DM - breeders question - Page 2

Good for you, Louise!!!!!!!!!!!!!!   I hope you advertise them as being N/N.  It would be great to give puppy buyers and bitch owners the option of going to these types of dogs. 

You can DNA test your pup for DM. If the pup is N/N, he will not change upon maturity.

I have never heard of a documented case of ALS-DM in the GSD. As stated
previously, DM in the GSD always progresses from the hind end forward. ALS can
start anywhere the muscle is damaged- it can present initially with swallowing
difficulty, front leg weakness, etc. The DM of the GSD targets the myelin and
axons of the spinal cord leading to Upper Motor Neuron signs but without
affecting the cell bodies of the neurons (which is what is seen in GSDM on
histopathology.) The DM OF THE GSD, in test results (see original post) and
presentation, are juxtaposed to the test results of ALS- at least in the GSD.
Perhaps there is an ALS-DM in other breeds-that I would not know. Dr C has
always maintained that the DM of the Corgi is not the same DM as the DM of the
GSD.

The Flash test was made specifically for GERMAN SHEPHERDS, tested and researched
upon GERMAN SHEPHERDS. I believe only 2-4 GSD spines were used in the ALS Study.
According to the article they published, they also used clinical signs as one of
the criteria for their study. As we all know, there are many diseases which can
mimic DM, but not, in fact, BE DM. Dr Coates should know that well. In the GSDM
research she did for the GSDCA, in which she also made use of clinical signs as
a criteria for admission to the study, it was discovered, upon necropsy, that
she only correctly dx 3 of the 12 dogs in the study. That's only a 25% accuracy
rate :(

The OFA Gene test only looks for SOD1 which is associated with 20% of human ALS
patients. It is not necessarily specific for ALS, since it can be altered in
other diseases or for non-specific reasons. According to U Missouri, however,
they believe that this is a reason to call DM, ALS. That is in spite of the
remaining evidence that it is not (again, please refer to my original post.) The
DM Flash test looks at a broader picture and seems to relate to GSDM better and
suggests along with all the other evidence even including the change reported by
U Missouri, that GSDM is more likely similar to Primary Progressive Multiple
Sclerosis. This is not just the genetic changes we have found, but also the
entire body of scientific evidence accumulated over 30 plus years working with
German Shepherds. We see a number of dogs where the tests do not agree and some
where they do; however, Dr C thinks they look at different aspects. He feels
confident in the DM Flash test, but is not sure that a change in SOD1
constitutes a reason to assume anything specific about where a GSD is likely to
get or have GSDM.


"ALS does not affect a person's ability to see, smell, taste, hear, or recognize
touch."

You can pinch the foot of a dog with DM, and they wont feel it, so how can this
be reconciled with ALS not affecting the ability to recogonize touch?

" ALS Patients usually maintain control of eye muscles and bladder and bowel
functions, although in the late stages of the disease most patients will need
help getting to and from the bathroom.""

In DM, when the hind end goes, so goes bladder and bowel and bowel control...ask
anyone who has had a DM dog if that dog has been able to maintain bladder and
bowel control. The answer is "NO!" Again, how can this be reconciled with ALS,
when DM dogs lose control of bladder and bowel?

" Not all familial ALS cases are due to the SOD1 mutation, therefore other
unidentified genetic causes clearly exist."

unidentified genetic causes --- >Exactly what Dr C has been saying for years...

"The parts of the body affected by early symptoms of ALS depend on which muscles
in the body are damaged first. In some cases, symptoms initially affect one of
the legs, and patients experience awkwardness when walking or running or they
notice that they are tripping or stumbling more often. Some patients first see
the effects of the disease on a hand or arm as they experience difficulty with
simple tasks requiring manual dexterity such as buttoning a shirt, writing, or
turning a key in a lock. Other patients notice speech problems-slurred and nasal
speech; or difficulty chewing or swallowing."

Interesting- DM always progresses from the rear, in German Shepherd Dogs, moving towards the front of the
body. I have never heard of a dog with DM having problems with its front end,
front legs, or chewing and swallowing, before it is already down in the rear.

I would be curious to know if anyone knows of a dog definitively dx with DM that
was not first affected by the disease in the hind end...2+2 has to=4..... This
is more than puzzling, to me. Doesnt it puzzle anyone else? HELLO? Is this an Emperor's New Clothes, sceanrio?????

Oh, well.........

Marjorie
Executive Director: New Beginnings Shepherd Rescue www.newbeginningsrescue.com 501 C3
OUR BUILDING PROJECT PHOTOS
http://gsd911.com/viewtopic.php?f=5&t=196

http://www.gsdbbr.org The German Shepherd Dog Breed Betterment Registry (including frozen/chilled semen database) BE PROACTIVE!
http://mzjf.com --> The Degenerative Myelopathy Support Group

"They are similar- the DM Flash test and the gene test. The main difference is
that without the resources of MIT behind Dr C, he had to look to see if there
was a genetic relationship to GSDM and using what he had that was reasonable- he
used RAPD (random access repeat primers) to look at the genome. Using these, he
found a pattern that was consistent in GSDM (and other forms of DM). While he
initially looked at a specific set of primers that he looking at the IRB1 region
and found a change there that was consistent in many GSDM patients, it was not
as consistent in all of them as the change in the RAPD analysis. Although he did
not continue to call the test in other breeds the DM Flash test, he continued to
call the test in the GSDs that in honor of Jack Flash. He also saw several other
changes that exist in GSD patients that are consistent, but he tracks the DM
Flash test to confirm the diagnosis. Of course, since demonstrated the potential
to find the gene associated with GSDM (and other DM cases) and that developed
the interest in other researchers who have now found the change in the SOD1
region of the canine genome. They were able to use the 18000 SNiP array (we
could not afford them since they were $2400 each), but MIT had developed these
when they did the canine genome project. The major difference between SNiPs and
RAPD is that SNiPs let you put a gene name to the product and the RAPD does not
(as easily). RAPD also may find something that SNiPs do not and vice serse, but
it does appear they have found the same thing here (or there are more than one
change which is still possible).

We took a different tact in using the RAPD, which was to determine the incidence
of the gene change so we determine it effectiveness as a diagnostic. As such we
found that 25% of the dogs care the trait we track, but only 10% of these ever
develop GSDM. So, it makes a poor screening test. Yes, 91% of the reason for
developing GSDM is due to the genetics and patients who are positive in the DM
Flash test have a 12 fold increase risk of developing GSDM, it cannot be the
soul factor as to why they eventually develop GSDM. On the other hand, if an
older GSD has clinical signs, it is a great diagnostic test with a 96%
sensitivity and 99% specificity. It correctly identifies those dogs who have
GSDM from those (proportionately more) who do not have GSDM once clinical signs
develop. Probably the gene test does that, but we do not know for sure, since
they do not have that information about their test yet or at least have not
presented it. The gene test might do one thing that we currently do not
(although future versions might) in that it may be able to tell who is a carrier
of the risk factor. We have only tracked those who are at risk and are
homozygous for the trait. However, since the gene is not the soul factor for
developing DM, I am not sure that genetic testing and elimination of carriers
and at risk patients is appropriate. Based upon our work, that could mean
removing 75% of GSDs. That is foolish.

Dr. Coates has stated that since the gene involved in their work is the SOD1
gene, that DM is a motor unit disease and an animal model of ALS. We have never
been able to demonstrate selective motor unit involvement even in late cases.
ALS does not have sensory abnormalities which would include proprioceptive
deficits which are a predominate feature in DM. We do not think you can build a
puzzle by starting with the last piece; the puzzle is built from all the pieces.
Only when all the pieces fit together, can the whole picture be seen. Too much
data says that GSDM is an immune mediate chronic neurodegenerative disease
associated with demyelination and axonal loss. This is most similar to PPMS
rather than ALS. The fact that the SOD1 is involved complicates things because
it is means that DM may be a "bastard child" where the change in SOD1 triggers
the immune disease and attack of the nervous system and so it looks like a cross
between ALS and PPMS. As such it is not a pure model of either. However, the
truth is the important thing. With that, we can devise appropriate strategies to
combat it.

Dr Coates has suggested that all dogs have oligoclonal bands and, therefore,
they were not important in DM. This is not true and we found that 60% of GSDM
patients do have more than one unique clonal band in lumbar CSF which is the
definition of oligoclonal band positivity. Finally, she keeps looking for CSF
changes in DM in the AO CSF which we have repeatedly shown to be normal. CSF
changes in DM occur in the lumbar CSF and if there are changes in the AO sample,
there is something other than DM.

If you only look at the gene test and do not advance beyond that, you are doing
a disservice to the dogs. First, if the SOD1 association is confirmed (DR
Clemmons is working on that), it still does not explain the disease nor why only
a very limited few get DM. Neither the gene test or the Flash Test can tell you
which dogs to eliminate from the gene pool- it is way too early in research to
be able to do that. Neither test can predict which dogs will develop DM!
However, since the gene is not the soul factor for developing DM, I am not sure
that genetic testing and elimination of carriers and at risk patients is
appropriate, at this stage of either research, as based upon our research work,
and again, that could mean removing 75% of GSDs. That is foolish. We need much
more info, since many factors not just one, cause a dog to develop DM.

If the gene test's advantage is that they can find the carriers as well as the
hnomozygous dogs, then the predictive value of a positive test is only 3%. If
they only report the homozgous dogs then the predictive value is 10% just like
the DM Flash test. Neither test is a good screening test, but we have shown that
the Flash test is a good diagnostic test in clinically affected dogs.

In discussions with Dr Clemmons I have learned that a test's significance is not
just based upon the sensitivity and specificity of the test, since the value of
the test is also a function of the incidence of the disease in the population.
So, some feel that the predictive value of a positive and predictive value of a
negative test which accounts for both of these factors may be a better way to
determine usefulness of a test. For a screening test to be useful, it should
have a very high predictive value, the disease should have a treatment, and the
test should be cost effective. Based upon these criteria, and particularly the
lack of treatment and low predictive value of a positive test, no reasonable
epidemiologist would recommend performing the DM Flash test or the gene test as
a screening test. We do know that the DM Flash test is a good diagnostic test,
but that is because the incidence of DM in clinically affected dogs is around
25%, not 2% .

I think that the DM Flash test only detects dogs with 2 copies of the gene
(homozygous for the condition), but I cannot absolutely confirm that. I do not
know if the gene test is designed to detect both heterozygous (carriers with a
single copy) and homozygous (2 copies) or just the homozygous affected dogs like
the DM Flash test. Either way, neither should be used as screening tests for the
disease in normal dogs, because the number who will actually come down with the
disease is only 10% of the homozygous affected dogs, at best. Over all only 2 %
of GSDs get GSDM. However, probably 25% of all GSDs are homozygous for what we
detect in the DM Flash test.

On the other hand, almost 100% of the dogs who have GSDM are positive in the DM
Flash test so that the presence of the homozygous trait does account for 91% of
the reason why a give dog will develop GSDM. That is still only 2% of all GSDs.

The answers to the DM riddle will most probably lie in the dark DNA. Dark DNA,
for those who do not know, is basically the concept that other genes influence
the expression of the main genes that are thought to control genetic disease
transmission. This is also the concept of gene "imprinting" where some genes
turn on or off and those influence whether other genes function and therefore
create consequences. That is what DR Clemmons has been saying! The presence of a
single gene change which does not explain who actually gets the disease is only
part of the answer. If you don't find which other genes determine whether the
"primary" gene acts, you are missing the answer. That is why the funding and the
search cannot stop now. If it does we will not find out what else if involved in
triggering the disease, even if it does turn out that SOD1 is needed for the
disease to happen. The trigger is from other factors outside SOD1.DR Clemmons
believes the triggers are environment and other factors which are set at
puberty. If you have the SOD1 change (or the change in the DM Flash test) and
your DNA (Dark DNA if you want) imprints at puberty in the wrong way, then you
get GSDM. Otherwise, you do not. That is why so many can be positive on either
test and only a few get the disease.

I dont think any test has a 100% accuracy. I know the Flash test has a 96%
sensitivity and 99% specificity. I dont know the sensitivity and specificity of
the gene test or if they even released those figures. No test is 100%, for sure!
Our test is broader and may look at things they do not. Even so, their test and
ours may look at different aspects of the disease. Even if they looked at the
same thing, there will be some differences.

Generally, combining 2 tests (even if doing the DM Flash test twice) will reduce
both false negatives and false positives to improve the overall outcome of the
results. We do that mostly in dogs who have clinical signs.

Another problem I can see, with the use of the Gene Test, is that if it does
yield a different result than the DM Flash Test, it still does not mean the
Flash Test is wrong, as far as the dog having DM. For example-If a dog is
negative on the Flash Test, and positive on the Gene test, the Gene test still
doesn't mean the dog has DM. People do not seem to understand this- the gene
test cannot say which dog has or does not have DM. It cannot predict which dog
that has the gene will get DM- It can only potentially let you know if the dog
has the gene or does not have the gene. The dog may have the gene, but not have
DM, even if it is displaying DM symptoms! There are so many conditions that
present in the same manner, so one has to remember that while the Flash test is
a great diagnostic tool, the Gene test is not! The DM Flash Test has been shown
to be quite accurate in accessing DM in symptomatic dogs, but the same is not
true of the Gene Test. It sure gets confusing, doesn't it!

Both are DNA tests. The gene test looks (supposedly) at SOD1 only. We may be
looking at additional areas as well when running the DM Flash test. No one knows
for sure which DNA regions (since it is probably more than one) are the most
critical in developing DM.

It is also important to realize that DR Coates has worked under the theory that
DM is ALS. Amyotrophic Lateral Sclerosis and related diseases are motor unit
diseases where the nerve cells in the body responsible for controlling movement
die off leaving the patient weak and with varying degrees of Lower Motor Neuron
dysfunction (loss of reflexes and flaccidity) or Upper Motor Neuron dysfunction
(hyperactive reflexes and spasticity). Those causing LMN disease affect the EMG
early in the course of the disease. Those causing UMN disease result is
selective shrinkage of the motor cortex visible on MRI. Neither of these
conditions exist in GSDM.

Immune diseases like MS attack varying parts of the nervous system and one of
them, Primary Progressive MS, specifically targets the myelin and axons of the
spinal cord leading to UMN signs but without affecting the cell bodies of the
neurons (which is what is seen in GSDM on histopathology). The CSF protein is
usually normal in ALS, but abnormal in MS. Oligoclonal bands of IgG are common
in MS and uncommon in ALS. The recessive forms of ALS are extremely slow in
development and do not result in shortened life-span. Even the one motor unit
disease known in dogs, Spinal Muscle Atrophy in Brittany Spaniels occurs in
young dogs with progressive EMG changes leading to death. That might be more
consistent with the "early onset DM reported in the GSD which is not the same
disease as GSDM on histopathology.

ALS diseases cause motor problems but not sensory ones. That is they do not
cause CP deficits or hypermetria (ataxia in which movements overreach the
intended goal.). People do not knuckle and scrap their toes when they walk, they
only show weakness. Most of them are painful because of muscle spasms. (Does
that sound like GSDM?....NO!)

So, even if there is a genetic change in SOD1, Dr Clemmons believes that a
change must also be explainable based upon the clinical signs. If not, it may
just be a casual relationship not a causal one. GSDM as a pure motor unit
disease just does not fit all of the available data. (Not just DR
Clemmons…everyone's!)