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Open Letter from Dr. Olby Vet MD, PhD
Introduction
The STCA
Board and the
Health Trust
are pleased to offer two open letters to
Scottie owners and breeders from Dr. Olby and Dr. Bell.
They both are working on an important research project that
is co-sponsored by the AKC and the STCA's Health Trust.
The letters attempt to explain the role that each of these
experts will play in solving the problem known as cerebellar abiotrophy (CA)
in the Scottish Terrier.
Dr. Bell's letter explains CA
and how it differs from other conditions. Dr. Bell
also explains the protocol that leads to the clinical
diagnosis of an affected dog. To date, this protocol
has resulted in a 100% reliable clinical diagnosis for CA.
Dr. Olby's letter explains how her genome research
project relies on access to a powerful set of full family
blood samples. These samples must be available before
her project will be approved. We must begin to collect
these blood samples now.
Both of these letters support the following key points:
- The clinical diagnosis for CA affected Scotties is
highly reliable;
- It is extremely important that we collect blood
samples from all CA affected Scotties and their related
family members while they are available;
- The process and time required to identify the
defective gene that causes CA could be significant; and
- There are positive steps that can be taken now.
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Dear Scottish Terrier owners and breeders
As you all know, with the help and support of the STCA
health committee, Dr Bell and myself have been working on
collecting blood samples for DNA extraction and storage from
dogs diagnosed with cerebellar abiotrophy, and from all of
their relatives. It has come to our notice that there is
significant confusion over various aspects of this project
and we would like to take the opportunity to address some of
the questions we have been asked and to give an update on
progress so far.
The research grant is entitled, “The Genetics of Canine Cerebellar
Degeneration.” It was approved and granted by the AKC Canine Health Foundation,
and the STCA Health Trust Fund has contributed to it. The research project
involves four breeds; American Staffordshire Terrier, Gordon Setter, Old English
Sheepdog, and Scottish Terrier. The two-year grant is to do genome screening in
the American Staffordshire Terriers and Old English Sheepdogs (where full family
blood samples have already been collected), and to undergo full family blood
collection in the Gordon Setter and Scottish Terrier. These breeds have similar
autosomal recessive inherited cerebellar disorders. If we find a mutation in one
of the former breeds, then we will immediately check the Scottish Terrier and
Gordon Setter breeds for the same mutation. If the causative gene is not found
in the Scottish Terrier (and we would consider ourselves to be extraordinarily
lucky if we found the gene in Scotties in this particular 2 year grant), and
full family blood samples are collected and stored, we will apply for funding of
a separate research project for genome screening in the breed.
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We have
been asked several questions
We have been asked several questions but by far the most
common is how certain are we that dogs actually have the
disease with which they have been diagnosed? For obvious
reasons, people want to be sure that the diagnosis is
accurate. From my point of view, this question is central to
my research because if you start with a misdiagnosed sample
when performing a genome screen, you will be lead away from
the defective gene, and the entire research project may be
doomed. Because of this, we have to take into account how
the diagnosis has been reached when we analyze our results,
and this can be done statistically without too much problem.
For clarity, we allocate dogs to different groups depending
on the diagnostic workup:
Dogs in group 1 are the gold standard: clinical diagnosis has been
confirmed by necropsy. We are absolutely certain that these dogs had CA. We
currently have 6 dogs in this group, but only 3 with blood samples
submitted. Painful as it can be, I would encourage all owners of affected
dogs to consider having a necropsy done when they die to confirm the
diagnosis. The more dogs in this group, the better we can delineate the
disease and the more sure we are of our data.
Dogs in group 2 show consistent clinical signs and history, and
have received a full diagnostic workup of MRI or CT of the brain with CSF
analysis in addition to the clinical diagnosis Five clinically diagnosed
Scottish Terriers have undergone MRI, and three of them had a CSF tap. There
is blood collected on 2 of these dogs.
Dogs in group 3 show clinical signs and history compatible with
the disease (and thus have been clinically diagnosed) but in addition they
are direct relatives of dogs in groups 1 and 2. We are therefore sure that
they are also affected.
Dogs in Group 4 have been diagnosed on their history and clinical
signs alone. Dr. Bell and Dr. de Lahunta have developed a set of
diagnostic clinical criteria (see attached statement from Dr. Bell) that
include showing consistent clinical signs, and a consistent history of
slowly progressive disease. They have worked extremely hard a) to review
histories and diagnostic video tapes of all dogs to determine that the
clinical signs are consistent with CA, and then b) to keep in touch with
the owners to ensure that the progression of the disease is consistent
with CA. We are collecting samples from all dogs that have been
diagnosed clinically in this way. Recent postings on a chat list have
suggested that I will not be using these samples: this is not true. I
will be using samples from clinically diagnosed dogs, but the way these
animals have been diagnosed will be taken into account statistically
when performing our analysis. As you can see from the answer to the
second question below, we have great confidence in the clinical
diagnosis.
The next point I want to make is that it is extremely important that a
clinical diagnosis be taken seriously. We must collect samples from all dogs
clinically diagnosed now while we can. When doing genome screens to look for
defective genes, the number of samples available, and the familial relationship
of those samples provides the power to be able to identify a chromosomal region
linked to the disease. It is very difficult to collect samples from parents and
grandparents of affected dogs, in addition to unaffected siblings, but that is
the type of family that provides the most statistical power. It is likely that
we will use samples from all four categories listed above to provide adequate
power. As we definitively confirm more and more dogs by necropsy or full workup,
the number of dogs in group 3 increases (i.e. dogs with relatives with confirmed
disease). Thus, dogs move from group 4 into group 3 over time. I have worked
with the American Staffordshire Terriers for six years now, and we have
established the familial basis so well, almost every dog referred to me is
directly related to a dog with confirmed disease, even when they come from as
far a field as Brazil and Poland.
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How accurate is the clinical diagnosis
The second question that is important to address is how
accurate is the clinical diagnosis as made by Drs Bell and
de Lahunta? We already have some great data: Every dog
diagnosed clinically that has gone on to have a necropsy has
been confirmed to have the disease. So with 6 dogs necropsied, the accuracy of diagnosis clinically is 100%.
This may change over time but Drs Bell and de Lahunta have
been extremely conservative in labeling dogs as affected and
I am very comfortable with this approach, particularly as we
definitively confirm disease in more dogs.
The final point we really wanted to address is to reiterate the scope of this
project. Performing a genome screen and linkage analysis with the aim of
identifying a mutation is a long, complicated and expensive process, and only
has a chance of success if the correct samples are available. Indeed, further
funding can only be obtained if we can already demonstrate that we have samples
from affected and related dogs. All funding agencies will require that we do a
statistical simulation of the screening and linkage process with the samples we
have collected to show that statistically we have a chance of finding the
mutation before they will consider supporting such work. The current project is
therefore the very first stage of this whole process: sample collection and
correlation with pedigrees. By the end of 2006 we hope to be able to show
statistically that we have a reasonable chance of finding the mutation with the
samples we have collected. If we cannot collect the samples we will not be able
to complete the actual genome screen and linkage analysis to identify a
mutation.
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Progress
with the DNA sample collection
We would also like to update you on how things have been
going with the sample collection. Dr Bell is an incredible
liaison, and as a result of his efforts, several Scottie
owners and breeders have done an outstanding job for us in
rounding up families of dogs and we have got much further
than I anticipated. If we continue to get this type of
support, we are hopeful that we will be able to apply for
funding to do the actual genome screen some time in the next
year. Remember that it often takes 6 to 12 months for
funding to come through. Our only chance of being successful
in receiving this type of funding is to demonstrate
statistically that we can do the work because we have the
appropriate DNA samples in hand.
It is not possible today to predict how long it will be until there is an
actual DNA test for CA. At the end of this grant cycle and when a new grant is
approved, we will be able to speak to that issue more accurately.
This work is being supported by the Canine Health Foundation of the American
Kennel Club, and the STCA health committee. Dog owners have also taken on some
of the cost by paying for the blood sampling and shipping, and the cost of
salaries for people working on the project has been covered by North Carolina
State University. Linda Orsborn of the STCA health committee has been invaluable
both with respect to her knowledge of the breed and her ability to articulate
the problems we have to overcome to get this work done. The health committee
clearly has experience in addressing the genetic problems within the breed
through their work on identifying the mutation for von Willebrands disease. I
have been very appreciative of their practical approach and their understanding
that we have to do this one step at a time. I would encourage you all to contact
Linda with your questions on this research. If we act through a single liaison,
there is less likely to be confusion. It has been and continues to be a pleasure
to work with you all as we try to tackle this problem. Dr. Bell and myself hope
that this addresses any points of confusion about the sample collection project.
Sincerely,
Natasha Olby Vet MB, PhD
Diplomate ACVIM (Neurology)
Associate Professor of Neurology/Neurosurgery
North Carolina State University
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Return to Dr. Bell's Letter
