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This article appears in the January/February issue of the ALBC newsletter. ALBC members receive 6 bi-monthly newsletters that contain articles about the breeds of livestock and poultry that we work to conserve as well as the people involved in these efforts. Members also receive an annual breeders directory that provides contact information for ALBC members who have breeding stock available, as well a list of products from these breeds that they offer for sale.

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From the January/February 2009 ALBC Newsletter:

Jacob Sheep Shed Light on Tay Sachs Disease
by Fred Horak

The American Livestock Breeds Con­servancy has long been committed to conserving genetic resources and diversity in livestock and poultry so that a genetic warehouse will be available for the future of agriculture. Conservation of our genetic resources rests on individual commitment, and successful stewardship of our agricul­tural inheritance rests on people working together. We usually think of genetic con­servation as saving the “good genes.” This is a unique situation involving the conser­vation of “bad genes” in a rare breed with a story that may not have an ending for several years. The story includes a wide cast of characters: Jacob sheep, shepherds, doctors, scientists, and moms and dads and their afflicted children. The story needs more characters: Jacob sheep breeders and some special Jacobs.

Unconfirmed suspicions: In 1999, Fred and Joan Horak of St. Jude’s Farm in Lucas, Texas, took two lambs to Texas A&M University suspecting an acute case of a skeletal congenital defect known as occipital condylar dysplasia. Researchers at the University of Missouri had described this congenital defect several years earlier as a genetic problem in Jacob sheep, but the source of sheep used in the study were not disclosed. Because congenital de­fects in any breed should be identified and monitored for the health of the breed, Fred and Joan planned to disclose the suspected skeletal problem they encountered and the familial source so other Jacob breeders could avoid similar problems.

An unusual suspect: The pathology department at Texas A&M called with two messages about the Horaks’ lambs: first, the defect was not occipital condylar dysplasia but a lysosomal storage disease; second, would they be willing to have a team from Texas A&M visit to draw blood from their other sheep, collect tissue samples, and review their pedigree records to identify the source of the disease? The Horaks agreed. While Fred went with Drs. Katherine Bretzlaff and Barbara Lewis to draw blood and collect tissue, Joan met with Dr. James Womack to review the pedigree records of their flock. At the end of the day a prime suspect source was identified as the sheep Turner 183K. How­ever, more breeding and DNA tests had to be done to prove the source, and the nature of the lysosomal disease had to be identi­fied and proven.

There are various types of lysosomal disease, a congenital disease that, in sim­ple terms, can be characterized as the ab­sence of an enzyme that breaks down the waste product from the spinal cord-brain connections. The buildup of waste affects the brain and leads to loss of coordina­tion, appetite, and sight; recumbency; and, eventually, death. The confirmation of the disease was good news and bad news: the sheeps’ pedigrees ran back to foundation Jacobs, but the foundation stock carried a defective gene. A congenital defect in a foundation ram, in a bottleneck breed rep­resenting a gene puddle rather than a gene pool, was a concern.

The long engagement: Between 2000 and 2004, Fred and Joan continued to breed suspect carriers and non-carriers so Texas A&M could verify their findings and identify the type of disease. They hoped Texas A&M would be able to identify the specific type of lysosomal problem and de­velop a “test” to identify carriers and make it available to concerned Jacob breeders so the congenital defect could be eradicated with minimal loss of genetic diversity. Over the years, Fred and Joan kept and bred carriers, and brought affected sheep to Texas A&M for testing, but finding the lysosomal type and the specific enzyme seemed elusive. What was known and confirmed was that the defect was a simple recessive gene and the source was Turner 183K; possible additional carriers arose but were unconfirmed.

In December 2002, Fred sent an article to the Jacob Sheep Conservancy, Jacob Sheep Breeders Association and ALBC de­scribing the lysosomal disease, symptoms, and source and asked for Jacob breeders to report any suspect cases. There were some reports of “sickly” lambs that died or were butchered, but breeders did not deem these remarkable and cause of disease or death was not confirmed, and animals dying from congenital problems are often buried in unmarked graves. As the years passed, Fred and Joan kept a remnant of the car­rier group and hoped for a breakthrough in identifying specific lysosomal type and that a test for carriers might be found. Since the Jacob breed is not commercially significant, hope for breakthrough research had low priority.

The human element: When Dr. Porter of Texas A&M called Fred in the summer of 2008, Fred expected it to be another “nothing new, no time or money for research on a disease in Jacobs” type call. The news was stunning: according to Dr. Porter, the lysosomal disease in the Horaks’ Jacob sheep was exactly the same form as a lysosomal disease fatal to children: Tay-Sachs disease. Further, Texas A&M had developed a test for poten­tial carriers. Dr. Porter then asked if the Horaks still had potential carriers in their flock. Hearing a “yes”, Dr. Porter said he would visit them in a couple of weeks to draw blood to be sent to Dr. Edwin Kolod­ny, Chair of the Neurology Department at New York University Medical Center, for DNA and enzyme tests. The carriers were identified and confirmed.

Dr. Kolodny is a member of the Tay-Sachs Gene Therapy Consortium founded in 2007 (www.tsgtconsortium.com), a group of research scientists in the U.S. and U.K. with the goal of initiating a state-of-the-art gene therapy clinical trial for Tay-Sachs disease in the next four years. Tay-Sachs disease has various forms: infantile (fatal at age 5), juvenile (fatal at 15) and late-onset (about age 30 but debilitating rather than fatal). In addition, there are about 40 Tay-Sachs-type related human diseases including epilepsy, muscu­lar sclerosis, muscular dystrophy and even Parkinson’s disease. Currently, Tay-Sachs and many of these related diseases are incurable, and some are fatal. The genetic similarities between sheep and man and Tay-Sachs and other neurological diseases are as close a match as we may ever get.

Another member of the Consortium, Dr. Miguel Sena-Esteves of the Massachu­setts General Hospital and Harvard Medi­cal School remarked: “The goal of identi­fying and eliminating Tay-Sachs in Jacob sheep in order to conserve the breed is a noble goal. But we who are working on a human gene therapy cure are very happy that you did not succeed and kept the car­riers for the last decade. These sheep are genetically significant.”

The arrangement for your involvement: Additional Tay-Sachs carrier sheep need to be identified so a sufficient number of af­fected sheep can be placed in gene therapy trials. The Horaks have given their carrier flock of eight Jacobs to the Consortium and Dr. Kolodny has offered the lysosomal carrier test at no cost to all Jacob sheep breeders. Why test? For the sake of finding a cure for human disease and conserving the breed. Who should consider testing for the defect? Jacob breeders who have sheep descended from Turner 183K; Jacob breeders who have had lambs dying be­tween the ages of six and nine months that show signs of loss of coordination, ataxia, loss of appetite, blindness, or recum­bency; Jacob breeders who want to know that a sheep is not a carrier of this lethal defect and be able to pass that assurance on to other breeders. To become involved, contact Dr. Edwin Kolodny by email at Edwin.Kolodny@nyumc.org.

Breed conservation does represent a genetic warehouse from which we may need to draw in the future. Part of the task is to identify how each of us can add to the content of the warehouse.
Jacob

Fred and Joan Horak live in Lucas, TX and manage a flock of 60 Jacobs including 10 rams. Fred has written a number of articles about effective populations, inbreeding and congenital problems in Jacobs. More information on naturally occurring Tay-Sachs and Jacob sheep may be found on the Internet or by contacting FHorak@aol.com

This abstract was presented at the American College of Veterinary Pathologists Natural Disease Specialty Group on 11/16/08.