FAMILIAL NEPHROPATHY (FN)
Familial Nephropathy (FN)-an overview of this kidney disease
by Addi Pittman
Introduction
Familial Nephropathy (FN) is a recessively inherited (Lees, Macdougall/Cattanach) renal disease that has been recognized in the English Cocker for more than 50 years (Krook 162). FN is a form of "hereditary nephritis" (Lees 189) which refers to a group of glomerular diseases that are linked to genetic collagen defects.
Onset of renal failure due to FN typically occurs between six and 24 months of age (Lees 189). Clinical signs may include polydipsia (drinks more), polyuria (urinates more), weight loss, lack of appetite, vomiting, or diarrhea. These symptoms are commonly associated with any type of renal failure.
Structure/Function
The kidney is an organ made up of hundreds of thousands of tiny structures called nephrons. Each nephron consists of a glomerulus and a tubule. Blood flowing through the kidney is filtered by the glomerulus, with the fluid that is filtered out of the blood subsequently passing down the length of the tubule. Cells that line the inner surface of the tubule process the fluid as it flows along, reabsorbing certain components of the fluid and excreting others. The fluid leaving the tubule at the end of this process is urine, which is a combination of water and waste products.
Dogs affected with FN have a genetic defect within the glomerulus. This defective glomerulus lacks a certain type of collagen that helps to hold the structure of the filter together. As a result of this collagen defect, a chain reaction of events takes place. Once the glomerulus begins to loose its ability to function properly, blood proteins leak through the defective filter into the urine. The glomerular abnormality also leads to subsequent tubular damage, and the chain of events eventually destroys the entire nephron. Nephrons that are severely damaged or destroyed can’t be replaced.
Since the kidney serves as the main waste-disposal system in the body, it is a master at compensation. When one nephron dies, another takes over its work. Over the course of time and with continual compensation the number of functioning nephrons is greatly reduced. Once at least 75 percent of the nephron population is destroyed, end-stage renal failure occurs. Since the disease is gradual and progressive, affected dogs do not appear sick until very late in the course of disease.
In the Beginning...
English Cockers affected with FN are born with normally developed kidneys. Because they lack a certain type of collagen, however, the kidneys begin to deteriorate while the dogs are just a few months old. As glomerular damage evolves, the kidneys will first allow protein (proteinuria) to escape into the urine. Generally, while proteinuria persists, the pup’s growth rate will slow down. Once the pup begins to spill protein into the urine, the ability of the kidneys to ‘concentrate’ the urine will also diminish. Finally, as a result of progressive nephron damage, the ability of the kidneys to excrete waste products (eg, urea and creatinine) will become impaired (Lees). As excretion of waste products by the kidneys progressively diminishes, the severity of renal failure will gradually worsen.
Sequence of Events
The sequence of events is always the same, but the rate of disease progression varies for reasons that are not fully understood (Lees). As a result, it is difficult to give a specific age when to expect various stages of the disease to take place. "For example, onset of proteinuria was at 5 to 8 months of age in 3 dogs in which it was carefully studied. Because we can’t be sure that these 3 dogs are representative of all FN-affected dogs, we are uncertain what age to say is the oldest an FN-affected dog can be when it first has proteinuria. Nonetheless, we suspect that all, or almost all, dogs with FN will have proteinuria before a year of age. The age range for occurrence of renal failure is 6 months to 2 years" (Lees).
Clinical Signs
One way to identify a pup that might have FN is through observation. Breeders and owners can watch the voiding patterns of young dogs. Make it a point to regularly check the color of the urine. The first morning release (assuming water hasn’t been available during the night) is probably best. There should be good yellow color (well concentrated). A youngster that lacks the ability to pass concentrated urine repeatedly should be taken to a veterinarian for a complete urinalysis. A test called a "specific gravity (SG)" should be performed as well as an analysis for protein (proteinuria). Usually, protein can be checked by using a color-coded plastic strip (Bili-Labstix). This strip is merely dipped into a urine specimen and the plastic strip changes color and is checked against a chart on the side of the bottle the strips come in. This strip will test for several things other than protein. A pup with a low specific gravity and excess protein (++) in the urine should be tested using a more specific test. This test, a ‘protein-creatinine ratio,’ will provide a better estimate of the amount of protein in the urine. A complete urinalysis should also be done to identify other urinary problems that may be present. A positive dip-stick for protein does not necessarily indicate that the dog has renal disease or will develop FN. It’s merely an indication that a more thorough evaluation is needed. Not all young-age renal failure in this breed is FN; however, the symptoms are the same.
End Stage
Once it is established that a young dog is consistently passing dilute urine with protein, serum chemistry tests should be performed. Such tests will only show significant elevations in specific areas once 75% of both kidneys are destroyed. Elevations in BUN (blood urea nitrogen), creatinine, and inorganic phosphorus suggest kidney disease. These findings coupled with a low urine specific gravity and proteinuria signal end-stage renal disease.
When the serum chemistry tests show "abnormally high levels of urea (BUN), creatinine, and other non-protein nitrogenous substances, a laboratory term called Azotemia is used to identify these specific abnormal levels (Barrett 1753).Generally, once the BUN reaches approximately 120 mg/dl, the dog only has a few weeks before critical illness sets in. When these animals become critically ill, they will not eat. If they do eat, they usually vomit. They may go for two or three days without food, loosing more weight. They will drink a tremendous amount of water and urinate even more. Sometimes there will be an ammonia odor from the mouth. Since the dog sleeps on the ear leathers, this ammonia odor may be apparent on the ear furnishings. The dog will become very weak, and may tremble as if it’s cold. They loose the ability to regulate their body temperature. Since the kidney’s are no longer able to filter the body’s waste products, and regulate many important functions essential for life, the animal is essentially poisoning itself with its own waste products.
Perhaps one of the most frequent questions asked by owners with a young dog in failure is how will they know when it’s time to say good-bye. Despite being in the critical stage of renal failure, these youngsters can always manage to wag their tail and greet family members, not with the usual exuberance, but the effort is there until the end. When the time comes to say good-bye you’ll know…
Those that have lost a dog to FN will tell you the loss is more profound with this disease process than any other they’ve experienced. It’s something no one wants to experience. Through the efforts of Dr. George Lees and his research team, hopefully in the very near future the mutation will be found. This will enable the development of a mutation-based DNA test that will unequivocally identify carrier animals.
by Addi Pittman
Introduction
Familial Nephropathy (FN) is a recessively inherited (Lees, Macdougall/Cattanach) renal disease that has been recognized in the English Cocker for more than 50 years (Krook 162). FN is a form of "hereditary nephritis" (Lees 189) which refers to a group of glomerular diseases that are linked to genetic collagen defects.
Onset of renal failure due to FN typically occurs between six and 24 months of age (Lees 189). Clinical signs may include polydipsia (drinks more), polyuria (urinates more), weight loss, lack of appetite, vomiting, or diarrhea. These symptoms are commonly associated with any type of renal failure.
Structure/Function
The kidney is an organ made up of hundreds of thousands of tiny structures called nephrons. Each nephron consists of a glomerulus and a tubule. Blood flowing through the kidney is filtered by the glomerulus, with the fluid that is filtered out of the blood subsequently passing down the length of the tubule. Cells that line the inner surface of the tubule process the fluid as it flows along, reabsorbing certain components of the fluid and excreting others. The fluid leaving the tubule at the end of this process is urine, which is a combination of water and waste products.
Dogs affected with FN have a genetic defect within the glomerulus. This defective glomerulus lacks a certain type of collagen that helps to hold the structure of the filter together. As a result of this collagen defect, a chain reaction of events takes place. Once the glomerulus begins to loose its ability to function properly, blood proteins leak through the defective filter into the urine. The glomerular abnormality also leads to subsequent tubular damage, and the chain of events eventually destroys the entire nephron. Nephrons that are severely damaged or destroyed can’t be replaced.
Since the kidney serves as the main waste-disposal system in the body, it is a master at compensation. When one nephron dies, another takes over its work. Over the course of time and with continual compensation the number of functioning nephrons is greatly reduced. Once at least 75 percent of the nephron population is destroyed, end-stage renal failure occurs. Since the disease is gradual and progressive, affected dogs do not appear sick until very late in the course of disease.
In the Beginning...
English Cockers affected with FN are born with normally developed kidneys. Because they lack a certain type of collagen, however, the kidneys begin to deteriorate while the dogs are just a few months old. As glomerular damage evolves, the kidneys will first allow protein (proteinuria) to escape into the urine. Generally, while proteinuria persists, the pup’s growth rate will slow down. Once the pup begins to spill protein into the urine, the ability of the kidneys to ‘concentrate’ the urine will also diminish. Finally, as a result of progressive nephron damage, the ability of the kidneys to excrete waste products (eg, urea and creatinine) will become impaired (Lees). As excretion of waste products by the kidneys progressively diminishes, the severity of renal failure will gradually worsen.
Sequence of Events
The sequence of events is always the same, but the rate of disease progression varies for reasons that are not fully understood (Lees). As a result, it is difficult to give a specific age when to expect various stages of the disease to take place. "For example, onset of proteinuria was at 5 to 8 months of age in 3 dogs in which it was carefully studied. Because we can’t be sure that these 3 dogs are representative of all FN-affected dogs, we are uncertain what age to say is the oldest an FN-affected dog can be when it first has proteinuria. Nonetheless, we suspect that all, or almost all, dogs with FN will have proteinuria before a year of age. The age range for occurrence of renal failure is 6 months to 2 years" (Lees).
Clinical Signs
One way to identify a pup that might have FN is through observation. Breeders and owners can watch the voiding patterns of young dogs. Make it a point to regularly check the color of the urine. The first morning release (assuming water hasn’t been available during the night) is probably best. There should be good yellow color (well concentrated). A youngster that lacks the ability to pass concentrated urine repeatedly should be taken to a veterinarian for a complete urinalysis. A test called a "specific gravity (SG)" should be performed as well as an analysis for protein (proteinuria). Usually, protein can be checked by using a color-coded plastic strip (Bili-Labstix). This strip is merely dipped into a urine specimen and the plastic strip changes color and is checked against a chart on the side of the bottle the strips come in. This strip will test for several things other than protein. A pup with a low specific gravity and excess protein (++) in the urine should be tested using a more specific test. This test, a ‘protein-creatinine ratio,’ will provide a better estimate of the amount of protein in the urine. A complete urinalysis should also be done to identify other urinary problems that may be present. A positive dip-stick for protein does not necessarily indicate that the dog has renal disease or will develop FN. It’s merely an indication that a more thorough evaluation is needed. Not all young-age renal failure in this breed is FN; however, the symptoms are the same.
End Stage
Once it is established that a young dog is consistently passing dilute urine with protein, serum chemistry tests should be performed. Such tests will only show significant elevations in specific areas once 75% of both kidneys are destroyed. Elevations in BUN (blood urea nitrogen), creatinine, and inorganic phosphorus suggest kidney disease. These findings coupled with a low urine specific gravity and proteinuria signal end-stage renal disease.
When the serum chemistry tests show "abnormally high levels of urea (BUN), creatinine, and other non-protein nitrogenous substances, a laboratory term called Azotemia is used to identify these specific abnormal levels (Barrett 1753).Generally, once the BUN reaches approximately 120 mg/dl, the dog only has a few weeks before critical illness sets in. When these animals become critically ill, they will not eat. If they do eat, they usually vomit. They may go for two or three days without food, loosing more weight. They will drink a tremendous amount of water and urinate even more. Sometimes there will be an ammonia odor from the mouth. Since the dog sleeps on the ear leathers, this ammonia odor may be apparent on the ear furnishings. The dog will become very weak, and may tremble as if it’s cold. They loose the ability to regulate their body temperature. Since the kidney’s are no longer able to filter the body’s waste products, and regulate many important functions essential for life, the animal is essentially poisoning itself with its own waste products.
Perhaps one of the most frequent questions asked by owners with a young dog in failure is how will they know when it’s time to say good-bye. Despite being in the critical stage of renal failure, these youngsters can always manage to wag their tail and greet family members, not with the usual exuberance, but the effort is there until the end. When the time comes to say good-bye you’ll know…
Those that have lost a dog to FN will tell you the loss is more profound with this disease process than any other they’ve experienced. It’s something no one wants to experience. Through the efforts of Dr. George Lees and his research team, hopefully in the very near future the mutation will be found. This will enable the development of a mutation-based DNA test that will unequivocally identify carrier animals.
CANINE DEGENERATIVE MYELOPATHY
by Casey Carl on June 5, 2015 in Ask The Vet
If there is anything that I have learned in Paw Print Genetics’ quest to prevent canine inherited diseases, it is that degenerative myelopathy (DM) is one of the most misunderstood diseases in the dog breeding community. This late-onset, progressive neurological disease is notorious for cutting affected dog’s lives short and preventing them from living out their golden years. Unfortunately, sometimes there are misunderstandings in regard to what causes DM, what DM genetic test results mean, and whether or not DM occurs in certain breeds or bloodlines. I will attempt to address the confusing aspects of DM in order to empower people to eliminate this devastating disease from their blood lines.
How Do DM Affected Dogs Present? How is it Inherited?
Dogs affected with DM typically begin showing signs of painless, hind limb weakness and loss of balance around 7 to 10 years of age. These dogs often have difficulty rising after lying down, will drag their hind feet while walking, and abnormally cross their legs while standing. As the disease progresses, affected dogs’ front limbs also become progressively weaker until the dog becomes unable to walk. Affected dogs also may develop urinary and fecal incontinence as the disease progresses. Most dogs are euthanized within 6 months to 2 years of the initial clinical signs due to poor quality of life.
Though it is no longer the only known mutation responsible for causing DM in the dog, the vast majority of DM cases are caused by a particular reported mutation in the canine SOD1 gene (another mutation, discussed below, has been identified to cause DM in the Bernese mountain dog). Though only described in 5 dog breeds in the initial publication, the same mutation has since been identified in over 100 different breeds. DM caused by this mutation is inherited in a recessive fashion with incomplete penetrance meaning that a dog must inherit two copies of the mutation (one from each parent) in order to develop DM. However, not all dogs that inherit two copies of the mutation will become affected. Dogs inheriting a single copy are considered carriers of DM and will not typically show signs of the disease, but can have affected puppies if bred with another carrier of the same mutation.
Interestingly, DM is the canine equivalent of Lou Gehrig’s disease (amyotrophic lateral sclerosis). In fact, at least one documented cause of Lou Gehrig’s disease is a mutation in the human SOD1 gene.
Breed or Bloodline Susceptibility to DM
Out of all of the misconceptions I have heard regarding DM, the most common one is that DM does not occur in a particular breed or bloodline despite the presence of the common SOD1 mutation in the breed. It is true that some dogs do not ever develop DM even when inheriting two copies of the mutation. This indicates to us that in some dogs, other genetic or environmental factors may play a role in producing a protective effect or slowing the progression of disease such that the disease does not clinically manifest during the dog’s lifetime. However, the factors producing a protective effect are not known and therefore cannot be manipulated to prevent disease in future litters. Since dogs inheriting two copies of the disease can have clinically affected puppies even if they never show signs of the disease themselves, the only predictable way to prevent DM caused by the most common mutation is to genetically test breeding dogs and to selectively breed carriers to dogs that did not inherit the same mutation.
In addition to the issues related to incomplete penetrance of DM, my experiences in clinical veterinary practice made it apparent to me that people may not be aware of DM issues in their line. It was my experience that most owners of DM affected dogs never considered the fact that their dog may be suffering from an inherited issue. Instead, the signs of DM were often written off as arthritis, hip dysplasia, or simply “slowing down” due to age. Without an accurate diagnosis or veterinary discussion of genetics, few owners would feel compelled to contact the breeder of their dog, given that they still knew how to contact them after the 7 to 10 years it normally takes for affected dogs to begin showing clinical signs. Without this vital information from owners, breeders could easily be in the dark when it comes to this condition in their line.
Genetic Testing for DM
Another misconception about testing for DM is that people think that the current genetic testing available for the disease is not useful. While there are probably many reasons why this misconception exists, in addition to the issues related to incomplete penetrance, there are other complexities of DM that likely confuse people.
One troubling finding for some is that a small portion of DM affected dogs will not have the common SOD1 mutation or only possess a single copy of the mutation when tested. The most likely explanation for this phenomenon is that there are other, unknown genetic mutations that are also responsible for causing this disease. If only testing for a single mutation, you may not know what other genetic mutations could be contributing to the condition. While it would likely make sense to most that a dog inheriting two copies of an unknown mutation could cause DM (and not show up on our current DM test) I have found that many people have a difficult time understanding how a dog could inherit a single copy of the common mutation, but still develop the disease. Let’s examine the case of the Bernese mountain dog to help us understand what could potentially be happening in these cases.
In a 2013 case study, a DM affected Bernese mountain dog was described to have inherited a single copy of the most common SOD1 mutation from one parent and a single copy of the Bernese SOD1 mutation from its other parent. Since this dog received a mutated copy of the SOD1 gene from each parent, it did not receive a normal copy of the gene to mask the effects of either mutation as in most recessively inherited conditions. This phenomenon, known as compound heterozygosity is well documented in humans. However, to my knowledge, the 2013 case report is currently the only one of its type in dogs. With discovery of additional disease associated mutations in dogs, it is likely that many similar examples will be found in our canine friends.
Despite the fact that there are likely other unknown mutations responsible for DM in our dogs, the originally described SOD1 mutation is believed to cause the VAST MAJORITY of cases. Given this knowledge, genetic testing and selective breeding could completely eliminate degenerative myelopathy in most blood lines. Thus, justifying the use of the currently available genetic test for DM, despite its limitations.
PREVENTING BLINDNESS THROUGH GENETIC TESTING
by Casey Carl on Nov. 15, 2016 in All Things Dog , Ask The Vet
Since we started working with the Boykin Spaniel Society (BSS), both Paw Print Genetics (PPG) and the BSS have learned much about the genetic disease concerns of these wonderful, little brown dogs. By using the founder breeds of the Boykin as a guide, PPG developed the first Boykin spaniel inherited disease testing panel in 2014. Based upon the results collected over two years of testing Boykins, in September 2016, the original disease testing panel was split into two panels; the Boykin spaniel essential panel (containing the most clinically important and/or common diseases) and the supplemental panel (containing diseases of less clinical importance and/or lower incidence).
Two of the four diseases on the Boykin spaniel essential panel are inherited diseases of the eye. Diseases resulting in vision loss or blindness are among some of the most life-altering and troublesome non-lethal diseases of dogs. However, with knowledge of a specific genetic mutation resulting in blindness as well as an understanding of how that specific eye disease is inherited, blindness caused by the mutation can be prevented through the use of genetic testing and informed selective breeding practices based upon test results. Two eye diseases known to be inherited in the Boykin spaniel are collie eye anomaly and a form of progressive retinal atrophy known as cone-rod dystrophy 4.
Progressive Retinal Atrophy, Cone-rod Dystrophy 4
Progressive retinal atrophy (PRA) is a group of inherited eye diseases in dogs marked by gradual degeneration of the retina, resulting in blindness. Over a dozen forms of PRA, caused by different mutations in various genes, are known to occur in dogs. Though each form of PRA has similar clinical signs related to retinal degeneration, the inheritance, age of onset, and speed of progression can vary between PRA types. Dogs affected with PRA typically display changes in the structure of the retina that can be identified on eye exam, prior to the dog showing signs of vision deficits. These changes include thinning of the retina and retinal blood vessels as well as an increase in reflectivity of light from the part of the eye known as the tapetum; the reflective part of the eye responsible for improving a dog’s vision in low light settings and for the “eye shine” seen when you shine a flashlight in your dog’s eye or take a photograph with a flash.
Paw Print Genetics found a mutation of the canine RPGRIP1 gene in Boykin spaniels that was previously associated with a form of progressive retinal atrophy known as cone-rod dystrophy 4 (PRA-crd4) in other breeds. PRA-crd4 has a variable age of onset and has been reported in dogs between one and 15 years of age. Progression of this form of PRA tends to be slow, but most affected dogs (especially those with an early age of onset) will progress to complete blindness.
Inheritance of PRA-crd4
PRA-crd4 is inherited in a recessive fashion, meaning that a dog must inherit two copies of the mutation (one from each parent) in order to be affected. However, this disease also displays a phenomenon called incomplete penetrance, meaning that not every dog that inherits two copies of the mutation will go on to develop disease. Dogs inheriting a single copy of the mutation are considered “carriers” of PRA-crd4 and will not display signs of the disease themselves. However, carriers of PRA-crd4 can produce affected dogs when bred with another carrier of the same mutation. Therefore, in order to prevent producing affected puppies, it is important to only breed PRA-crd4 carriers to dogs that have not inherited a copy of the same mutation (“clear” dogs). It should be noted, however, that approximately half of the offspring from breeding a PRA-crd4 carrier to a dog clear of PRA-crd4 will be carriers of the mutation. In general, it is not recommended to breed affected dogs if you wish to eliminate the mutation from your blood line. In addition to identifying non-symptomatic carriers of PRA-crd4, genetic testing is crucial to identify affected dogs that have not yet begun to show clinical signs of disease.
As an important aside, a test for a common and widespread mutation associated with a different form of PRA known as progressive rod-cone degeneration (PRA-prcd) was included on the original PPG Boykin spaniel panel in 2014 based upon reports describing the mutation in the cocker spaniel and the Chesapeake Bay retriever; two of the founder breeds used to create the Boykin spaniel. However, this mutation was not identified in more than 200 Boykins tested at PPG through September 2016. Thus, indicating that the associated mutation is likely rare (or absent) in the Boykin spaniel. For this reason, the test was moved to the Boykin spaniel supplemental panel. Because it is possible that this mutation exists in a small percentage of the Boykin spaniel population, the test is still an available option for testing Boykins in which there is a concern about PRA.
Collie Eye Anomaly
Out of all of the disease-associated genetic mutations we have identified in the Boykin spaniel, the mutation associated with collie eye anomaly (CEA) has been found in the highest frequency in the dogs tested in our laboratory. However, during my conversations with Boykin breeders, I have found that there is some confusion about CEA in terms of its age of onset, progression of disease, and what inheriting the mutation means for a given individual. It is important to understand the nuances of CEA to lessen the confusion about this disease.
Inheritance of CEA
CEA is a developmental disease of dogs which is present at birth (congenital) and caused by a genetic mutation in the canine NHEJ1 gene. Like PRA-crd4, CEA is inherited in a recessive fashion and the same breeding recommendations for PRA-crd4 apply to CEA in terms of breeding carriers or affected dogs. However, it should be noted that CEA displays a slightly different phenomenon than PRA-crd4 known as variable expressivity in which there is significant variability among individuals in the severity of clinical signs associated with the disease. Therefore, in addition to identifying non-symptomatic carriers of CEA, genetic testing is crucial to identify only mildly affected dogs.
CEA Clinical Signs and “Going Normal”
Though dogs with two copies of the NHEJ1 gene mutation are born with CEA, variability in disease severity makes genetic testing an important part of eliminating this disease from blood lines. Dogs affected with the “classic” presentation of CEA suffer from underdevelopment of a part of the eye known as the choroid (giving CEA its other commonly used name, choroidal hypoplasia). The choroid is the layer of tissue in the eye containing blood vessels important in providing oxygen and nutrients to the retina. This malformation of the eye results in the clinical signs associated with CEA.
Dogs with severe CEA are typically easy for a veterinarian to recognize on an eye exam due to the presence of one or more common disease characteristics, often resulting in vision deficits or complete blindness. These include retinal folds, abnormal blood vessel structure, retinal detachment, hemorrhage in the eye, or malformation of the retina, optic disc, or white of the eye (coloboma).
Dogs with mild clinical signs of CEA may be more difficult to diagnose on eye exam due to the normal process of pigmentation of the retina which occurs in puppies by 12 weeks of age. After 12 weeks of age, retinal pigmentation can mask mild clinical signs of CEA, making it difficult or impossible to identify the disease on an eye exam. This phenomenon, which many breeders refer to as “going normal”, is very important for breeders to understand because dogs examined after 12 weeks of age may be affected with CEA, but lack any obvious structural or vision problems. It is also important to note that mildly affected dogs can still have severely affected puppies when bred. In addition, affected puppies within a litter may vary in the clinical findings.
Since we started working with the Boykin Spaniel Society (BSS), both Paw Print Genetics (PPG) and the BSS have learned much about the genetic disease concerns of these wonderful, little brown dogs. By using the founder breeds of the Boykin as a guide, PPG developed the first Boykin spaniel inherited disease testing panel in 2014. Based upon the results collected over two years of testing Boykins, in September 2016, the original disease testing panel was split into two panels; the Boykin spaniel essential panel (containing the most clinically important and/or common diseases) and the supplemental panel (containing diseases of less clinical importance and/or lower incidence).
Two of the four diseases on the Boykin spaniel essential panel are inherited diseases of the eye. Diseases resulting in vision loss or blindness are among some of the most life-altering and troublesome non-lethal diseases of dogs. However, with knowledge of a specific genetic mutation resulting in blindness as well as an understanding of how that specific eye disease is inherited, blindness caused by the mutation can be prevented through the use of genetic testing and informed selective breeding practices based upon test results. Two eye diseases known to be inherited in the Boykin spaniel are collie eye anomaly and a form of progressive retinal atrophy known as cone-rod dystrophy 4.
Progressive Retinal Atrophy, Cone-rod Dystrophy 4
Progressive retinal atrophy (PRA) is a group of inherited eye diseases in dogs marked by gradual degeneration of the retina, resulting in blindness. Over a dozen forms of PRA, caused by different mutations in various genes, are known to occur in dogs. Though each form of PRA has similar clinical signs related to retinal degeneration, the inheritance, age of onset, and speed of progression can vary between PRA types. Dogs affected with PRA typically display changes in the structure of the retina that can be identified on eye exam, prior to the dog showing signs of vision deficits. These changes include thinning of the retina and retinal blood vessels as well as an increase in reflectivity of light from the part of the eye known as the tapetum; the reflective part of the eye responsible for improving a dog’s vision in low light settings and for the “eye shine” seen when you shine a flashlight in your dog’s eye or take a photograph with a flash.
Paw Print Genetics found a mutation of the canine RPGRIP1 gene in Boykin spaniels that was previously associated with a form of progressive retinal atrophy known as cone-rod dystrophy 4 (PRA-crd4) in other breeds. PRA-crd4 has a variable age of onset and has been reported in dogs between one and 15 years of age. Progression of this form of PRA tends to be slow, but most affected dogs (especially those with an early age of onset) will progress to complete blindness.
Inheritance of PRA-crd4
PRA-crd4 is inherited in a recessive fashion, meaning that a dog must inherit two copies of the mutation (one from each parent) in order to be affected. However, this disease also displays a phenomenon called incomplete penetrance, meaning that not every dog that inherits two copies of the mutation will go on to develop disease. Dogs inheriting a single copy of the mutation are considered “carriers” of PRA-crd4 and will not display signs of the disease themselves. However, carriers of PRA-crd4 can produce affected dogs when bred with another carrier of the same mutation. Therefore, in order to prevent producing affected puppies, it is important to only breed PRA-crd4 carriers to dogs that have not inherited a copy of the same mutation (“clear” dogs). It should be noted, however, that approximately half of the offspring from breeding a PRA-crd4 carrier to a dog clear of PRA-crd4 will be carriers of the mutation. In general, it is not recommended to breed affected dogs if you wish to eliminate the mutation from your blood line. In addition to identifying non-symptomatic carriers of PRA-crd4, genetic testing is crucial to identify affected dogs that have not yet begun to show clinical signs of disease.
As an important aside, a test for a common and widespread mutation associated with a different form of PRA known as progressive rod-cone degeneration (PRA-prcd) was included on the original PPG Boykin spaniel panel in 2014 based upon reports describing the mutation in the cocker spaniel and the Chesapeake Bay retriever; two of the founder breeds used to create the Boykin spaniel. However, this mutation was not identified in more than 200 Boykins tested at PPG through September 2016. Thus, indicating that the associated mutation is likely rare (or absent) in the Boykin spaniel. For this reason, the test was moved to the Boykin spaniel supplemental panel. Because it is possible that this mutation exists in a small percentage of the Boykin spaniel population, the test is still an available option for testing Boykins in which there is a concern about PRA.
Collie Eye Anomaly
Out of all of the disease-associated genetic mutations we have identified in the Boykin spaniel, the mutation associated with collie eye anomaly (CEA) has been found in the highest frequency in the dogs tested in our laboratory. However, during my conversations with Boykin breeders, I have found that there is some confusion about CEA in terms of its age of onset, progression of disease, and what inheriting the mutation means for a given individual. It is important to understand the nuances of CEA to lessen the confusion about this disease.
Inheritance of CEA
CEA is a developmental disease of dogs which is present at birth (congenital) and caused by a genetic mutation in the canine NHEJ1 gene. Like PRA-crd4, CEA is inherited in a recessive fashion and the same breeding recommendations for PRA-crd4 apply to CEA in terms of breeding carriers or affected dogs. However, it should be noted that CEA displays a slightly different phenomenon than PRA-crd4 known as variable expressivity in which there is significant variability among individuals in the severity of clinical signs associated with the disease. Therefore, in addition to identifying non-symptomatic carriers of CEA, genetic testing is crucial to identify only mildly affected dogs.
CEA Clinical Signs and “Going Normal”
Though dogs with two copies of the NHEJ1 gene mutation are born with CEA, variability in disease severity makes genetic testing an important part of eliminating this disease from blood lines. Dogs affected with the “classic” presentation of CEA suffer from underdevelopment of a part of the eye known as the choroid (giving CEA its other commonly used name, choroidal hypoplasia). The choroid is the layer of tissue in the eye containing blood vessels important in providing oxygen and nutrients to the retina. This malformation of the eye results in the clinical signs associated with CEA.
Dogs with severe CEA are typically easy for a veterinarian to recognize on an eye exam due to the presence of one or more common disease characteristics, often resulting in vision deficits or complete blindness. These include retinal folds, abnormal blood vessel structure, retinal detachment, hemorrhage in the eye, or malformation of the retina, optic disc, or white of the eye (coloboma).
Dogs with mild clinical signs of CEA may be more difficult to diagnose on eye exam due to the normal process of pigmentation of the retina which occurs in puppies by 12 weeks of age. After 12 weeks of age, retinal pigmentation can mask mild clinical signs of CEA, making it difficult or impossible to identify the disease on an eye exam. This phenomenon, which many breeders refer to as “going normal”, is very important for breeders to understand because dogs examined after 12 weeks of age may be affected with CEA, but lack any obvious structural or vision problems. It is also important to note that mildly affected dogs can still have severely affected puppies when bred. In addition, affected puppies within a litter may vary in the clinical findings.
GLYCOGEN STORAGE DISEASE
What is Glycogen Storage Disease?
Glycogen, often referred to as “animal starch” is the primary way by which mammals store energy. An enzyme called glucose-6-phosphatase handles converting the glycogen into glucose, which the body can then use as fuel. Rarely, some puppies can be born with a genetic deficiency in this enzyme. Without the action of glucose-6-phosphatase, the animal is unable to produce glucose on its own in response to changes in blood sugar. This leads to chronic low blood sugar. Also, since the animal cannot effectively break down glycogen and fat, both of these accumulate in the liver, kidneys and muscle, causing damage and impairing the proper function of these organs. The abundance of glycogen by-products has to go somewhere, and when it is processed via additional metabolic pathways, it can lead to other disorders like lactic acidosis and elevated triglycerides. Dogs with this condition do not usually survive past four months. Glycogenosis, often referred to as Glycogen Storage Disease, is a genetic defect in dogs. The enzyme glucose-6-phosphatase, a key step in the production of glucose, is found to be deficient. The excess of glycogen and inability to perform the glucose-freeing step in the metabolic pathway leads to chronic low blood sugar, liver damage and premature death.
Symptoms of Glycogen Storage
Disease in Dogs: Weakness Chronic low blood sugar Collapse Lethargy Enlarged liver Anorexia Types I-a: occurs in toy breeds. Low body weight, lethargy and low blood sugar. II: occurs in Laplands. Gastrointestinal upset, weakness and heart trouble. III: occurs in German Shepards and Curly-Coated Retrievers. Weakness, low body weight and slight low blood sugar. IV: occurs in Springer Spaniels. Damage to red blood cells, urinary abnormalities.
Causes of Glycogen Storage Disease in Dogs
Inherited genetic defect. Diagnosis of Glycogen Storage Disease in Dogs Owners who notice their new puppy failing to gain weight and seeming weak should see an appropriately skilled veterinarian as soon as possible. There are a multitude of possible reasons why your puppy is ill, and many of them may be curable. In the event that your dog does have Glycogenosis, the veterinarian will attempt to rule out similar diseases such as hepatitis, mucopolysaccharidosis, and ketoacidosis as a symptom of diabetes. First, a number of blood panels checking liver and kidney function will be performed. Blood sugar will be checked, and an insulin-production test may be given to rule out diabetes. As the veterinarian comes to suspect Glycogenosis, a genetic test will definitively diagnose this condition with a blood or saliva sample.
Treatment of Glycogen Storage Disease in Dogs
Unfortunately, Glycogenosis is always fatal. During the diagnostic process, there are a number of ways low blood sugar may be corrected, such as a high-carbohydrate diet and administration of dextrose intravenously. These are only short-term measure, and it is a rare occurrence for dogs afflicted with Glycogenosis to survive more than a year. Recovery of Glycogen Storage Disease in Dogs There is no cure for Glycogenosis, and many veterinarians deem it kinder to euthanize the dog rather than subject it to the suffering incurred as its condition deteriorates. A diet high in carbohydrates in conjunction with intravenous dextrose solutions can temporarily manage crises of low blood sugar, but is not a permanent solution. Dogs suspected of carrying the gene for Glycogenosis should not be bred, and the parents of the affected puppy should also be kept from breeding again. The owners of seemingly healthy dogs from that litter should be notified of the risk their dog is a carrier.
Read more at: https://wagwalking.com/condition/glycogen-storage-disease
Glycogen, often referred to as “animal starch” is the primary way by which mammals store energy. An enzyme called glucose-6-phosphatase handles converting the glycogen into glucose, which the body can then use as fuel. Rarely, some puppies can be born with a genetic deficiency in this enzyme. Without the action of glucose-6-phosphatase, the animal is unable to produce glucose on its own in response to changes in blood sugar. This leads to chronic low blood sugar. Also, since the animal cannot effectively break down glycogen and fat, both of these accumulate in the liver, kidneys and muscle, causing damage and impairing the proper function of these organs. The abundance of glycogen by-products has to go somewhere, and when it is processed via additional metabolic pathways, it can lead to other disorders like lactic acidosis and elevated triglycerides. Dogs with this condition do not usually survive past four months. Glycogenosis, often referred to as Glycogen Storage Disease, is a genetic defect in dogs. The enzyme glucose-6-phosphatase, a key step in the production of glucose, is found to be deficient. The excess of glycogen and inability to perform the glucose-freeing step in the metabolic pathway leads to chronic low blood sugar, liver damage and premature death.
Symptoms of Glycogen Storage
Disease in Dogs: Weakness Chronic low blood sugar Collapse Lethargy Enlarged liver Anorexia Types I-a: occurs in toy breeds. Low body weight, lethargy and low blood sugar. II: occurs in Laplands. Gastrointestinal upset, weakness and heart trouble. III: occurs in German Shepards and Curly-Coated Retrievers. Weakness, low body weight and slight low blood sugar. IV: occurs in Springer Spaniels. Damage to red blood cells, urinary abnormalities.
Causes of Glycogen Storage Disease in Dogs
Inherited genetic defect. Diagnosis of Glycogen Storage Disease in Dogs Owners who notice their new puppy failing to gain weight and seeming weak should see an appropriately skilled veterinarian as soon as possible. There are a multitude of possible reasons why your puppy is ill, and many of them may be curable. In the event that your dog does have Glycogenosis, the veterinarian will attempt to rule out similar diseases such as hepatitis, mucopolysaccharidosis, and ketoacidosis as a symptom of diabetes. First, a number of blood panels checking liver and kidney function will be performed. Blood sugar will be checked, and an insulin-production test may be given to rule out diabetes. As the veterinarian comes to suspect Glycogenosis, a genetic test will definitively diagnose this condition with a blood or saliva sample.
Treatment of Glycogen Storage Disease in Dogs
Unfortunately, Glycogenosis is always fatal. During the diagnostic process, there are a number of ways low blood sugar may be corrected, such as a high-carbohydrate diet and administration of dextrose intravenously. These are only short-term measure, and it is a rare occurrence for dogs afflicted with Glycogenosis to survive more than a year. Recovery of Glycogen Storage Disease in Dogs There is no cure for Glycogenosis, and many veterinarians deem it kinder to euthanize the dog rather than subject it to the suffering incurred as its condition deteriorates. A diet high in carbohydrates in conjunction with intravenous dextrose solutions can temporarily manage crises of low blood sugar, but is not a permanent solution. Dogs suspected of carrying the gene for Glycogenosis should not be bred, and the parents of the affected puppy should also be kept from breeding again. The owners of seemingly healthy dogs from that litter should be notified of the risk their dog is a carrier.
Read more at: https://wagwalking.com/condition/glycogen-storage-disease
IMHA & ITP: unfortunately there are no genetic tests available for these diseases in Spaniels but the information can be found here: