Here is a Prime Example of what National Clubs do!!

[gemy]

Many of us whether breeder members or non breeder members be it that we are in the USA or Canada, will contribute to this funding of this important research.

As you can read this is a devastating genetic recessive disease. It is imperative we find a genetic test as soon as possible.

This is a very important part of Protect and Defend the breed we all sign up for when we join a National Club.






Juvenile Laryngeal Paralysis & Polyneuropathy

September 2013

The BRTCA Officers, Board of Directors and members of the Health Committee are pleased to announce that the first major Health Initiative undertaken by the BRTCA will be a research project conducted by Dr. Dennis O’Brien, DVM PhD and Gary Johnson, DVM PhD, at the University of Missouri to research finding a genetic marker for Juvenile Laryngeal Paralysis & Polyneuropathy (JLPP) in Black Russian Terriers.

While JLPP is by far not the most common problem affecting the breed, we feel that it is the first area to concentrate on because of the devastating effects of JLPP, with a 100% mortality rate in affected puppies. There is no treatment to offer and all will die at between 4-6 months of age. The disease is difficult to diagnose so the true incidence is unknown, as the deaths are generally attributed to respiratory failure, such as pneumonia, which is secondary to the disease. We are just now in the infancy stage of seeing this disease in the United States; however, we know that carriers are present and we feel that it is imperative to find the genetic marker before an explosion of cases develop now that these descendants are of breeding age.

Description:
The effects of the disease are first seen in the larynx and throat. Affected pups appear to develop normally, but shortly after weaning age they develop difficulty breathing caused by paralysis of the muscle in the larynx (voice box). The muscles fail to pull the vocal folds out of the way when the dog inhales causing a wheezing sound as air flow into the lungs is restricted. The paralysis rapidly progress to the limbs and if the pups have not succumbed to pneumonia first, they ultimately are totally paralyzed and humanely euthanized.
JLPP appears to be an autosomal recessive hereditary disease. That is, each parent must be a carrier of the gene. Recessive genes, whether they deal with conformation traits or genetic defects, can stay hidden for generations.

Incidence:
There is conclusive lab diagnosis of JLPP occurring in three litters in the United States. JLPP is also suspected in two other United States litters and one litter in Canada. Dr. Obrien has information on two affected litters in Europe.
Of big concern is that the pedigrees of the documented litters are showing some common lineage which includes some very famous and popular modern lines. Remembering that recessive genes can stay hidden for generations, there are many litters with these ancestors here and around the world that are just coming to breeding age.
Without a genetic test, the only way to know if a dog is a carrier is after the disease shows up in a litter. Being a simple recessive inheritance, the statistical odds for an average litter where both parents are carriers are: 25% affected (1-3 pups will die), 50% carrier, and 25% clear. However, more could be affected and die and more could be carriers. More carriers in the breeding pool will increase the probability of producing affected litters in just a few years.
Dr. O’Brien believes that this recessive gene has probably been in the breed from its early days, but is just starting to concentrate enough to show up more and be recognized as a genetic disease.
Until a marker and DNA test are developed, there is no way, short of diagnosing an affected puppy, of identifying parents as carriers; and surviving puppies of carriers may themselves be unknown carriers that may eventually become part of a breeding pool.
The awareness of JLPP in Black Russians has been as a direct result of a few dedicated individuals who recognized a potential genetic problem and took the initiative to make a difference. This is an opportunity for the BRT Community worldwide to step up and work together for the future of the breed.

Funding
Funding is a major issue. This study will cost $12,000. The study will yield benefits beyond this JLLP project because all of the genetic data will be mapped and can be used in other studies.
BRTCA has already contributed $5,000 to the University of Missouri towards the study. Additional funding will need to be raised through direct donations and other fundraising events.
It is our hope that the BRT Community will donate to this much needed research project. Donations may be made by check or through the “donation PayPal” link on the website http://www.brtca.org/juvenile-laryngeal-parylasis--polyneuropathy.html. This study needs to happen as quickly as possible, so that these carriers can be identified. It is too important to the future of the breed to delay it any longer.
Items that can be sold through the Website to raise funds dedicated to this important research project as well as items donated and ear-marked for the Auction and Raffle at the upcoming National will also be accepted. Our ability to fund this project has been the direct result of the successful nationals we have held and ask you to support our continued efforts to raise funds for health research.
Please do whatever you can to help and circulate to any other BRT owners who you may know.

Checks can be mailed payable to: Black Russian Terrier Club of America, Inc.
607 Idyllwild Rd.
San Jacinto, CA 92583
Additional information on the study and JLPP will be in the next issue of the Footnotes and BRTCA website.

BRTCA Board of Directors and Health Committee

[gemy]

JLPP MUTATION IDENTIFIED---DNA TEST COMING SOON!!
It has just been a little over one year ago that BRTCA took on the financial undertaking to fund research by Dr. Dennis O’Brien and the University of Missouri, College of Medicine to find the genetic mutation responsible for Juvenile Laryngeal Paralysis & Polyneuropathy (JLPP) in Black Russian Terriers.
The BRTCA board and Health Committee are thrilled to report that researchers at the University of Missouri, College of Veterinary Medicine, working with collaborators around the world, have FOUND the mutation associated with JLPP in our breed!!
Your donations and contributions to JLPP fundraising efforts have resulted in a tremendous accomplishment for our breed’s future, as well as other breeds that may also be affected by JLPP.
The Orthopedic Foundation for Animals is in the process of updating its website and the lab is getting the DNA test optimized for increased volume of testing. They are predicting that everything should be ready to roll out by the end of this month. Check the OFA website at http://offa.org/. What this means is that DNA testing for JLPP will very, very shortly be available! A notice will be sent out as soon as we know that OFA is ready to begin JLPP DNA testing.


The kit is now available just go to the above organization for ordering details.

[gemy]

I thought to ask Phil in private my questions about this genetic test; how-ever for the few members who are interested in genetic tests, and the truly exciting world of how science based studies can help we breeders eradicate a genetic disease or two; I will ask them here.


Phil: I will have the opportunity to speak directly with Dr O'Brien as he is the guest speaker at our Banquet dinner during the BRT Nationals.


I think my overweening question is on the reliability of a test that seemed to be so quickly developed? I don't know if a research paper has been published yet, so I can't link you to the research.


What are the other types of questions I should be asking?


I do hope your weekend is going well, and Bella is thriving

[pstinard]

Originally Posted by gemy

I thought to ask Phil in private my questions about this genetic test; how-ever for the few members who are interested in genetic tests, and the truly exciting world of how science based studies can help we breeders eradicate a genetic disease or two; I will ask them here.

Phil: I will have the opportunity to speak directly with Dr O'Brien as he is the guest speaker at our Banquet dinner during the BRT Nationals.

I think my overweening question is on the reliability of a test that seemed to be so quickly developed? I don't know if a research paper has been published yet, so I can't link you to the research.

What are the other types of questions I should be asking?

I do hope your weekend is going well, and Bella is thriving

Hi Gail,

Here is a link to a recent article on genetic testing for neurological disorders in dogs by Dr. O'Brien that came out just this year, and is NOT behind a paywall:

DNA Testing in Neurologic Diseases - O'Brien - 2014 - Journal of Veterinary Internal Medicine - Wiley Online Library

It doesn't specifically reference the new test for JLPP in BRTs, but it gives a good general background and is fairly readable to the lay person.

This paper does mention tests for polyneuropathy in Table 3. There are two different genes mentioned, and several breeds of dogs, but not BRT's specifically. Maybe one of these two genes is affected in BRT's with JLPP? Here is a copy of the part of Table 3 about polyneuropathy:

Polyneuropathy - NDRG1 - c.1080_1089del10 - Greyhound

Polyneuropathy - NDRG1 - c.293G>T - Alaskan Malamute

Polyneuropathy, LPN1 - ARHGEF10 - c.1955_1958+6del10 - Leonberger & St. Bernard

So, the questions I would ask Dr. O'Brien are:

(1) Which gene is the new test measuring? Is it NRDG1, ARHGEF10, or some other gene?

(2) What is the test measuring? Is it a change in the DNA, RNA, or the protein?

(3) What type of sample is collected? (I'm guessing it's probably blood, but it could be a cheek swab.)

(4) How reliable is the test?

(5) What is the cost?

Please look over Dr. O'Brien's paper and let me know if you have any other questions. Maybe we can think of something else you could ask Dr. O'Brien. How soon is the dinner?

PS--My weekend is going well. The weather here is chilly, but sunny and dry. Tomorrow I'll be raking leaves. Right now, Bella is curled up on the back of my legs, warming herself .

[gemy]

Originally Posted by pstinard

Hi Gail,

Here is a link to a recent article on genetic testing for neurological disorders in dogs by Dr. O'Brien that came out just this year, and is NOT behind a paywall:

DNA Testing in Neurologic Diseases - O'Brien - 2014 - Journal of Veterinary Internal Medicine - Wiley Online Library

It doesn't specifically reference the new test for JLPP in BRTs, but it gives a good general background and is fairly readable to the lay person.

This paper does mention tests for polyneuropathy in Table 3. There are two different genes mentioned, and several breeds of dogs, but not BRT's specifically. Maybe one of these two genes is affected in BRT's with JLPP? Here is a copy of the part of Table 3 about polyneuropathy:

Polyneuropathy - NDRG1 - c.1080_1089del10 - Greyhound

Polyneuropathy - NDRG1 - c.293G>T - Alaskan Malamute

Polyneuropathy, LPN1 - ARHGEF10 - c.1955_1958+6del10 - Leonberger & St. Bernard

So, the questions I would ask Dr. O'Brien are:

(1) Which gene is the new test measuring? Is it NRDG1, ARHGEF10, or some other gene?

(2) What is the test measuring? Is it a change in the DNA, RNA, or the protein?

(3) What type of sample is collected? (I'm guessing it's probably blood, but it could be a cheek swab.)

(4) How reliable is the test?

(5) What is the cost?

Please look over Dr. O'Brien's paper and let me know if you have any other questions. Maybe we can think of something else you could ask Dr. O'Brien. How soon is the dinner?

PS--My weekend is going well. The weather here is chilly, but sunny and dry. Tomorrow I'll be raking leaves. Right now, Bella is curled up on the back of my legs, warming herself .

Thanks Phil. Test cost is $65 Dinner is one week from today:-)

[Yorkiemom1]

This is a FABULOUS utilization of this forum!!!! Thank you Phil for your contributions helping we breeders as we try to stumble around finding research results that as you know, are snug behind a paywall and out of our reach, short of a HUGE subscription rate or fee! Thank YOU too Gail, for your involvement in this noble breed and the issues that affect it......and for keeping fellow breeders up on genetic testing and markers.....all invaluable for the progression of our breed's health!

Phil, I try to keep up with genetic markers on liver shunts....communicating with Dr.Tobias and her research team.....I dont want to pester her or them, but I do check in with her and her associates about every 3-4 months....we are close, but no brass ring as of yet. If you happen to have your ear to the ground some day, or your eyes on the skies, and you catch wind that the genetic marker for liver shunt has been identified, which of course will lead to availability of DNA testing of our breeding stock, please be so kind as to let us know!!

[gemy]

Phil one more question for you: I have heard that with designer breeds, it is difficult to develop genetic tests for, and if done, there are not the same degree of reliability with? Do you know if this is an accurate statement or not? And if it is on what basis is it so difficult to develop genetic tests for designer breeds.


Is their a quick mathematical formulae, that can be constructed that would take say the stats of diseases that the offa records by breed type - let us say the Yorkshire Terrier and the Maltese and develop what would be the risk of a disease when you cross a YT with a Maltese?


Say as the offa shows YT as the number 2 breed for LP at I think 46% and off hand I am not sure with the Maltese at IDK say 30% is there a way to project what the cross is at risk for?


This is important I feel if scientifically there is some reliable way to offset the highly touted *fact* that designer breeds are healthier than most purebreds etc etc.

[pstinard]

Originally Posted by Yorkiemom1

This is a FABULOUS utilization of this forum!!!! Thank you Phil for your contributions helping we breeders as we try to stumble around finding research results that as you know, are snug behind a paywall and out of our reach, short of a HUGE subscription rate or fee! Thank YOU too Gail, for your involvement in this noble breed and the issues that affect it......and for keeping fellow breeders up on genetic testing and markers.....all invaluable for the progression of our breed's health!

Phil, I try to keep up with genetic markers on liver shunts....communicating with Dr.Tobias and her research team.....I dont want to pester her or them, but I do check in with her and her associates about every 3-4 months....we are close, but no brass ring as of yet. If you happen to have your ear to the ground some day, or your eyes on the skies, and you catch wind that the genetic marker for liver shunt has been identified, which of course will lead to availability of DNA testing of our breeding stock, please be so kind as to let us know!!

I'll try to remember to search the literature every month or so to keep on top of things. Thanks for the reminder!

[pstinard]

Originally Posted by gemy

Phil one more question for you: I have heard that with designer breeds, it is difficult to develop genetic tests for, and if done, there are not the same degree of reliability with? Do you know if this is an accurate statement or not? And if it is on what basis is it so difficult to develop genetic tests for designer breeds.


Is their a quick mathematical formulae, that can be constructed that would take say the stats of diseases that the offa records by breed type - let us say the Yorkshire Terrier and the Maltese and develop what would be the risk of a disease when you cross a YT with a Maltese?


Say as the offa shows YT as the number 2 breed for LP at I think 46% and off hand I am not sure with the Maltese at IDK say 30% is there a way to project what the cross is at risk for?


This is important I feel if scientifically there is some reliable way to offset the highly touted *fact* that designer breeds are healthier than most purebreds etc etc.

With respect to genetic testing of designer breeds, I'm going to speculate that the reason that it is difficult to design tests for them is because they are not a pure breed--they are a cross between two other breeds. Therefore, you'd have to have a test that works for both breeds that make up the designer breed. Let's use Labradoodles as an example, which are a cross between a Labrador and a Poodle. If you have test that works in a Labrador and not a Poodle, you might be out of luck testing a Labradoodle.

The answer to your second question about taking the risks of a disease in two separate breeds to mathematically determine the risk of disease in the hybrid is definitely no. There are far too many unknown interactions that would occur between the genes in the two separate breeds once they are brought together in the hybrid to make a simple determination. Maybe someday when all of the genomes of the different breeds are sequenced, they will come up with a complex formula to figure it out, but I bet it will take a supercomputer to do the math.

You are right, it's definitely not a "fact" that designer dogs are healthier than the individual breeds. This is a generalization based on outdated concepts of hybrid vigor, and it does not take into account the interactions between the genes of the breeds going into the cross. Designer breeds are like a box of chocolates--you never know what you'll get .

[pstinard]

Doing a little detective work, I think I was able to find some more information about the genetic test for JLPP in BRT dogs. First, there is the description of the disease on the University of Missouri website:

JLPP

Juvenile Laryngeal Paralysis & Polyneuropathy (JLPP) in Black Russian Terriers


Recently, Dr. Nicolas Granger reported a syndrome in Black Russian Terrier pups in Europe characterized by difficulties breathing and weakness shortly after weaning age. We have now seen affected dogs in the USA. The purpose of this article is to provide information about the condition so that breeders and veterinarians can be alert to any future cases and help us find the gene responsible.


What is Juvenile Laryngeal Paralysis & Polyneuropathy?

The brain controls muscles via signals that travel through nerves. A disease that affects the nerves is called a polyneuropathy: poly- (many), neuro- (nerves), -pathy (a disease). Due to a quirk in the way an embryo develops, one of the longest nerves in the body supplies the muscles of the voice box (larynx). The vocal folds vibrate as air moves over them allowing a dog to bark. When the dog breathes in, muscles in the larynx pull the vocal folds aside so that air can move easily into their lungs. These nerves also help to close the larynx when the dog swallows so they do not choke on their food.



If nerves are unable to convey messages properly, the muscles become weak or paralyzed. The longest nerves are often affected first; hence laryngeal paralysis is the first symptom. The vocal folds cannot be pulled out of the way as the dog breaths in. They vibrate noisily and can obstruct the flow of air into the lungs particularly when the dog is exercised or hot. The dog may also choke on their food or water or regurgitate, which can result in pneumonia.



The next longest nerves in the body go to the back legs, thus they are affected next. The dogs have difficulty getting up and wobble as they walk. Eventually the front legs will also be affected. The symptoms do not occur until after weaning age, and thus the disease is called juvenile laryngeal paralysis/polyneuropathy or JLPP for short.

I was able to find a paper that came out just a month ago that describes these very symptoms in Leonbergers and Saint Bernards, and this paper also cites the Nicolas Granger paper:

PLOS Genetics: An ARHGEF10 Deletion Is Highly Associated with a Juvenile-Onset Inherited Polyneuropathy in Leonberger and Saint Bernard Dogs

I'm not sure whether this article is behind a paywall, but if it is, let me know, and I will quote parts of it. The paper describes JLPP in Leonbergers in a very similar way as that described in BRT's by the University of Missouri people. They describe the mutation and how they test for it in Leonbergers and Saint Bernards. A good question for Dr. O'Brien would be, is the BRT mutation the same mutation as that described in Leonbergers in this paper?

[gemy]

Thank you Phil

[gemy]

Thank you Phil your questions went over very well at the talk with Dr O'Brien


He was reluctant to disclose the actual gene, due to if I understood him correctly maybe Patent issues or some such necessity for confidentiality.


The test is very reliable. The confidence value is not published yet, but will be soon.


We had a great talk afterwards, as I exploredwith him the relatively recent availability of genetic testing for HD, and if the science might move forward more quickly now to find it for our other breeds so affected.


Once again my thanks for your help and your expertise!

[pstinard]

Originally Posted by gemy

Thank you Phil your questions went over very well at the talk with Dr O'Brien


He was reluctant to disclose the actual gene, due to if I understood him correctly maybe Patent issues or some such necessity for confidentiality.


The test is very reliable. The confidence value is not published yet, but will be soon.


We had a great talk afterwards, as I explored with him the relatively recent availability of genetic testing for HD, and if the science might move forward more quickly now to find it for our other breeds so affected.


Once again my thanks for your help and your expertise!

I understand his reluctance to discuss the gene involved--I'm sure that will be revealed after it is published or patented. I'm glad that the event went well .