Genetic Neurologic Disorders in Dogs with Dr. Casey Carl, DVM

Watch the recording of our webinar with Dr. Casey Carl, DVM, the Associate Medical Director at Paw Print Genetics, to learn more about genetic neurologic disorders in dogs. He also answers questions from viewers, so be sure to stick around to the end!

Transcript

Nicole Engelman [0:01] Thank you all so much for joining us today for our Facebook Live with Dr. Carl! If you have any questions that you’d like to ask at any point during the presentation, feel free to drop them in the chat box, and we’ll make sure that Dr. Carl gets them. So, for those of you who are unfamiliar with Good Dog, we are on a mission to build a better world for our dogs and the people who love them by advocating for dog breeders, educating the public, and promoting canine health and responsible dog ownership, especially through webinars and Facebook Lives just like these. We’re a secure online community, created just for dog breeders. We are completely free for dog breeders also, so definitely check us out. We’ll be dropping a link in the chat so you can learn more about us and our community of Good Dog Breeders. As part of our mission to promote canine health, I’m really excited to talk a little bit more about our first annual health symposium that we just announced a few weeks ago. It’s actually coming up pretty soon! It will be on Saturday, September 18th. It’s an entirely virtual symposium. It is completely free. We’re bringing together some leading experts in canine veterinary medicine, health testing, and genetics to really help breeding programs excel. It’ll be really awesome. We’ll drop the link to register in the chat, in case you haven’t done that already. We can’t wait to see you there. It will be a great event. With that, I will pass things off to Dr. Mikel Delgado. 

Dr. Mikel Delgado [1:35] Hey, everybody! I’m Mikel, the Standards and Research lead here at Good Dog. I’m so honored, as always, to have Dr. Casey Carl with us here today, talking about genetic neurological disorders in dogs. If you are not familiar with Casey Carl, you’re in for a real treat. We always learn so much from his talks. Dr. Carl received his veterinary degree from Washington State University, and he worked in clinical practice before joining Paw Print Genetics, where is the Associate Medical Director. He is deep in the trenches of dog genetics and health. With that, please welcome Dr.Carl. 

Dr. Casey Carl [2:14] Hey, everybody! So glad to be here with you today. Hope everybody is doing well, physically and mentally, during this challenging time. We’ll chat about some interesting topics today. It’s always a little challenging when we’re trying to determine exactly what to talk about when we have a particular topic. I’m trying to focus today on some neurological diseases that affect a large number of breeds. Hopefully we’ll get a large number of people out there that are listening. Hopefully their breed will at least have one of these diseases or more that is associated with their particular breed of choice. Let’s see if I can get this to roll here.

[2:55] First of all, we’ll go over a few definitions—probably things that, if you’ve been to any of my talks before, we’ve kind of gone over in the past. They’re just a few things I like to define before we get rolling, just in case the terms happen to come up over the course of the talk and there’s confusion about what those terms mean. We’re going to talk about Degenerative Myelopathy (DM). This is a very common disorder in dogs and one that’s quite misunderstood in many ways. It’s one that is definitely applicable to well over 100 dog breeds. We’re going to talk about another genetic mutation, known as the Early-Onset Risk Modifier that has been discovered and how that relates to DM. We’re going to cover Exercise-Induced Collapse (EIC), which is another neurological condition that is first described in Labradors but has been found in several other breeds since then. We’ll talk about a newer test to us here at Paw Print, this Juvenile Laryngeal Paralysis and Polyneuropathy. And then two causes of Ataxia, known in the Russell Terrier group; one of these diseases is found in other groups as well. We’ll talk about both of those. Lastly, we’ll talk about Neuronal Ceroid Lipofuscinosis 4A, or NCL 4A, which is a neurological condition seen in some of the Pitbull and Stature Terrier breeds. And then we may have some time for questions. This presentation may be a little bit shorter than some of my other ones, so we should have plenty of time for questions. I’m happy to stick around as long as people have those. 

[4:30] First of all, definitions! We’ll start with this definition of a genetic mutation, also known as a variant. Essentially this is just an alteration in DNA that affects gene function. It may result, in some cases, in a disease or a particular trait, but it doesn’t always have to. Sometimes mutations are not compatible with life, so they never really get passed on. In this case, we’re talking about ones that are compatible with life but maybe not necessarily a good life. That is definitely an important consideration when we talk about all of these as that particular term. Variant is used much more commonly these days than mutation. Allele is a term for 1 copy or version of a gene from a single parent. When we take a look at both alleles, one version of the gene from one parent and one version from the other, that makes up our genotype—the combination of both of those alleles that we get, one from each parent. And if we have two versions of the gene that are identical, we refer to that as being homozygous. So, two exact copies or versions of that gene. But if they’re different, which is in the case of dogs that, say, are carriers of a particular genetic mutation—they may have 1 copy of the mutation, one version of the gene with 1 copy of the mutation from one parent and a normal copy from the other parent—we refer to that as heterozygous when we see that. The phenotype is the clinical or physical presentation of the genotype in the individual. That may be a bit different, depending on the particular condition and how it may manifest. It all has to do with the inheritance of the disease and all of those things. 

[6:10] We have a couple of different inheritance patterns that we’ll talk about. The vast majority that we’ll talk about is autosomal recessive inheritance today; a dog would need to inherit two copies of the associated genetic mutation, one from each parent (and that’s an important consideration) in order to develop the disease or be at an increased risk of disease. But then also we’ll talk briefly about one particularly dominantly inherited mutation, specifically the DM Risk Modifier that I talked about a moment ago. In this case, with dominant mutations, dogs only need to inherit 1 copy of the associated mutation from a parent in order to develop the disease or be at an increased risk for a particular disease or trait. 

[6:50] First we’ll discuss Degenerative Myelopathy. There are now two known mutations, which are associated with DM in dogs. The first one is a very common mutation that’s now been found in well over 100 breeds of dogs. It was originally described in the German Shepherd, as we see here, but it has since been found in a lot of other breeds. I learned about this disease in veterinary school in the German Shepherd, and they’ve kind of been the poster child of this, but they are definitely not the only breed that’s affected, and we’ll go into more of that. Then there’s also a second mutation that’s only found in the Bernese Mountain Dog. So we’ll talk about that a little bit, too, and how that may impact a dog’s risk of DM. This is an autosomal recessive condition, so dogs do need to inherit either 2 copies of either one of these mutations, but we’ll talk about it in a moment. With this particular condition, dogs can also have 1 copy of each of these mutations, specifically in Bernese because they’re the only ones that inherit the second mutation. If they inherit 1 copy of each mutation, they can actually also be at risk of disease, and we’ll talk about that. But not every dog that’s technically at risk for DM will actually go on to develop clinical signs. We don’t fully understand all of that yet, but there seems to be some breed differences, and there may be some other genetic factors or environmental factors that are playing a role. As I mentioned, Bernese Mountain Dogs can experience something known as compound heterozygosity. This is a fancy way of saying that if they have 1 copy of each of these mutations, they can still be at risk for this disease. Some DM-affected dogs have been found to have a single copy of the mutation, 1 copy. The question is what’s going on in these dogs? Is it actually being inherited in a dominant fashion in these dogs? Are there other mutations in SOD1 that are playing a role? Are there other risk factors? I still think a lot of this needs to be worked out. Maybe it’s different for different breeds, as to why we may see this manifest in that way. But it’s not very well understood. 

[9:00] As I mentioned, there’s a lot of different breeds that are affected by DM. I kind of wanted to put these on here because it’s just pretty massive, and it can be pretty profound to think about. This is just the first half of the alphabet. But wait! There’s more! We’ve got the back half of the alphabet as well. A wide variety of breeds here. Most of these are going to be purebreds. There are maybe two in here that are not recognized by any breed club or only a couple of breed clubs, and there’s a couple of hybrids in here as well. All of these breeds are potentially at risk.

[9:32] When we look at DM, our typical age of onset is quite old: 7-10 years of age is most common, but it can be variable. There are dogs that present earlier than that. There are some dogs that present later than that. It may vary by breed. As we mentioned, the incomplete penetrance as well, where not every dog that inherits 2 copies of this mutation or these mutation goes on to develop disease. It likely does vary by breed and is due to a variety of other factors that are not fully worked out yet. The general disease process—when we talk about DM—is very similar to ALS (or amyotrophic lateral sclerosis, which is another name for Lou Gehrig’s disease in people). In fact, one of the genetic mutations associated with Lou Gehrig’s disease in people is actually a mutation in the same gene in humans. This would be one gene. It results in a progressive, noninflammatory nerve degeneration of the spinal cord and the peripheral nerves. 

[10:35] Clinical signs of this disease: when dogs do start showing clinical signs, the first thing we notice out of the gate is there’s usually some hind limb weakness. Over time, it does progress to involve all of the limbs, but in the beginning, it would typically only be the hind limbs involved. Usually after the first initial clinical signs are seen, between about 6 months and 2 years after the initial signs, dogs are not able to walk. In many cases, it’s before even a year that they’re no longer able to walk as this progresses. A lot of times, people will notice that their dogs—when they take them out for a walk—they may notice them dragging their feet slightly or may hear nails scraping on the sidewalk. You may notice, too, when we go through these clinical signs for these diseases—many of them are very, very similar across multiple neurological diseases. That’s true for a lot of neurological diseases. They may present in the exact same way, so it can be very tricky sometimes to determine exactly what’s going on when it comes to neurological disease. In many cases, general practitioner veterinarians will end up referring these dogs out to neurologists because it’s a very specific field that has a lot of nuances and, as I said, many of these dogs can present very similarly. So it’s nice to have somebody with a lot of experience to work through these. As I mentioned, the foot dragging. And there’s also abnormal foot placement that we see in these dogs. Sometimes they’ll have their legs out to the side or they may even stand with their legs crossed, which is unusual-looking. It’s due to something known as conscious proprioception loss, which essentially means that they don’t exactly know where their limbs are in space and aren’t able to keep them under them like a normal dog would. Over time, muscle atrophy will be seen due to loss of innervation or the proper innervation to these nerves. In the very late stages of disease (which is not seen incredibly commonly because, sadly, a lot of people may decide to euthanize their dogs prior to getting to that), they may also see urinary and fecal incontinence. If they’re not humanely euthanized, usually dogs —very similarly to Lou Gehrig’s disease—respiratory failure is typically the end point for them, due to paralysis of respiratory vessels, sadly. And presence or absence of pain and the progression—both of these can play a major factor in differentiating this disease from other diseases. It can be tricky, because there’s not a great test before these dogs die, to diagnose this with 100% certainty. That can be tricky. A few important factors about that is that DM does not result in pain itself. In addition to that, DM doesn’t come on suddenly. Sometimes I’ll get a phone call from someone that says, “My dog went down this weekend. He can’t get up. He seems to be in a lot of pain.” Those types of things. We would not expect that to be DM, although they may be calling in sometimes, looking for DM testing, because they know it’s something that occurs in their breed. We wouldn’t expect it to be a very acute onset or have pain as a major component. DM also doesn’t wax and wayne in severity over time. DM will get progressively worse. But you wouldn’t expect them to have a really bad day, and the next day they’re going to be bouncing around like a dog again. That’s just not going to happen with this condition. But we do need to note that some affected dogs may have concurrent diseases that also result in pain. There can potentially be other factors that we have to rule out in order to know: Does this dog likely have DM or not? 

[14:17] As I mentioned, there’s no 100% reliable diagnostic test for DM prior to death, unfortunately. Typically what they would do is they would take a look at the spinal cord of these dogs, get a good microscopic analysis of the spinal cord. They’d be looking for particular factors that would play a role in this. They’d be looking for certain aspects of neuronal degeneration or certain characteristics there and myelin loss. Myelin is a very important substance that essentially covers nerves, as insulation in wiring. It helps a nerve transmission. A loss of that myelin can end up resulting in faulty nerve transmission and cause a variety of problems. The clinical signs of DM, in combination with genetic test results showing that the dog has 2 copies of the mutation, can be highly suggestive of DM. But we do have to think about other potential causes. There definitely are other potential things that can result in similar clinical signs. These are just a very short list of things that could potentially play a role. Intervertebral disc disease is very common, specifically type 2 IVDD is the old age version of IVDD. This is different than if you’ve watched some of my other presentations. We talked about chondrodystrophy and IVDD type 1 that occurs in those dogs with slightly shorter legs and those types of dogs. This is more likely to be type 2 in these cases, where dogs are basically developing IVDD because of old age. Spinal tumors and infections of the spine can also result in somewhat similar signs. Spinal stenosis or narrowing of that spinal canal can result in these things. There can also be musculoskeletal disease, especially things like hip dysplasia or other arthritic conditions in older dogs that may make them have clinical signs that are similar to some of the signs of DM. Other neurological conditions and stroke. There are a lot of possible disorders that end up resulting in somewhat similar signs, so it’s really important to get the others ruled out. 

[16:30] I mentioned earlier, with the Bernese Mountain Dog, we have this phenomenon known as compound heterozygosity. The definition that I got here from the Internet from this site I’ve linked here is that “the presence of 2 different mutant alleles at a particular gene locus, 1 on each chromosome of a pair.” I wanted to show how this might manifest. Let’s just say that both of these dogs here that I have notated are Bernese Mountain Dogs. We have a dog here, the sire on the left, that has 1 copy of the original common DM mutation on 1 copy of the gene. The other gene that it got from its other parent is actually normal. Then we have a dam here that has 1 gene that is normal again. But the other gene for this particular Bernese Mountain Dog has the Bernese Mountain Dog-specific mutation in the same gene as the mutation that the sire carries. So when dogs are bred, each parent is going to give either 1 or the other gene to each of the offspring, so in this particular case, if the sire happens to give this version of the gene to the offspring, and then the dam gives this one, you can have a situation where the offspring has 1 copy of each mutation. These are both in the same gene, so this dog doesn’t have a normal copy of the gene. This is a major concern with Bernese because if you happen to do a genetic test for either one of the specific mutations alone, you may just think that your dog is a carrier when in actuality they actually have the other mutation as well. It’s important for us to consider both of these tests in any Bernese Mountain Dog, in any dog that has Bernese Mountain Dog in it. It would be particularly important. 

[18:09] So how often do we see the specific genetic mutation? Well, I’ve accumulated some of the data that we have at Paw Print Genetics, but there’s a few caveats here about this that I want to go over a little bit. I took a look at the percentage of dogs identified as having 1 copy of the SOD1A mutation, the original common mutation in dogs. I also will have some information about the Bernese Mountain Dog and the frequency of their other mutation as well. I collected this data a couple of days ago. It is important to note that all of the breeds here have been self-reported by the client. So if they happen to accidentally put in the wrong breed or they typed in the wrong thing or something like that, we get some skewing of our data. In addition to that, our sampling is definitely not a random sampling of the population, which would really be needed if we really wanted to get the understanding of the overall frequency in the population at large. It would be really important for us to make sure that that random sampling from the breed. We actually have litter testing, so that can skew our numbers to some degree as well. Lastly, I’ve only included dogs—and I’m going to be giving carrier frequencies for all of these disease we talk about today—but I’m only including dogs from the list that have had a minimum of 100 dogs tested at Paw Print Genetics because we very well may have missed some dogs that are out there if we’re testing less than that. I just believe it’s a lot more accurate if we can at least get to 100 dogs in order to talk about these things.

[19:36] These are all the breeds that we’ve done testing on where we’ve tested more than 100 dogs. This is the carrier frequency of the SOD1A mutation here. As I mentioned, for the Bernese Mountain Dog, they also carry the SOD1B. We’ve seen in about 17.6% of the dogs we’ve tested have had this other mutation. Some breeds are definitely a lot more highly represented than others. Again, it’s important to note that this doesn’t necessarily mean that all of these dogs have the same likelihood to actually develop DM. There are some breeds that are much less likely. Some people may argue that some of the breeds couldn’t develop it at all. There’s a lot of discussion about French Bulldogs that have myelopathy and that they may not actually manifest this. Unfortunately, there hasn’t been any publications coming out that have looked at this yet. I’m really waiting to see some more publications from some of the people that aer working on this because I think it will be really beneficial for both the genetic testing community as well as breeders, to know what the actual true risk by breed might be. Hopefully, over time, we get some more of this information. But, as you can see, there’s a lot of different breeds that this could be a factor for.

[20:44] As I mentioned earlier, there’s also another genetic mutation, which has been discovered that is referred to as an “early onset risk modifier,” and it’s a mutation in the Sp110 Gene. It is a dominant modifier, so if a dog inherits 1 copy of this mutation, it can have an affect on them, but the prerequisite is that the dog also has to be at risk for DM because they’ve either inherited 2 copies of either of those mutations we talked about or, in the Bernese, inherited 1 of each copy. It was originally described in the Pembroke Welsh Corgi. We don’t really know anything about the effect of this mutation in other breeds at this point. But Corgis that were at risk for DM, meaning that they had two copies of that SOD1 mutation also had at least one copy of this modifier, were also at risk of developing DM at an earlier age than other dogs were. I also wanted to point out as well—I have these superscript numbers here, and these are referring to the references that I’ll have at the end of the talk today, so if there’s a particular disease that you’re seeing here that you’re interested in, just write down that number. When we get to the end, I’ll have all the references. If you want to take a look at anything yourself, you’ll be able to do that. With dogs that do have the mutation and are also at risk of DM, they had about a 77% chance of developing DM by 11 years of age in these Corgis. Dogs that did not have the modifier only had about an 18% chance of developing it by 11 years of age. You can see there’s quite a significant difference between those two groups when they actually inherited this. The mutation is only known to have a negative effect on dogs if they’re also at risk for DM. That is a major factor that we have to consider. And other breeds do inherit this mutation. We have found this mutation in quite a few other breeds, but at this time, it’s not really known if this mutation has a similar effect in other breeds or how significant that effect may be. We still have more to learn in that regard. It’s definitely something for us to keep an eye on, but we don’t exactly know what it means in other breeds outside the Pembroke. But I highly recommend anyone breeding Pembroke Welsh Corgis—if their dog is at risk for this, definitely this test would be useful. Bottom line is if we can prevent dogs from inheriting 2 copies of the DM-specific mutation and keep them from being at risk, then this mutation is not really going to be a significant factor either way.

[23:19] The next disease we’ll talk about is exercise-induced collapse. This is a disorder that’s been found in a whole host of breeds. There is one here on the list that I do want to make a quick statement about. We have Border Collie here, but I will say that Border Collies do experience a completely different form of EIC than any of these other breeds. Most Border Collies that have some collapse do not actually have this specific genetic mutation. We have actually found 2 dogs that were listed as Border Collies at Paw Print that were carriers of this specific mutation. We don’t really know much more about it than that. It here on our list, especially if there was somebody who really wanted to rule that out as a potential concern, then they could. But I will say the vast majority of Border Collies do not have this specific mutation in the DNM1 gene. I just like to point that out because occasionally we will have clients call and ask about that. It does seem to be a particular concern in Border Collies. This particular disorder is autosomal recessive again. So it will take 2 copies of the mutation, 1 from each parent, to end up showing most clinical signs. It does display incomplete penetrance, kind of like DM, where not every dog that inherits 2 copies of the mutation will develop it. It does have some variable expressivity, meaning that dogs that do collapse and have this episode may have different severities in how frequently they collapse or what physical activities they need to participate in to actually cause a collapse to occur. That penetrance, again, may vary by breed. There could be multiple risk factors involved that can play a role. 

[24:57] In terms of age of onset for EIC—this is definitely a disease that is most commonly associated with Labradors, but as you can see, there’s a host of other potential breeds that could carry it. Not all of them carry it in the same frequency. Some of these—as I mentioned, like the Border Collie—we may have found dogs carrying a specific mutation listed for those breeds, and we’re still trying to figure out, “Is this really a factor in these breeds to be worried about?” In some, it may not be a factor and it may be misattributed to breeds there. When it comes to age of onset for EIC, it’s most common in dogs before 2 years of age. That’s the most common. If they are going to collapse, most commonly they’ll collapse before 2 years. The average age is about 17 months in this one particular study. In that study, they found that of the at-risk Labradors, the dogs that had 2 copies of the mutation—83.6% of them collapsed by 4 years of age, so there may have been some additional dogs that had their first episode of collapse after that. But by 4 years, 83% of them did show that. This is specifically in Labradors. We don’t really have these numbers for other breeds. But in Labradors, this is what has been seen. In addition to that, 95.9% or greater than that percentage of Labradors that will collapse, they do so before the age of 4. There’s only a very small percentage that go on and collapse after that, if they’re going to collapse at all. The general disease process in this particular case is essentially dysfunction of the nerve signal transmission from nerve to nerve. The EIC, as I mentioned, has been reported in Labradors and other breeds without mutation. There actually have been quite a few Labradors that have been discovered to have a similar condition, but at this point, we don’t know the underlying cause of it. There are other breeds that have EIC-type syndromes or diseases that seem to be related to this particular mutation. 

[27:04] The clinical signs associated with this are fairly similar, though as I mentioned, they can be variable in severity. One of the earliest things you’ll see when they start to show some signs is an uncoordinated gait. Eventually, as the dog keeps continuing its physical activity, it may end up resulting in that eventual collapse. It’s most common in dogs after about 5-20 minutes of strenuous activity, but I’ve talked to some people that have had dogs that get so excited in anticipation of exercise or of hunting or of those types of things that they may even collapse getting out of the truck or before they even exercise, because they’re just so ramped up and they’ve built up this anticipation that seems to play into this as well. Dogs may drag their hind limbs as they’re starting to show signs of collapse. Hind limbs are going to just get weaker and weaker, especially if they’re really driven dogs, especially hunting. They may try to continue to carry out their paths but may not be able to do so, so they may drag their limbs behind them a short distance before they decide, “Okay. I’m going to go ahead and lay down here and collapse and stop fighting this.” Most dogs will remain alert in consciousness and will recover within 15-30 minutes, but there are some rare cases that can result in more severe clinical signs. There have been reports of dogs completely losing consciousness, especially if they keep going after the initial collapse. They can result in low muscle tone. We’ve seen significant confusion in these dogs and seizures. In rare cases, they’ve talked about death in some of these dogs, especially if they continue to push themselves after the initial collapsing episode has started. Collapsing episodes can be particularly dangerous, if they’re swimming at the time or participating in other activities where they really have to have full control of their movements in terms of their safety. It can be troublesome in that regard.

[29:01] I have a video here. Hopefully it will play for us. It may take just a minute to load here, but it is a video of a dog in a field trial situation that has EIC. Hopefully this will show up well over the Internet. If you watch this dog, you’ll notice with time, it starts to break down in the hind end and starts showing some significant weakness. This dog goes out on this hunt trail here. You can kind of notice the legs are starting to flail out to the sides a bit. The dog is starting to lose some strength back there. When the dog starts running towards us here, you’ll notice a really significant change in gait. It’ll start to fall down, just a touch. Here, he’s starting to have a very significant difficulty keeping those under him. It starts to get pretty profound here. You’ll notice that a couple of times, he’ll drag his legs just a little bit here at the end. He’s dragging them there. There he goes. It stops here before he fully collapses, but I would assume here that he probably collapsed shortly after this and needed some time to recover from that. 

[30:11] When it comes to EIC mutation frequency, all the same caveats apply here as well. These are the frequency that we’ve seen these mutations. There are 3 breeds here that, for one reason or another, had been associated with this particular mutation but we actually haven’t seen the mutation in the breeds. The Australian Shepherd—it’s not a breed that is typically recognized as having EIC but we did find some carriers of this mutation. Same is true for English Cocker Spaniels and Golden Retrievers. Not breeds that are traditionally thought of as having this disease, but we did find some carriers in similar testing. Maybe they were misattributed because the breeds were incorrect. It’s possible. One interesting difference here between the Cocker Spaniel (or the American Cocker Spaniel in English) is it does appear that the American Cocker Spaniel may carry this mutation, whereas the English Cocker may not. We may just not have tested bloodlines that have it. It’s hard to say. These are the only breeds here that we’ve tested more than 100 dogs on. Fairly frequent in some of these breeds.

[31:23] This next disease we’ll talk about is known as Juvenile Laryngeal Paralysis and Polyneuropathy (JLPP). It’s also been known as Polyneuropathy with Ocular Abnormalities and Neuronal Vacuolation (POANV). This is very similar. This particular one that we’ll be talking about today is a disease that is found in the RAB3GAP1 gene. It is autosomal recessive as well. Dogs would need 2 copies of this mutation to develop it. This particular mutation is known to affect Black Russian Terriers and Rottweilers, but there is another mutation in this same gene that has been associated with disease in the Alaskan Husky. So that is a very similar condition as well. 

[32:08] Age of onset for this particular mutation and this form of the disease is usually very early, usually within the first few months of life. It is typically after weaning for these dogs. The general disease process is very diffuse, generalized progressive nerve degeneration in the brain, spinal cord, and peripheral nerves. Both motor and sensory nerves are effected. It is so vast that it ends up resulting in a syndrome of clinical signs that are not specifically associated with the Polyneuropathy.

[32:30] Many other features associated with this as well. These dogs do suffer a very significant loss of innervation to the larynx, so they end up having laryngeal paralysis that ends up resulting in very loud, raspy breathing. It’s pretty obvious to recognize when they come into the exam room, as a veterinarian, because it is quite noisy. They may have a very uncoordinated gait and poor muscle tone and be very flaccid in the muscles. They develop hind-limb weakness. Some of these things are going to be things that you see with other neurological diseases, but they also have decreased reflexes. They have difficulty swallowing food, and in some cases, that can end up resulting in aspiration pneumonia, where they’re trying to swallow but they accidentally inhale that food. That can be absolutely devastating for a dog to develop aspiration pneumonia. It’s very difficult to treat. They have decreased esophageal motilities. Their esophagus may not have as much muscle tone as normal and may end up resulting in some challenges getting that food bolis (as it’s called) down into the stomach. These dogs often will have very small pupils (or miotic pupils) which can’t fully dilate, even in a dark environment. They may not reach full size. Some of these dogs have very small eyes (or microphthalmia) that is associated with the condition. They may suffer from something known as persistent pupillary membrane, which is actually a persistent membrane that attaches from the colored portion of the eye (the iris) and actually spans across the black area (the pupil) and attaches to the other side of the iris as well. You can see in these dogs, they also often develop cataracts. Sadly, this is a pretty severe disease and usually these dogs either pass away or are euthanized by 6 months of age, because it is such a significant disorder.

[34:31] It’s still too new to our PPG testing to assess the frequency in either breed. We haven’t tested enough dogs from either breed to get a good idea as to the frequency, but I thought this was a good one to discuss because it is a hot topic in Rottweilers especially. Actually, probably both breeds right now. Something to think about if you have any of those breeds. Right now, I couldn’t find any reliable estimates of the frequency in general population in either breed. Maybe they’re out there, but I couldn’t find anything specifically. 

[35:06] Here are some other somewhat similar diseases, other Polyneuropathies that we also test for at Paw Print Genetics in different breeds. They may have many of the similar clinical signs but could have different ages of onset or other factors. There could be some other disorders as well that also have some Polyneuropathy components as well, but these ones are the ones that are significantly marked as Polyneuropathy. 

[35:30] The next disease we’re going to talk about is known as Spinocerebellar Ataxia. This is a disorder that is very similar to another disorder that we’ll talk about in a moment called Late-Onset Ataxia that is also found in some of the similar breeds. We’ll talk about both of these and compare them a little bit. There’s one major factor for Spinocerebellar Ataxia. One clinical sign that seems to differentiate this a bit from the Late-Onset Ataxia that we’ll talk about in a moment. Spinocerebellar Ataxia, though, is caused by a mutation in the KCNJ10 gene. It’s also known as Spinocerebellar Ataxia with Myokymia, seizures, or both (SAMS). It is autosomal recessive, so it takes 2 copies of the mutation to develop the disease. There are several effected breeds: the Russel Terrier group, which is also the one associated with the Late-Onset Ataxia (we’ll talk about it in a moment). They do develop this disease, and there’s a couple of other breeds as well that have been found to carry this mutation as well.

[36:36] The age of onset for this in these dogs is about 2-6 months of age for this particular form of Ataxia. The general disease process is a general degeneration of nerves in the brain, specifically the cerebellum (which plays a really important role in motor control in dogs) and also in the spinal cord in connection to the cerebellum. It’s secondary, in this case, to dysfunction of potassium transport in the body from cell to cell. That ends up resulting in the degeneration of these nerves.

[37:03] Clinical signs: there’s a set of clinical signs that are very common in any disorder related to cerebellar dysfunction. The signs of Cerebellar Ataxia—you don’t necessarily have to have all of them, but these are all common symptoms or signs seen in dogs that have cerebellar dysfunction. An uncoordinated gait—again, this is something seen in many, many neurological diseases. It’s often referred to (in cerebellar disorder) as a “swaying” or “truncal swaying,” where the hind end seems almost unattached from the front end, where they may sway out from the sides, back and forth, and don’t seem in full control of where their body is at. They’ll definitely see some limb weakness in many cases. They can have poor balance and actually fall down because of that. They often will have this high stepping (exaggerated gait or movement) known as hypermetria. This is a common sign in cerebellar dysfunction, where they want to carry out a particular movement but the movement doesn’t stop exactly where they want it to. They may shoot beyond an intended goal of normal movement. When these dogs run, they may actually lift their legs up higher than you would expect or may have exaggerated movements. There are some other disorders of cerebellar dysfunction in both cats and dogs, where there’s actually an infectious cause in cats and dogs where they can have some really profound effects in this regard, where cats may try to jump on a toy and actually completely overshoot it because they don’t have that volume control in movement. Dogs with cerebellar dysfunction can also have involuntary eye movements, where they have some tremor to their eyes (also known as nystagmus), where the eyes will actually twitch essentially in their sockets there. Interestingly, this is also something that’s looked for in humans. When humans have been in drunk driving incidents, when they’re doing a sobriety test, they’re looking for something known as horizontal nystagmus because alcohol actually has an impact on the cerebellum and you can actually see this in those cases. So it’s kind of similar in that regard. This particular condition results in this involuntary muscle twitching, known as myokymia. It’s a very common thing seen with this condition. This differentiates it from that Late-Onset Ataxia that we’re going to talk about in a moment. This is a really important differentiating factor. They can also end up resulting in this rigid limb extension, where they actually have all of their limbs at full extension and can actually have a difficult time getting up. Those muscles may have a little challenge in the relaxation phase of the muscle contraction, causing issues there. Some of these dogs show excessive facial rubbing as well, trying to drag their face on the carpet or on furniture. It’s not fully understood what’s going on in those dogs. It may be possible that these dogs are experiencing some sort of neurological tingling or other sensation that is unusual to them. There are situations where that is assumed in some conditions, where dogs may chew at their feet and things like that. There has been some suspicion that maybe these dogs are feeling some tingling experience that is driving them crazy, so they’ll rub their face on things. And then seizures are also seen with this condition. In many cases, stress seems to play a role in the manifestation of those seizures. It is something that’s seen fairly commonly with this condition. 

[40:34] In terms of the mutation frequency for this condition, we haven’t found it in the Chihuahua yet, in our laboratory, but it does seem to be pretty common in the Russell Terrier group. We haven’t seen it in the Russell Terrier yet, but in dogs listed as Parson Russell and Jack Russell Terriers, we’ve found it. Also in that Toy Fox Terrier as well. With all the same caveats as before, this may not represent the whole population of these breeds. 

[41:05] That takes me to Late-Onset Ataxia, which is a mutation associated with a very similar condition. This particular mutation is only found (as far as we know, at this time) in the Russell Terrier group. At times, we’ll have somebody order testing and they accidentally order this test when they’re really looking for the Spincerebellar Ataxia, because this one tends to be a little bit less common, I believe. At least it seems to be less of a concern in these breeds than the Spinocerebellar Ataxia. It is autosomal recessive, meaning they have 2 copies of the mutation (1 from each parent) in order to develop it. Again, it is the Russell Terrier group that seems to be impacted by this.

[41:47] It’s considered Late-Onset Ataxia, but it’s only because it’s a little bit later than the other one. This is commonly seen between 6-12 months of age. The general disease process is somewhat similar in this disorder, but it doesn’t seem to have as much of an impact on the brain itself. It is more in the nerves and the spinal cord and brain stem and in connections going to the cerebellum, so it can result in very similar disorders but is a little bit different in terms of the clinical signs that would be seen when trying to describe this.

[42:25] The signs of this disorder, again, have all the same signs as Cerebellar Ataxia, with the gait and the weakness and the falling down and the exaggerated movements and also the nystagmus. And then these dogs, unfortunately, are often euthanized by 2 years of age because it is progressive, and people will often have quality-of-life concerns. 

[42:49] We have gotten to the point of testing more than 100 dogs in the Jack Russell Terrier and the Parson Russell Terrier. In the Parson Russell, we found it in about 20%, so a pretty high incidence in the dogs that we have tested. Really, both the Late-Onset and the Spinal Cerebellar Ataxia should really be on your list if you’ve got the Russell Terrier group. It may be an important factor. 

[43:18] Interestingly, there’s also a third mutation in the Russell Terrier group, which also causes a similar condition, but it’s neonatal in onset, so it’s very early—usually seen in about 2-3 weeks of age in these dogs. It results in a very severe, progressive Cerebellar Ataxia. We do not offer testing for this at Paw Print Genetics, currently, but it is offered at the University of Missouri. Most puppies are euthanized very young, due to quality of life concerns with this condition. This mutation has not been published in scientific literature, but the testing is available through the University of Missouri at this time. Again, it’s another consideration for that Russell Terrier group. I’m not actually sure the frequency of this mutation in the population, but maybe the University of Missouri has some more data if you’re interested.

[44:05] The last disease we’ll talk about today is a disease known as Neuronal Ceroid Lipfuscinosis 4A. It’s a mutation in the ARSG gene and is known as “Ataxia” by many breeders of these bully breeds that it is seen in. It is, again, autosomal recessive. The affected breeds here are from these bully-type breeds: the Pitbull and Staffordshire Terrier are the ones it’s most commonly seen out there, but in some of the other breeds (the Bull Terrier and American Bully), it’s also been seen.

[44:40] Age of onset is a little bit later. It has to do with the way that this disease manifests. First, the signs are common from 3-5, but it can vary. They can sometimes be a little earlier; they can sometimes be a little later. But it does take some time for this disease to manifest. The general disease process is something we refer to as a Lysosomal Storage Disease. This is a large group of diseases that are seen in dogs that are pretty common across the board. It results from a build up of storage material in the neurons. It’s secondary to a dysfunctional enzyme. The genetic mutation changes the shape of that enzyme and keeps it from being able to do its tasks, an enzyme known as Sulfatase. The build up of these products in those neurons end up resulting in a slowly progressive neuronal dysfunction and degeneration of the neurons in the brain, primarily the cerebellum. Again, another Cerebellar Ataxia. It does take a while for these products to build up in there, which is why (as I mentioned) the age of onset is a little bit later. It does take a while for those products to build up over the course of 3-5 years before they really start showing clinical signs of this.

[45:51] The clinical signs we would expect to see—again, all the same signs of Cerebellar Ataxia that we talked about before, but these dogs can also end up dealing with blindness, seizures. And as this disease progresses, it can get pretty profound for them. The affected dogs are often euthanized within 4 years of their initial clinical signs, due to quality-of-life concerns. There are rare dogs that may develop milder symptoms and may have a longer life span. They may not have a quite-as rapidly-progressing disease, for whatever reason, and may be able to carry out almost a normal life span, in some cases. 

[46:31] Again, here are those carrier frequencies for this particular mutation. Pretty high frequency for these breeds. It’d be a real important test to consider if you’re breeding any of the bully breeds. 

[46:44] Here we have a couple more. I’ve got this slide here showing other diseases that we test for at Paw Print Genetics that are also associated with Cerebellar Ataxia. There are some other conditions, too, that can have components of Cerebellar Ataxia because the disease also disrupts the cerebellum, but it may not be isolated to the cerebellum. There are a few different diseases that we test for there. 

[47:08] When it comes to NCLs or Neuronal Ceroid Lypofuscinosis, we actually have a lot of genetic mutations associated with this known in the world. So there can be quite a few different underlying mutations in different genes that are associated with a very similar clinical outcome. 

[47:27] As I mentioned earlier, we’ve got a whole list of references that covers the information that I’ve talked about today. I have two slides here as references, and I’ll keep both of them up for a few minutes, so if you see a particular disease that you want to know more about here and want to go back to the original publications that I took this information from, there is this information here. I’d be happy to keep these up here and happy to answer questions at this time. I know we probably have some on chat. 

MD [47:54] Thank you so much, Dr. Carl! And, yes, we’ve had a few questions come in. I’m just going to jump in. First of all, what is your opinion on DM in Miniature Aussies and breeding animals that are carriers? 

CC [48:09] Well, I think there’s reason to think that Australian Shepherds do develop DM. Again, we don’t know how likely they may be to actually develop it when they inherit 2 copies of the mutation. I think breeding carriers of any recessive genetic disease needs to be considered and really should be something that is encouraged when we do it responsibly. That’s the beauty of genetic testing—we can identify these carriers or dogs that have just a single copy of the mutation that are not expected to develop the disease in most cases. In DM, as I mentioned, there have been some dogs known to develop the disease when they only have a single copy, but it does seem much more rare that that’s actually the case. So I think, for the most part, unless you had reason to believe that that was occurring in your line, I think for the most part, breeding carriers of that mutation is very reasonable as long as you’re breeding them to a clear dog. It would be very unlikely in most circumstances that you’d actually have any of those puppies develop a disease. 

MD [49:06] This is related, very similar, which is just: What approach is recommended when you have a DM carrier but the breed is not known to be one that gets diagnosed with DM?

CC [49:17] It’s a tough question. This has been a hot discussion in French Bulldogs because there are some people that believe—and people with a lot of knowledge in this subject—that French Bulldogs may not be at risk. I don’t know yet exactly what to make of all of it because there just hasn’t been any publications released with great data to really support all of this, though they are finding that in many cases when they’ve done necropsis on French Bulldogs, for example, that have 2 copies of DM—it’s actually something that may have been causing the clinical signs in neurological disease that they see in them and it doesn’t necessarily seem to be associated with DM. It’s not an easy question to answer. Really, the only way we know of preventing this disease with much certainty is to prevent dogs from inheriting 2 copies of these mutations. Really, that could be best practice—across the board. On the other hand, we don’t want to limit genetic diversity. That’s a really important thing. We don’t want to remove dogs unnecessarily from breeding. We’re always balancing. There are definitely people out there that would say in a breed, like the French Bulldog, to not take that into account. I just haven’t seen all of that data yet to prove to me that this is absolutely not a risk. But I think that that’s possible for sure. I don’t mean to discount the people that are saying that out there. I just don’t have that data in my hands to really know how to address that. 

MD [50:48] We have a viewer, Polly, who says she has a dog affected by idiopathic epilepsy. Can you speak to any type of genetic testing for this condition that she should be looking into? 

CC [51:00] Unfortunately, there’s not much at all. There are a few breeds that do have some known epilepsy associated with it, but it’s very minimal. Idiopathic epilepsy—the name idiopathic implies there’s no underlying cause understood. Maybe at some point, that will no longer be idiopathic, if we start to determine this. Unfortunately, there’s probably many, many, many different reasons why dogs end up having seizures. Even though they all kind of look the same, there could be many underlying conditions or underlying genetic mutations that could end up resulting in seizure activity. Most dogs that develop idiopathic epilepsy will have their first seizure, quite commonly, between the ages of 1-6. It’s a very common time period where they’ll have that first seizure. If they have it before a year of age or after 6 years of age, there’s often an underlying cause that can be identified. But at this time, unless it’s a specific breed that has been known to have a particular mutation associated with a form of epilepsy or seizure activity, it may be near impossible to really know exactly what’s going on with that dog, or really know: Can I breed this dog, or do I? I highly recommend against breeding a dog that has seizure activity, but it gets a little bit more tricky when you’re talking about related dogs and whether to breed them or not because it’s just not known how that might be inherited or if it’s going to be passed on in any sort of predictable manner to the offspring. 

MD [52:30] Pam has a dog who was diagnosed with Kyphosis. I’m not familiar with this. Can you speak to whether or not there’s a genetic component to this disease? 

CC [52:41] There probably is. Kyphosis is an alteration in the actual formation of the spine, so it’s more of a muscular-skeletal condition that, in some cases, can result in neurological signs. There likely are genetic components to it, but at this time, I’m not aware of any specific genetic mutations which have been associated with it. At this time, there’s not really a way to diagnose or prevent it through testing. 

MD [53:10] Okay, we’re going to just keep throwing conditions at you. Do you know if there’s a genetic component to Chiara malformation and any chance of a genetic test in the future?

CC [53:20] There’s not anything yet. I am hopeful that something gets figured out with this and an underlying mutation or mutations are found. Unfortunately, for a lot of these types of skeletal malformations or those types of things, it seems to be complex from a genetic perspective, so it can be pretty tricky. I wish we did, because it is a major cause of neurological issues in dogs that have this malformation because they have issues related to the brain, even the cerebellum. There could be lots of issues related to that. At this time, unfortunately, I have not heard of any particular genetic test coming down the pipes. 

MD [54:05] What about Syringomyelia?

CC [54:09] Same situation, unfortunately. This person is probably a Cavalier breeder, because it’s really common in King Charles Spaniels. We just don’t have great genetic information about it yet. 

MD [54:23] Can you speak to how we can test neonates under 8 weeks of age? Can you do a swab with them, or do you need blood work?

CC [54:29] That’s a good question! Really, either will work. I usually recommend that puppies, if they’re going to be swabbed, we wait until they’re about 4-5 weeks of age for a couple of reasons. It’s important to consider isolating them from their litter mates and from mom and dad for about an hour prior to that swabbing. What we’re trying to do is prevent any contamination from mother’s milk or from other puppies, shared toys, those kinds of things that could have DNA on them that we might be able to pick up on those swabs. At 4-5 weeks of age, they’re starting to wean anyway. It’s going to be much less stressful on both mom and the puppies if we wait until that time period. So it definitely can be done without blood. Blood’s also another good option. A lot of times, people are really concerned with taking blood from their young puppies, but it can be done for sure. It’s actually another great source, but it doesn’t have to be the only source. Those swabs will also be really effective as well. 

MD [55:27] Great. I’m going to try to squeeze in a few more questions. 

CC [55:31] While we’re answering this next one, I’ll put this up here, too: the coupon code for Good Dog there: GDOG21. That can help people get either 40% off any order with us at Paw Print or 50% off if you order an entire disease panel. Also, my contact information. Please feel free to send me an email or give me a ring during business hours. I’m happy to chat with you if you have other questions we didn’t get answered today. You can also send me a friend request on Facebook. I’m not going to blast you with a bunch of ads and those types of things. It’s mostly for me to be on there as another source for people. You can contact me and send me messages on there. If you need a quick response, email or phone is usually better. 

MD [56:17] That’s awesome. Thank you for being so generous with your time. That’s great. This might be the last question: Linny wants to know if Osteochondritis is always genetic.

CC [56:30] Probably. It probably does have a highly genetic component, but it’s not been well worked out. Osteochondritis is a condition in which we get inflammation in the joint associated with the cartilage not being quite properly formed in dogs. It’s not exactly a neurological disorder, but definitely a muscular-skeletal disorder. It is likely highly genetic, or inherited, but there may be some other components that we don’t understand. There could be environmental components to that, perhaps, or dietary things, those types of things. At this point, it hasn’t been very well understood from a genetic perspective. 

MD [57:14] Thank you so much! I want to remind everybody that we have all of Dr. Carl’s previous webinars with us on our website, GoodDog.com. He’s done talks on coat color genetics, eye disease, IVDD. You may have some of your questions answered by viewing those amazing webinars. This one will be presented on our website very soon as well. Don’t forget to sign up for our health symposium, happening September 18th. It’s free. The link is somewhere in the chat, so please feel free to register. We hope to see you there. Dr. Carl, I want to thank you once again for your time and expertise on this amazing topic. Thank you. Hopefully, we will have you back again soon! 

CC [57:59] Feel free to give me a ring or send me an email! I know there’s probably a lot of questions out there that didn’t get answered, so please feel free to send those to me, and I’ll get back to you as soon as I can on that. Hope you all have a great day! Stay safe out there! Hopefully, we’ll get to see each other again soon here.