Norwich Terrier Club
On-going AHT Research Project
18 December 2009

Please read this current Report carefully, particularly the end section which is printed in red.

Canine Genetics Progress Report

Breed: Norwich Terrier

Condition: Epileptoid Cramping Syndrome

Date: 18.12.2009

Recent / Current Funding:

The project is currently being funded, in part, by the LUPA project ( www.eurolupa.org ), of which the AHT is a participant, and by donations from individuals.

The AHT is studying the genetics of an epileptoid cramping condition in this breed, in the hope of identifying the mutation(s) responsible.

Sample Collection

Sample Collection has been progressing very well. We have collected samples from 243 Norwich Terriers, of which around 50 are reported by their owners or their vets to suffer from ‘epilepsy' or ‘cramps'. We continue to collect samples from affected dogs and their close relatives. The affected dogs we have collected so far are all relatively closely related to one another, and all descend from a single founding dog within 5 or 6 generations, which is indicative of an inherited condition.

 

Additional Information Needed

Discussions with neurology colleagues at the AHT revealed that epilepsy/cramping in the Norwich Terrier is quite poorly defined, from a clinical perspective, and our chances of eventually identifying the mutation responsible for the condition will be greatly enhanced if we can obtain a better clinical description of the condition.

To try and find out more about the condition we devised a questionnaire that we sent out to the owners of 43 affected dogs, asking for details about their dog's condition. We got replies back from the owners of 25, which has helped us understand a little bit more about this condition. We also asked the owners of all the dogs for which we have samples stored to update us on the clinical status of their dogs, for which we received 119 updates. If any owners have still to return their questionnaires, or to update us on the health status of their dogs please do so as soon as possible. If anybody would like another copy of the questionnaire please email oliver.forman@aht.org.uk to request a replacement. Knowing the type of condition we are studying helps us predict the type of genes that might be involved which could significantly expedite mutation discovery.

To continue to help us find out more about epilepsy/cramping in the Norwich Terrier there are two more things that would be very helpful:

  • Video clips of affected dogs while they are experiencing a ‘fit' or a ‘cramp attack'.
  • Better clinical information about the affected dogs for which we currently have samples and also any ‘new' cases we collect. Ideally, affected dogs would have a full neurological work-up, to eliminate other causes of the seizures/attacks. Dogs can experience seizures for many reasons, and only once all possible causes have been eliminated can a dog truly be diagnosed as having idiopathic epilepsy. We understand full work-ups of this nature are expensive, but the more information we can gather regarding which tests affected dogs have and haven't had, and the results of those tests, is very helpful. The owners of affected dogs whose samples are held at the AHT are encouraged to contact us if they think they have any information that wasn't submitted along with the original sample that might be useful, or additional information that might have developed since the samples was submitted. It is also very important the AHT is informed if any dogs develop epilepsy / cramps after their sample was submitted.

Progress to Date

The AHT is part of a European consortium (the so-called LUPA project; www.eurolupa.org ) that is investigating several conditions (including epilepsy) that affect both humans and dogs. As part of the LUPA project the AHT has been able to access funds, and also samples owned by collaborative partners at the University of Helsinki, Finland, to begin research to identify the mutation(s) responsible for epilepsy/cramping in the Norwich Terrier.

Clinical Investigations

Full neurological work-up have now been carried out on three Norwich terriers confirmed as affected with the epileptoid cramping condition after discussions with the owners and also information submitted in the questionnaires. The work-ups were performed by the head of the AHT neurology department, Luisa De Risio, and included haematology, comprehensive biochemistry (including CK, bile acids and electrolytes), Urinary organic acid and amino acid assessment, MRI of the brain, Electroencephalography (EEG), Electromyography (EMG) and Motor Nerve Conduction Velocity (MNCV) tests. The results of the tests showed no factors that could be stated as the cause of Epileptoid cramping, so the syndrome can be described as idiopathic in nature. On this evidence it was decided that epileptoid cramping is best described clinically as “Paroxysmal episodes of hypertonicity affecting the pelvic limbs and lumbar muscles”.

DNA Analysis

We previously reported that we had undertaken a Whole Genome Scan (WGS) with samples from 38 affected (referred to as cases ) and 38 unaffected Norwich Terriers (referred to as controls ). A WGS involves comparing 49,663 DNA markers from the DNA of affected and unaffected dogs to find regions of the genome that are shared between affected dogs and different in unaffected dogs. This is the first step to finding the mutations that are associated with the condition. When we analysed the data from the WGS we were very excited to identify at least three regions of the canine genome that seemed to be associated with epilepsy/cramping. Since our last report we have investigated the data in more depth, and have also used it to study the genetic relationships between the cases and the controls. This analysis has revealed that the cases are more related to one another than they are to the controls, and vice versa, whereas ideally the cases and the controls are equally related to one another. A danger that can arise when the cases are more related to one another than they are to the controls is that the WGS can indicate regions of the genome that are shared between the cases, but are not associated with the disease under investigation. To try to illustrate this phenomenon we will use a hypothetical and extreme example. Imagine a there is breed that has an inherited condition segregating within its population. Also imagine that breeders in different countries prefer slightly different shaped ears, and so have selected for slightly different ‘ear shape' genes. When we undertook the WGS, if we collected our disease cases from one country and our controls from another country there would in fact be two differences between the cases and controls; disease status and ear shape. When we analysed the WGS data we would hope to find regions of the DNA that contained mutations responsible for the disease, whereas we might just as well identify regions containing genes that control ear shape, and it would be very difficult to distinguish between these two scenarios. For our real WGS we have obviously tried to make sure the cases and controls are not geographically clustered, nevertheless we believe the cases and controls are still sufficiently different in some way for us to be cautious about interpreting our results.

The Solution

We need to collect DNA from siblings of affected animals, to use as controls. By using controls that share the same parents as the cases we can be confident that the only significant genetic difference between the two groups will be the genes responsible for the disease. We would like to collect DNA from at least one healthy ‘control' sibling for as many affected dogs as possible. We would encourage the owners of any healthy dogs that are known to have an affected sibling to please consider donating a cheek swab to the AHT. If owners of healthy dogs don't know whether their pet has an affected sibling we invite them to contact us, and we will happily let them know whether a DNA sample from their dog would be useful.

 

To request a free DNA swab kit please email Bryan McLaughlin
bryan.mclaughlin@aht.org.uk

To enquire whether or not your healthy dog could contribute to our study please contact Oliver Forman at
oliver.forman@aht.org.uk

 

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Friday, September 24, 2010 11:01 AM