GM1 & GM2 GANGLIOSIDOSIS

 

GM1 and GM2 GANGLIOSIDOSIS

The following document has been distributed to all Korat breeders and lovers via the Koratworld Mailing List and given to all interested people who have asked about it. Another more technical document is also available which describes the GM1 Gangliosidosis in Korats, written by Dr. Massimo Castagnaro (Turin University - Italy) that can be found here. (title of the document: Beta-galactosidase deficiency in a Korat cat: a new form of feline GM1-gangliosidosis)

WHAT IS GM?

We would like to tell you about two inherited diseases which affect our Korat breed. Actually, these diseases have been observed in other cat breeds but, they are critically important to Korat breeders. Unless a program is established to identify and eliminate carriers, these gene defects will actually become more frequent and if left unchecked, could jeopardise our breed. Some Korat breeders have experienced these diseases and are anxious to find a way to detect carriers. The good news is that such a solution has been found - a gene analysis for carriers.

The gangliosidoses are inherited diseases of a category known as lysosomal storage diseases because they affect the cell compartment which functions to recycle chemicals, including the gangliosides which are vital for normal brain cell function. There are two types of Gangliosidosis based on which ganglioside, GM1 or GM2 accumulates in lysosomes. The most obvious signs in affected cats are neurological. In GM2 gangliosidosis the signs generally start earlier (2 months of age) and progress more rapidly. In GM1 gangliosidosis neurological signs start a little later (3 months) and progress at a slower rate. Affected kittens have head tremors at the beginning, followed by impaired co-ordination of leg movements which eventually lead to paralysis. If allowed to progress to terminal stages seizures may occur. Diagnosis is by clinical signs, laboratory tests and pathological lesions in brain. The most useful tests are urine tests for the presence of complex sugars (not specific), an enzyme assay of white blood cells or a skin biopsy (specific but not entirely reliable for carrier detection). The results must be interpreted by someone experienced with these diseases and the diagnostic tests. There are also specific changes found at the light microscopy level of cats that die or are euthanized. There is no specific treatment for these diseases.

Although both types of gangliosidosis cause fatal progressive brain disease, they are caused by entirely different genetic errors of two different lysosomal enzymes. Therefore, a genetic test must analyse each disease independently. GM1 gangliosidosis is due to an inherited deficiency of the enzyme beta-galactosidase and has been studied and characterised in Siamese, and other cats, but has been recognised only very recently in Korats by Dr. Massimo Castagnaro of the Veterinary University of Turin, Italy. GM2 gangliosidosis is due to an inherited deficiency of the enzyme beta-hexosaminidase and has been observed in Korats and other cats. The GM2 mutation in Korats is different than the one causing the same disease in non-Korat cats. The Gangliosidoses also occur in other species: dogs, cows, sheep and humans. In humans GM2 is known as Tay Sachs or Sandhoff's disease. Although several different errors can occur in an enzyme gene which may cause these diseases, each species and breed has unique mutations, meaning that a genetic test can be designed to look for only the two Korat mutations (GM1 and GM2).

HOW TO DEAL WITH CARRIERS?

All gangliosidoses are inherited as autosomal recessive traits. The "autosomal" part means that males and females are equally likely to inherit the disease gene. The "recessive" part means that cats which inherit only one copy of the disease gene appear normal, but "carry" the disease gene which can be passed on to their kittens. When two carriers mate, only 25% of kittens which have two defective genes may show neurological disease. More importantly, when two carriers mate, or even when carriers and normal cats mate, HALF of all their kittens will be carriers. This is the reason that recessive traits like the gangliosidoses are so dangerous. Matings between carriers and normals is actually the most dangerous because even though enormous numbers of carriers are produced, a diseased kitten is never born, consequently there is no reason to even suspect that the mutation is present in a family. For this reason, anyone who believes that the mutations may not be present in their cats simply because they have not seen a diseased kitten might be lead to a critically important false conclusion. Carriers appear to be healthy cats that live long and normal lives, but should not be used in breeding programs with the possible exception that they may be used to preserve a particular trait, but then only if all kittens are tested and only those which are genetically normal are used for breeding. A genetic test might allow such selective testing. The only way to accurately identify the genetic status of cats which have not delivered a diseased kitten is by DNA analysis.

HOW TO ELIMINATE GM FROM OUR CATS?

A DNA analysis for carriers of Korat GM1 and GM2 has been developed by Dr. Henry Baker and his colleagues at the Scott-Ritchey Research Center at Auburn University. Dr. Baker, who was the first to describe a gangliosidosis in cats, has been studying these diseases for more than 20 years. It must be understood that GM1 and GM2 gangliosidosis are two different diseases caused by different defects which affect two separate genes, even though their names and the clinical symptoms of the diseases are similar. Therefore, it is required that both tests be performed and found negative before any Korat can be said to be free of these diseases. Molecular testing for these diseases is somewhat complicated. It starts with DNA extracted from a small blood sample (1cc). Through a process called polymerase chain reaction (PCR) the lab amplifies a portion of the genes containing the mutation of interest. After many amplifications, the sequence of the DNA coding for the subject gene is read, much like reading a sentence which contains many letters arranged into words. They look for a "spelling mistake" in the genetic code which identifies the mutation of interest. Some times the spelling error involves only one letter in one word of a sentence (gene) that contains 2,500 letters! In other mutations, large portions of the sentence are deleted or rearranged. Affected cats have no normal gene, they have two copies of the mutant gene. Carriers have one copy of the normal gene and one copy of the mutant gene (appear normal, but may pass a disease gene to kittens). Cats with two copies of the normal gene, are genetically normal and safe to use for breeding. Dr. Baker is offering to make DNA testing for both diseases available as soon as he has discovered the exact mutation of Korat GM1. Dr. Baker intends to offer testing for breeders in North America and Dr. Castagnaro has agreed to test samples from breeders in Europe. When testing for both mutations is possible, Korat breeders will be instructed about how to request testing.

CREDITS

The above document has been prepared and signed by the following Korat breeders:

and has been reviewed and approved by:

The above document, as well as others about this same subject, has been translated in different languages that are available on request.
For this reason I want to express my gratitude to the following Korat Friends:

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