Hi all:

I passed along the key points of the comments on syringomyelia and inheritance put forward by Bet Hargreaves -- the main elements that were included in a recent editorial she has posted elsewhere (Rod Russell has posted regarding this editorial here: http://www.cavaliertalk.com/phpBB2/viewtopic.php?t=844 ), and additional comments posted elsewhere regarding whether 10 families of cavaliers would be needed to get any useful insight into inheritance. These points were put to Zoha Kibar, the molecular geneticist in charge of fine mapping and identification of the gene(s) defective in SM for the CKCS genome scan currently underway in Canada. Here is her reply below; crossposting is permitted. A reminder that for those interested in this and other subjects, there are two lists for detailed discussion of SM issues, CKCS-SM and the SM Breeder Support List (breeders only); info on these available here: http://sm.cavaliertalk.com/2005/10/s...ion-lists.html ).


Chiari Malformation (CMI) in humans with or without syringomyelia has been shown to segregate in families, suggesting the involvement of genetic factors in the development of this malformation. The number and identity of these genes remain to be determined. The heritability i.e. the relative contribution of genes vs environment is also not known. In the CKCS breed, dogs were bred for their shape (including their head) and this could explain the presence of this malformation in almost 100% of this breed. Syringomyelia is present in around 60% of human CMI cases suggesting the presence of other factors, genetic and/or environmental, that interact to modulate the incidence and severity of the symptoms.

In the CKCS, I tend to think it is the same story. Clare Rusbridge and Penny Knowler’s study tracing back the affected dogs to one founder and to 6 of 8 grandparents represents strong evidence for the presence of aÂ*founder effect in this breed. Clare Rusbridge is planning to study other determinants in the MRI-ed group and I think this is a very good idea. Not all cavaliers have this SM problem and this is where tracing back to a founder with a disease (i.e. with a mutation or mutations) pinpoints the spreading of this disease to descendents and its high incidence.Â*Founder effects are well-established genetic forces that lead to a disequilibrium in the genetic pool. I am sure all cavaliers will share other traits more than distantly related breeds.

Would SM develop stochastically e.g. the way the dogs are treated as pets? Given the similar incidence in human cases, I doubt this is the case. If the environment is the major culprit, what do these dogs that develop SM have in common?Â*These are not easy questions. In the genome scan, I have included dogs with CMI and with or without SM hoping to be able to identify modifiers. If these modifiers have a small contribution, we will not be able to map them using this approach.

Would MRI-ing 10 families help understand the genetics of SM in this breed? If a detailed MRI is done with the other research ClareÂ*Rusbridge is suggesting to do, that could help. Otherwise, I doubt it. It is more complicated. And what about the age of onset? An MRI study of 10 families would definitely not give a definitive answer.

I understand the fear of genes, which we cannot change, as opposed to environmental factors, which we can (to a certain extent). But unfortunately this trait seems to involve both. Breeders should understand that our study will not be the magic solution that will help them identify dogs that will not develop SM for breeding purposes (at least not in the short term). But identifying a gene will open the door to understanding pathways involved in the development of this disease and hopefully in the long run, a cure for these suffering dogs. Of course we are also interested in the biology.Â*Irrespective of the complexity we are dealing with, we have to try to understand the disease with the tools we have and hence the genetic approach. And irrespective of this complexity, and if we don’t want to think about the multifactorial etiology, the breeding protocol scheme Dr Rusbridge came up with is the best solution for now. Then later we can deal with the causes.

(Zoha Kibar has been appointed as the molecular geneticist in charge of fine mapping and identification of the gene(s) defective in SM in the CKCS breed. Zoha pursued her postdoctoral studies at McGill University working on a mouse model for neural tube defects (NTDs) in humans. She is interested in identification and characterization of the molecular basis of congenital malformations of the central nervous system, particularly NTDs and Chiari malformations and she is planning to pursue her career as an independent researcher in this field.)>>