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Lafora’s – the story of the search for the gene


Lafora’s disease was first recognised and described by veterinary neurologist Sue Fitzmaurice in 1996 (for Sue’s biography click here). After learning about the disease from Sue, Clare Rusbridge diagnosed a few cases and, anxious to find a better treatment for them, read the human literature on this rare disease. She stumbled upon the work of the eminent scientist and neurologist Dr Berge Minassian who made his life’s mission  investigation of Lafora’s disease and bettering the understanding and treatment of this fatal disease. Dr Minassian works at the Sick Kids hospital in Toronto, Canada and had already discovered two distinct genetic mutations causing Lafora’s in humans.

Clare Rusbridge contacted Dr Minassian and so begun a ground breaking collaboration between human and veterinary medicine. Sue Fitzmaurice and Clare Rusbridge collated their clinical information and arranged for DNA samples to be sent to the Toronto Hospital. Subsequently Dr Minnasian was able to determine that the dogs did not have the human mutation. This was exciting as it meant that finding the distinct mutation in the dogs would ultimately lead to much better understanding of Laforas and why suffers of the disease were not able to produce the protective protein malin E3 ubiquitin ligase. However it did mean considerably more work as to find the genetic mutation in the dog would require extensive familial studies and therefore help from dog breeders.
In 2002 Dr Minassian visited the Miniature wire-haired Dachshund (MWHD) breed club in the UK. The breeders, after hearing of the plight of human Lafora sufferers, offered enthusiastic support for the project. Subsequently, several breeders provided pedigree information and DNA samples from their dogs. Clare Rusbridge’s research assistant Penny Knowler coordinated much of the DNA collection and pedigree analysis. Dr Diane Shelton from the University of California provided vital help because she had stored the original muscle biopsies sent by Sue Fitzmaurice and Clare Rusbridge to aid diagnosis of the early cases. This muscle was used to extract RNA essential to identify the gene.
Finally in 2005 the Toronto based team at was able to announce to the world that the genetic mutation causing the disease in MWHD and the Bassett Hound had been discovered (BBC News Friday, 7 January 2005) The results were published in Science magazine. The discovery of the first genetic mutation causing epilepsy was not the only scientific advancement as the mutation causing canine Laforas was also the first description of a repeat-expansion disease outside humans. The Toronto based team with the help of Elaine Ostrander  (who pioneered work on the dog genome) were able to identify a dog specific dodecamer repeat (that is a 12 nucleotide sequence which repeats) and was unstable. Expansion of the repeat resulted in disease. The team traced the repeat origins and determined that was the consequence of two successive events, starting 50 million years ago, that was unique to canine evolution. 
Work on Lafora’s disease continues and researchers are particularly grateful to veterinary surgeon Suzanne Baxter who has donated valuable tissue samples from her own pet Dachshunds after they died from the disease. These and other tissue and cell samples are vital for furthering understanding the disorder. Dr Hannes Lohi who did the considerable sequencing work on the Lafora gene is continuing to work on the genetics of canine epilepsy in particular Benign Familial Juvenile Epilepsy in Lagotto Romagnolo Dogs and inherited epilepsy in the Finnish Spitz dog.
In the UK, the Wirehaired Dachshund Club launched a DNA screening program for Lafora Disease in Miniature Wire-haired Dachshunds in Spring 2010. As of March 2012, Nearly 300 dogs have been submitted for testing , but the proportion is still quite low in comparison to the total population. If you are in the UK and have mini wire dachshunds, or know anyone with mini wires, who intends to breed, it is important for the future health of the variety that those dogs are tested in this program. UK based breeders and owners of MWHDs wishing to have their dogs tested should contact:

Nora Price: E-mail tel: 01543 276797