GM1 & GM2 GANGLIOSIDOSIS
Korat Gangliosidosis Screening Program
Update May 1st, 1999
Written by Dr. Henry J. Baker
Presented during the 1st "United Korats of the World" Meeting in Odense (DK) on May 8th, 1999
This report provides a summary of the latest results of the Korat Gangliosidosis Carrier Screening Program sponsored by the Scott-Ritchey Research Center.
We received the first samples for testing in March 1998 and currently we are processing sample number 263, which translates to 526 separate tests, since each sample is tested for both GM1 and GM2 gangliosidosis. Samples have been received from 80 Korat breeders in 11 countries including: Australia, Belgium, Canada, Denmark, Finland, Great Britain, Germany, Italy, Norway, Sweden and the United States. This high level of participation is really quite remarkable for a program that is barely a year old and makes this a truly international Program.
Of the 260 tests completed to date, we have detected 40 GM1 carriers and 12 GM2 carriers. Therefore, the total carrier frequency rate for both mutations approximates 20%. Only one country (Great Britain) appears to be unaffected, so far. To provide some basis for comparison, human GM2 gangliosidosis (Tay Sachs disease), which was first described in 1881 and is considered to be one of the most common inherited human diseases, has a carrier frequency among American Jews of Eastern European origin of 1 in 30, or 3% and in the non-Jewish population only 1 in 300 or 0.3%. The possibility that as many as one in every 4 breeding Korats is a carrier of one of the gangliosidoses is staggering!
In addition to the very high carrier frequency, these results provided a few additional surprises. First, GM2 gangliosidosis has been known as an inherited disease of Korats for more than two decades, although until now the actual magnitude of the problem had not been determined. Second, GM1 gangliosidosis was not even known to exist in Korats until early last year, but it is clear from our sampling to date that GM1 appears to be by far the more important of the two mutations, in terms of the breadth of family lines affected. Thus far, we have not found a single Korat who carriers both mutations, which is very good news, since such "compound heterozygotes" would add materially to the complexity of the problem and could slow elimination of these diseases.
A few other observations fit more into the category of satisfying, rather that surprising results. The strong leadership of the few breeders who took the initiative to start this Program has been the keystone from which progress has been built and these foresighted Korat breeders are congratulated and thanked. Their example lead directly to the remarkably high rate of participation that we are experiencing. Continued success of the Program must be attributed to the 80 breeders who comprehended the gravity of this problem for the Korat breed and who made the effort to determine which cats are effected, so that the continuing spread of these dangerous mutations can be stopped. The additional strong leadership provided by breed associations and registries who have emphasized the importance of testing and who organized sample submissions, demonstrate the best of community spirit, leadership and cooperation. I admire and applaud the forthright attitude of most breeders who share their results, happy and sad, with others in the spirit of a unified effort to eliminate the gangliosidoses from the breed. We predicted that testing a relatively few Korats could have far reaching effects in detecting carriers because the power of pedigree analysis can compound the test results enormously by identifying the carrier status of parents, grandparents and siblings. This benefit of compounding is beginning to be realized and will become even more powerful as the number of family lines tested increases. Finally, I am certain that the rapid success and international impact which this program has enjoyed would not have been possible without the Internet and nearly universal use of email. I have personally met less than a dozen of the 80 participants, but feel a kinship to all and hope to become personally acquainted with every one.
There have been a few features or refinements added to the Program recently. When the Program started, we received blood samples from USA and Canadian participants, but because we were unsure about the reliability and speed of shipment, some samples from other continents were processed to the more stable DNA before shipping. We learned that DNA extraction from cat blood is sufficiently different from other species that most laboratories are not uniformly successful in the DNA extraction process and as a result we spent much time and effort trying to use some of these samples without success. In several cases, bloods had to be redrawn. It is clear now that overnight delivery service provided by most carriers, and relatively easy compliance with United States import requirements make it unnecessary to do any processing outside of our laboratory and whole blood can be submitted from any of the participating countries.
In consultation with several Korat breeders who helped launch this Program, we have developed an official certificate which verifies test results. We will continue to report results by email so that owners will have access to this information as soon as possible, but the Certificate is recognized as the formal document for verifying the gangliosidosis status of any Korat. We have just begun to issue these Certificates and we have quite a backlog of results to report, so we ask for your continued patience as we work through the certificate preparation process as quickly as we can. To facilitate processing official certificates of test results, we have developed a "Sample Submission Form" to accompany new samples. This form has been accepted readily and substantially aids in our record keeping. In fact, we cannot process Certificates unless all of the information on the Sample Submission Form is provided. We encourage your comments about these documents and welcome suggestions for improvement.
In the early months of this Program, some participants experienced substantial delays in receiving results largely because of the flood of submissions, and a few technical problems. The last 50 samples which have been processed required an average of less that 30 days, and we anticipate that this response time can be reduced even more.
When it became apparent that the very high carrier frequency rate would not allow simple removal of carriers from the breeding pool because of the genetic bottleneck that could result, we offered to assist breeders who wished to breed known carriers to known (tested) normals by testing all kittens. As many as 50% of kittens from these mating will be normal and available to perpetuate the best characteristics of that family line, while carriers should be neutered and used as pets. That strategy is being adopted by a few breeders and based on the limited experience that we have accumulated to date, it appears to be working well.
What does the future hold? I am optimistic that based on the enthusiastic participation experienced to date and the self imposed or organized restrictions placed on breeding Korats for whom the gangliosidosis status is not known, it is possible to substantially reduce the carrier frequency rate or even eliminate these diseases from the Korat breed entirely! It may not be widely appreciated, but this screening Program is actually an historical event. In fact, never before in veterinary medicine has molecular diagnosis been applied so widely and successfully in an attempt to eliminate an inherited disease from a pure breed. If this Program is ultimately successful, it will be the first time that inherited diseases have been systematically controlled or eliminated from a pure breed through an organized testing program. Not only is this achievement possible, it is likely if the current Program is followed. I predict that this historic "experiment" will be imitated many times in the decades ahead and may become the standard procedure to control inherited diseases, in much the same way that vaccination is now the standard for controlling infectious diseases.
We continue to use direct genetic sequence analysis for detecting carriers. Although this method is tried and true it is laborious, time consuming and expensive. Therefore, we are developing other methods that can be more easily adapted to high throughput processing which will reduce processing time and expense. I will report progress in this research when we are able to begin field testing. As almost everyone knows, the Scott-Ritchey Research Center has underwritten the entire cost of developing and operating this program. I estimate that the Center invested approximately $30,000 as of the Fall of last year when the first 150 samples had been processed. We continue to perform these tests without charge because it remains a developmental project and because the need and the success of this Program are so apparent. However, the Center must find sources to offset at least some of the heavy financial burden if the Program is to continue, as it must!
Finally, I wish to acknowledge and thank my colleagues of the Scott-Ritchey Research Center who form the team which has made this Program successful. My professional partner, Dr. Bruce Smith is a talented veterinarian and molecular biologist who spearheaded the discovery of the normal cat genes involved and their mutations. He and I independently analyze each test result as a safeguard against misinterpretation. Dr. Alex Samoilov is a molecular biologist who is responsible for sequencing every specimen and helping us work through any technical problems that might arise. Mrs. Samantha Kwasigroh preforms the DNA extraction and amplification prior to sequencing and coordinates all of the many, varied steps in the process from receipt of blood to preparation of sequence tracings for interpretation. Dr. Polly Foreman, a veterinary student, served a Research Fellowship for two summers in the Center and assisted in defining the GM1 mutation in Korats. This team also forms the core of scientists who continue to develop new and improved methods for molecular testing. We all look forward to continued operation of the Korat Gangliosidosis Screening Program and working with all of the fine Korat breeders world-wide.
Dr. Henry J. Baker
Questions should be addressed to Dr. Henry Baker and samples should be sent to:
Dr. Henry J. Baker, Director - Scott-Ritchey Research Center - Auburn University - Auburn, AL 36849
voice: 334-844-5951 - fax: 334-844-5850 - email: email@example.com - Website: http://www.vetmed.auburn.edu/srrc