The epilepsy these dogs suffer from is called Lafora disease (LD) in humans. In LD, the normal glycogen of neurons is somehow changed to starch. As in potatoes and rice, starch is insoluble and accumulates in the neurons in LD, specifically in neuronal dendrites. Whether the massive starch formations in dendrites simply physically interfere with their normal functions leading to epilepsy, or whether there is energy starvation in the dendrites due to accumulation of neuronal glucose into these starch molecules is unclear. In humans, it takes approximately 15 years for enough of this starch material to deposit within the billions of dendrites, before the seizures start. When they do start, nothing can stop these fits, and the patients suffer horrible intractable continuous epilepsy leading to dementia and death within a few years. LD is seen in a number of dog breeds most notably the miniature wirehaired Dachshund and Bassett hound. The most common sign, starting between 5 and 9 years of age, is a myoclonic jerking, typically a rapid backwards movement of the head, the jaw snapping shut or chattering and rapid eyelid blinking. The myoclonus occurs spontaneously, during sleep and in response to noise, flickering light, and sudden movement in the visual field. Many dogs also develop epilepsy. The myoclonus and seizures may worsen with time and older dogs may become blind and uncoordinated compelling the owner to euthanasia. There is a more severe version of the disease in other breeds for which the mutation is yet to be found.
The research team at the University of Toronto previously discovered two genes for the human disease. The first, EPM2A, encodes the protein laforin which helps to protect normal mammals against the formation of starch compounds in the brain. The second is EPM2B (NHLRC1) a gene which encodes malin E3 ubiquitin ligase. How this protein, normally involved in protein destruction and recycling, is integral to Lafora disease is still an important puzzle. The principal finding of the current research is that dogs are predisposed to developing a mutation in the Epm2b gene. This predilection has stemmed from two evolutionary events one ~60 million years ago when canoids and felines diverged, and the other between 50 and 10 million years ago when canoids diverged into canids (dogs, wolves etc) and arctoids (bears and related carnivores).
The predisposition is in the form of a 12 nucleotide sequence repeated three times in the dog Epm2b gene. This repeat tends to expand once in a while, which destroys the gene. This is not a problem in a large gene pool however when the mutation becomes frequent e.g. because of a historically popular breeding dog(s) then the chance of two destroyed copies of the gene increases. Absence of Epm2b then results in LD. In the UK, more than 5% of miniature wirehaired dachshunds have the disease, and the carrier rate is probably close to 25%. This discovery can now help lovers of this breed to eliminate the disease by being able to diagnose carrier and affected dogs.
This discovery is also important for developing successful treatment of Lafora disease in both dogs and humans. The research team do not plan to experiment on dogs however the veterinary and medical teams are learning from some successful experiences in treatment of seizures in the dogs and applying them to humans and vice versa.
The study appears in the 7 January 2005 issue of the journal Science.
Any further enquires please feel free to contact:
Stone Lion Veterinary Centre, 41 High Street Wimbledon. Tel: 020 8946 4228
Wey Referrals, Woking, Surrey, GU21 5BP. UK
Dr Berge Minassian
Division of Neurology, Department of Pediatrics, Department of Genetics Room 6536B, Hospital for Sick Children, 555 University Ave, Toronto, Ontario, M5G 1X8 Canada. Tel: 416-813-629
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