritis-prone dog.

Hereditary Eye Diseases

Canine inherited retinal degeneration causes characteristic optic changes that are consistent among various breeds. Progressive retinal atrophy (PRA) is a gradual, blinding disorder. Affected dogs develop degenerative changes in the retina with age. Early in the disease, they become night blind. As more of their photoreceptors degrade over time, these dogs lose their day vision as well. The pupils of their eyes become increasingly dilated and prone to developing cataracts.

The major indicator that PRA represents several different pathogenetic mechanisms is the breed-related difference in the age of onset and rate of progression of the disease. Certain breeds, such as the collie, Irish setter, Norwegian elkhound and miniature schnauzer, have early-onset forms of retinal degeneration. In these breeds, the disease results from abnormal or arrested development of the photoreceptors and affects dogs early in life. In other breeds, such as the Miniature Poodle, Labrador Retriever and Cocker Spaniel, PRA has much later onset.

Studies were conducted to determine whether all of the early-onset forms, though they occur in several dog breeds, represent the same molecular disease pattern. In one trial, the test mating of an affected Irish setter to an affected Elkhound produced a litter of unaffected puppies. The phenotypically-normal puppies (carriers of both disorders) were then bred to affected Collies. This second litter consisted of all normal puppies. Given that PRA is an autosomal recessive trait in all breeds but the Siberian Husky, in which it is x-linked recessive, it is apparent that different genetic forms of PRA occur in the three breeds.

Likewise, test matings were conducted between dogs of several breeds that develop late-onset PRA. The results of these matings pointed toward a single gene at work. Thus, the late-onset forms of PRA result from mutations in the same gene.

In order to delineate these disease mechanisms, researchers are working to pinpoint the genes responsible for PRA in specific breeds. A reliable DNA test for the presence or absence of rod-cone dysplasia 1 (rcd1) and rod-cone dysplasia 2 (rcd2) already exists.

Treatment of Genetic Diseases

Even the best detection systems to diagnose and prevent genetic diseases don't alleviate the need for therapy to treat disorders produced by new mutations. It's possible to treat these diseases by getting around the genetic problems that exist. Several therapeutic approaches exist. The simplest of these are reconstructive surgery for structural malformations, such as polydactylism, hip dysplasia, and patent ductus arteriosus. But this type of treatment is dissatisfying in some respects. The reason is that it doesn't really get to the core of the problem.

For metabolic problems, there are therapies that work at the biochemical level. They might limit the availability of a compound in the diet that can become toxic due to genetic deficiencies in processing, remove the toxic product made by the body, or provide a missing non-protein product, such as vitamin B12.

For disease caused by dysfunctional or deficient proteins, it's possible to either enhance the activity of the defective enzyme or provide the normal gene product, such as insulin or enzymes. For example, a dog with exocrine pancreatic insufficiency has inadequate secretion of digestive enzymes. These enzymes can be therapeutically replaced in the food, thereby eradicating the clinical manifestations of maldigestion and malabsorption. For a dog with von Willebrand's disease, which is characterized by the deficiency of clotting factors that leads to prolonged bleeding, the missing coagulation proteins can be restored by plasma infusion.

Enzyme replacement can also be used for lysosomal storage disorders. These diseases encompass a variety of rare, genetic (mostly autosomal recessive) defects described in several breeds, including the beagle, German shorthaired pointer and wirehaired dachshund. Lysosomes - small intracellular organelles that contain hydrolytic enzymes -- are the little garbage disposals of cells. Deficiency of any of these enzymes can lead to accumulation of metabolites inside the lysosome. Lysosomes become grossly enlarged in these storage disorders to ping pong balls that grow to the size of basketballs.

Animals with one group of these disorders, mucopolysaccharidosis, exhibit stunted growth, facial dysmorphia, corneal clouding, organomegaly, and neurological and skeletal abnormalities. Human children with mucopolysaccharidosis are mentally retarded and typically die by the age of ten.

Lysosomal storage diseases are caused by defects in the genes coding for lysosomal enzymes. Replacement enzymes can be produced in vitro by genetically-engineered cells and then infused into affected individuals. This has been shown to be successful in children, but may not work well in the dog because of an immune response to the new enzymes and also must be given IV weekly for the life of the dog.

Gene transfer can also be a permanent fix to the problems caused by mutant genes. It involves cloning normal copies of a defective gene and then delivering them, via retrovirus vectors, to the patient's own abnormal cells. Still in the experimental stages, this method, which also utilizes bone marrow transplantation, has several hurdles to overcome before it can be used clinically.

These innovative therapies incorporate different approaches ultimately designed to alleviate disease in affected dogs. Yet with years of experimentation ahead, they are still at the bottom of the refinement curve.

(Adapted from "27th Annual Canine Symposium," Joan Capuzzi, VHUP.)




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