Chiari-like Malformation and Syringomyelia Research

The Friends of Lola Fund is supporting the canine genome research into CMSM. Chiari-like malformation (CM) can be a painful condition and is considered to contribute to syringomyelia (SM) in the Cavalier King Charles Spaniel. These two conditions in dogs are often seen together. CMSM is a neurological condition with a complex inheritance involving more than one gene. The initial research results suggest that two or more genes interact to produce the disease. The canine CMSM genome research is divided in to two parts. The search for the syringomyelia gene/s in the Cavalier King Charles spaniel and the search for the chiari gene/s in the Griffon Bruxellois. This research is underway in the griffon because unlike 99% of cavaliers, griffons do not all have chiari -like malformation.

Progress so far on the syringomyelia CKCS genome research includes:
Identification of an area on the chromosome for SM associated with CM in the cavalier.
Identification of a haplotype (small group of linked genes which harbour the variant) that infers protection against SM
The next step is for a wider dense SNP coverage and candidate gene sequencing.

The progress so far on the chiari-like malformation genome research involving griffons has:
Identified 2 possible sites of genes on the chromosomes (candidate loci) which are thought to be involved with chiari- like malformation.

The next step is the fine mapping of the candidate loci (analysis of the chromosome area in greater depth) and candidate gene sequencing (to decode genes that might be involved).

Philippe Lemay, BSc
Philippe is a Biochemistry graduate from Sherbooke University who is now studying for his Masters in Biochemistry at Montreal University.

He has been a research student in Dr. Zoha Kibar’s Laboratory at the CHU Sainte Justine Research Center, Montreal since January 2010 and is responsible for the genotyping, sequencing and bioinformatic analysis of the genomic data for the Brussel Griffon project investigating canine Chiari-like Malformation (CM).



One possible candidate gene has been completed called Fibrillin. Fribrillin-1 has already been associated with genetic conditions that involve misshapen skulls including Marfin syndrome and Shprintzen-Goldberg syndrome (the defects in this syndrome include CM). Fibrillin has been suggested as a possible positional candidate gene. It is a very large gene coding for an amino acid which is a constitutive element of extra cellular micro fibrils in connective tissue. Fibrillin-1 sequence analysis in affected CKCS, Yorkshire Terriers, Bull Terriers, Boston Terriers, Chihuahuas, King Charles Spaniels and Griffon Bruxellois is ongoing.

Research into understanding various aspects of CM/SM has been carried out by several researchers worldwide. In the UK Dr Clare Rusbridge is a leading researcher into chiari-like malformation (CM) and syringomyelia (SM) in cavaliers. In Canada Dr Zoha Kibar with Dr Guy Rouleau is undertaking the genome DNA research. In the USA Dr Simon Platt is researching CM/SM in the Griffon Bruxellois (Brussels Griffon).

Since 2004 the CM/SM genome research has been underway. The International Research Team believe CM/SM is polygenetic. This indicates that CM/SM is controlled by different genes which may affect one another in particular ways. There appears to be separate genes for CM and SM. Finding the gene’s involved in this complex trait is very challenging because studies suggest some environmental influences are also involved. Another problem is the 'late onset' nature of SM (it is a progressive condition and dogs may show no signs for several years).

The Genome Researchin Canine CM/SM is currently lead by Dr Zoha Kibar and Dr Clare Rusbridge. The mammoth task of finding the genes was initiated by Dr Rusbridge and Dr Guy Rouleau whose laboratory is at CHU Sainte Justine Research Centre in Montreal Canada. The DNA collection has been ongoing since 2004 and many individual owners and veterinarians worldwide have contributed, funding the MRIs mostly themselves. Additional CKCS DNA samples have been provided by North Carolina University and Guelph University in conjunction with their own investigations into CM/SM.

In 2010  Genome wide linkage studiesidentifies a novel locus for syringomyelia associated with chiari-like malformation in the Cavalier King Charles Spaniel. This states that researchers have identified an area on the cavalier genome that is highly likely to be the genetic site specifically for SM, and that this area is unaffected in clear dogs.In the Cavalier King Charles Spaniel the continuing work on this project is to hone in on the fine mapping of the genes, to determine in as much detail as possible, exactly where this is happening.

CMSM in Griffon Bruxellois - research in this breed initially investigated chairi-like malformation because, unlike 99% of Cavaliers, Griffons do not all have chiari-like malformation. A radiograph study of the skull identified abnormalities and this study underpinned an investigation at Georgia University ‘The MRI, Clinicopathology and Prevalence’ funded in part by the American Kennel Club Canine Health Foundation. The USA team is led by leading researcher Dr Simon Platt and in collaboration with Dr Rusbridge and Dr Kibar, the project will also provide additional DNA and phenotypic information to investigate chiari-like malformation . The team have already identified the part of the chromosome where the gene/s are located.

The Griffons Bruxellois and other breeds which have been identified with CM/SM play a critical role in the identifying the gene/s for CM. The Fine mapping now underway requires more DNA from Griffons WITHOUT CM, and DNA from other breeds WITH and WITHOUT CM/SM. The gene’s are involved in the development of the skull and brain and understanding what goes wrong will help ALL breeds with CM and SM.

If you're living in the USA and are a Brussels Griffon pet owner or  breeder, and you would like your dog to help in the DNA research, please contact Dr Simon Platt for further information on the free MRI

 

Dr Simon Platt, BVM&S MRCVS Dipl. ACVIM (Neurology) Dipl. ECVN, Associate Professor Neurology Service, Department of Small Animal Medicine & Surgery, College of Veterinary Medicine, University of Georgia, 501 DW Brooks Drive, Athens GA USA 30602                           Tel: 706 542 3221 Fax: 706 542 6460 Email: srplatt@uga.edu

 http://www.vet.uga.edu/hospital/smallanimal/neurology/syringomyelia.php#qualify

Application form  http://www.vet.uga.edu/hospital/smallanimal/neurology/bg_syringomyelia_application.pdf

Dr Simon Platt shares - "the on going research in to syringomyelia and chiari - like malformation in the Brussels Griffon is proving extremely valuable to the international DNA genome research. There are still places available under the grant for which we will still need more dogs of any age to help us establish the answers to many questions about this condition."


Chiari-like malformation and syringomyelia in children and adults

The Ann Conway Trust is a charity which supports children and adults who suffer with the condition of CM/SM. The Trust has taken a keen interest in the syringomyelia research in our beloved dogs. There is hope that the syringomyelia and CM/SM  DNA research in our dogs will help in finding solutions to human sufferers. Please consider the Anne Conway trust in your charitable donations. The Ann Conway Trust have made generous donations to syringomyelia research in our dogs. They have donated to our cause because they believe finding the gene's in  dogs may help them too. You can follow the work of the trust and read personal accounts of humans living with CM/SM at http://theannconroytrust.org.uk/.