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Summary:
What
is Mucopolysaccharidosis type IIIB (MPS IIIB). The
disease MPS IIIB, also known as Sanfilippo syndrome type IIIB,
is an inherited disease classified as a lysosomal storage
disease (LSD). Lysosomes are "bags" within cells of
the body, filled with special enzymes which disassemble
molecules in an orderly manner. If one of the enzymes is
missing, due to mutations in the gene for that enzyme, the
disassembly stops, and undegraded molecules accumulate in
lysosomes (hence the term LSD), and the cells become sick or
die, which leads to disease. The compound accumulating in MPS
IIIB is heparan sulfate and the affected enzyme is
N-acetyl-a-D-glucoseaminidase (NAGLU).
What are the symptoms of MPS IIIB. The clinical signs in the
dogs are related to brain disease, appear between 2-4 years of
age, and include tremor, and difficulty in balancing, walking,
and negotiating obstacles such as stairs. The disease is
progressive, and owners have chosen euthanasia, usually 1-2
years after recognizing clinical signs.
How is MPS IIIB inherited? The inheritance pattern of MPS IIIB
is autosomal recessive. Both males and females are equally
capable of having the disease, or of being carriers. Carriers
are absolutely normal, and will not have signs of the disease.
Is there a DNA test and if so what do the DNA test results
mean?. We have a mutation based test for the NAGLU mutation in
the Schipperke breed. Testing offered through at the
University of Pennsylvania reports a result of affected,
carrier, or normal.
How do I go about getting my dog tested? See the submission
form, and attached instructions and check list.
Who receives notification of the DNA test results? Results are
confidential and are released only to the individual that
submitted the sample.
How common is this disease and how long has it been in the
Schipperke breed? The mutant gene may be as far back as eleven
generations, and hence may be very broadly distributed in the
Schipperke population. The carrier frequency is unknown, but
judging from similar diseases in cattle, it may be as high as
15%.
If the mutation is so old, why has this not been seen before?
Probably this disease has been seen before, but was not
recognized. Factors contributing to this including a low
frequency of cases, non-specific clinical signs, an adult
onset, a lack of post-mortem examinations, and very limited
knowledge among medical professionals.
Who should have their animals tested? Every breeding animal
should be DNA tested for this disease. All pups that are
waiting to be placed in permanent homes should be considered
for testing, to spare their new owners a great deal of anguish
and anxiety.
When can I test my dog and how much does testing cost? Testing
begins April 1, 2003, and costs $75/dog. A price of $50/per is
in effect until July 1, 2003.
How soon can I expect to get results back? Results will be
available in 3-4 weeks from the time of receipt of samples.
What do I do if I have pups waiting to go to homes? Priority
testing to ensure that pups waiting for placement are not
affected will be made. See the details below.
Do we provide "rush" testing on samples, bulk prices
or special litter prices? Rush testing is not available. There
are also no bulk submission or litter submission price
adjustments.
What samples is the test run on? The test can be run on either
1-2 ml of EDTA blood (lavender topped tube), or on cheek
swabs.
Detail:
What
is MPS IIIB
The disease MPS IIIB, also known as
Sanfilippo syndrome type IIIB, is an inherited disease. It is
one of a group of eleven different genetic diseases known as
the MPS disorders. The MPS disorders are all classified as
lysosomal storage diseases. Other better-known lysosomal
storage diseases that occur in humans include Tay-Sachs
disease and Gaucher disease. The feature that unites lysosomal
storage diseases is that they have abnormal lysosomal
function. The lysosome is an important structure of virtually
all cells in the body, and serves as the "garbage
disposal" of the cell. In humans MPS IIIB is seen in
approximately one out of 73,000 live births.
The lysosome is essentially a "bag" within cells of
the body, which is filled with special enzymes. The lysosome's
function is to disassemble large molecules of a cell that need
to be recycled or disposed of. The way in which molecules are
dissembled in the lysosomes involves a series of steps,
something like an automobile assembly line, but in reverse. In
place of the "disassembly" line workers who each do
one specific job, the lysosome employs many different enzymes,
which again have just one job each. These enzymes, when all
are present, disassemble molecules in an orderly and efficient
manner. When one of the enzymes is missing, due to mutations
in all copies of the gene for that specific enzyme, the
orderly processes of disassembly stops, and large undegraded
molecules begin to accumulate in the lysosomes, hence the name
lysosomal storage disease. Eventually the lysosomes of a cell
become so large, that it interferes with the normal job of a
cell, and the cells become sick or die, which leads to the
clinical signs and symptoms of the disease.
In MPS IIIB the compound which is stored is called heparan
sulfate. Heparan sulfate is one of a number of compounds known
as glycosaminoglycans (GAGs), which are themselves long
strings of chemically modified sugar molecules important in
structures like bone and cartilage and in the communication
machinery betweens cells in the body, especially in the brain.
The term mucopolysaccharide is actually on old-fashioned term
for GAG, hence the name mucolpolysaccharidosis. The enzyme
that is not functioning appropriately in MPS IIIB is called
N-acetyl-a-D-glucoseaminidase (NAGLU).
What are the symptoms of MPS IIIB
In humans the signs and symptoms of MPS IIIB are related to
the mental deterioration that is seen. By the age of 3-6
years, affected children start to show delayed development.
The mental deterioration progresses through mental retardation
and finally to dementia. As part of this progression the
children may show behaviorial abnormalities which can include
hyperactivity, poor sleeping patterns, and aggressive and
destructive behaviors. If the children have acquired speech
and toilet training skills these are eventually lost. In the
last stages of the disease the children lose the ability to
walk or feed themselves. Most do not see their third decade of
life. At this time there is no proven and effective treatment
for this disease. To learn more about this condition in
children one can visit www.mpssociety.org
The clinical signs in the dogs are in many ways similar to the
children, in that the clinical signs are related to the brain
disease. However, the dogs differ from children in two
important ways. The age of onset is seen in the dogs during
early adulthood, and the clinical signs are related to a
particular part of the brain called the cerebellum. The
cerebellum plays an important role in balance and smooth and
coordinated movement. The clinical signs in the dogs have been
reported to appear between 2-4 years of age, and include
tremor, difficulty balancing, walking, negotiating obstacles
such as stairs, head tilts, falling to both directions, and
other clinical signs associated with the generalized balance
problems . Some have reported a change in coat color from
black to auburn, however, coat changes can be associated with
many other diseases and illnesses. In the dogs the disease is
progressive, and the initial problems with balance become
worse until the dogs cannot stand, walk, eat, etc., without a
great deal of difficulty. Owners have eventually chosen to
have their dogs euthanized. This was usually chosen within 1-2
years after clinical signs were first recognized. Affected
bitches are fertile, and can have pups. We expect that
affected males may also be fertile, but we have not observed
this.
How is MPS IIIB inherited?
The inheritance pattern of MPS IIIB is autosomal recessive. As
is the case with all autosomal genes (genes not found on the
sex-chromosomes), an individual has two copies of a specific
gene, one copy on each of a pair of autosomes. With MPS IIIB,
if an individual is affected with the disease, both of the
NAGLU genes that the affected dog inherited were the mutant
form of the gene. Both males and females are equally capable
of having the disease, in other words the disease in not
sex-linked, and inheritance of the mutant copy of the gene
must come from both the sire and dam. Carriers, or individuals
that have inherited one normal copy and one mutant copy the
NAGLU gene are absolutely normal, and will not have signs of
the disease. Parents of an affected animal are what is called
"obligate carriers", in other words, since an
affected was produced from them, they must both be carriers of
a mutant copy of the NAGLU gene.
Is there a DNA test and if so what do the DNA test results
mean?
There is now a DNA test available. We have found a mutation in
the NAGLU gene in the Schipperke breed and the test for this
mutation is offered through the Josephine Deubler Genetic
Disease Testing Laboratory at the School of Veterinary
Medicine at the University of Pennsylvania. The DNA diagnosis
will report a result as either affected (affected with the
disease-both genes are mutant), carrier (clinically normal-one
mutant and one normal gene), or normal (clinically normal-both
genes normal). This test is the most efficient way to diagnose
affected animals with MPS IIIB. It is also the only way to be
sure of whether a breeding animal is a carrier or a normal
dog. This DNA test can be run from DNA extracted from either
EDTA blood (lavender top tube) or from special cytology
brushes used to get a sample of cells form the inside of the
mouth (cheek swabs). Please see the attached documents for
instructions on the collections and submission of samples.
How do I go about getting my dog tested?
If you would like to have your dog
tested, please see the submission form, and attached
instructions and check list. A 2-3 day delivery service which
provides the ability to track the progress of the delivery, is
recommended. Samples to submit can be either 1-2 ml of EDTA
blood or 2 cheek swabs. Testing materials for cheek swab
submissions, to include 2 cheek swabs and submission form will
be provided for all registered attendees of the 2003 National
Specialty Show. Additionally, extra swabs and forms will be
available at the 2003 National Specialty Show. Animals need
not attend the National Specialty Show as owners can take
cheek swab samples at home and send samples in according to
submission instructions. For those not attending the National
Specialty Show, or for future testing needs, testing materials
(swabs and submission forms) can be requested by calling (215)
898-8894.
Who receives notification of the DNA test results?
It is the policy of the Josephine Duebler Genetic Disease
Testing Laboratory that all results are kept completely
confidential. No results are released to anyone other than the
individual that submitted the sample. This may be the
veterinarian, the owner, or an agent for the owner. No result
that is identified as being from a specific dog is made in
scientific communications or publications unless by the
written consent of the owner. Results will be sent out within
3-4 weeks from the receipt of samples.
How common is this disease
and how long has it been in the Schipperke breed?
We cannot be certain of how
common this disease is in the Schipperke, either in terms of
how many affecteds there are or how many carriers there are.
We had initially seen two cases of this disease, which we
diagnosed from samples submitted for analysis to the school's
metabolic genetic screening laboratory. Since then we have
documented MPS IIIB affected dogs in a total of five different
families. From comparisons of the pedigrees of these dogs we
can say that the nearest and most likely common ancestor was
an animal found as far back as eleven generations in some
pedigrees. This would mean that the mutant gene may be very
broadly distributed in the Schipperke population. We cannot
predict what sort of frequency of carriers there may be in the
population at large without a controlled study. However a
similar lysosomal storage disease, called ß-mannosidosis,
which was seen in the Salers breed of cattle was shown to have
a carrier frequency of 15%. If a similar carrier frequency was
to be seen in the Schipperke breed this would mean that on
average, up to one out of every seven dogs could be a carrier.
If the mutation is so old, why has this not been seen before?
Although it is impossible to prove, we feel that this disease
has been seen before, but was just not recognized. There is a
report in the scientific literature that describes a case of a
lysosomal storage disease in a Schipperke that was published
in 1993. The authors were unable to say exactly which
lysosomal storage disease it was. Their findings however were
nearly identical to what we have seen in two cases from the
late 1990s. Many factors may have contributed to MPS IIIB not
having been recognized earlier. It may be that the mutant gene
is rare enough in the population at large, that the chances of
two carriers being mated and producing offspring was low, and
such sporadic cases escaped the attention of veterinarians,
breeders, and owners. The clinical signs of MPS IIIB are not
themselves specific to MPS IIIB, but can be caused by a host
of other illnesses. The disease is seen in adulthood, which is
not usually the case with such severe genetic diseases. Many
owners may have declined a post-mortem examination. Unless a
post-mortem examination was conducted, it is unlikely that
anyone who had a case of this disease would have known about
it. Even if a post-mortem examination was conducted all that
could be determined was that the patient had a lysosomal
storage disease. Knowledge of these sorts of diseases is
limited among medical professionals. Very few veterinarians
will have ever heard of this disease, and if so, never in a
dog, since the Schipperke breed is the first case of the
diagnosis of MPS IIIB in any dog. The difficult in finding an
accurate diagnosis is not a situation that is unique to
veterinary medicine, as families whose children have this
disease are not infrequently given other diagnoses before a
definitive diagnosis of MPS IIIB is made. We believe a
combination of all these factors may have served to obscure
earlier cases of this disease.
Who should have their animals tested?
Considering the fact that the disease is progressive, cannot
be treated, is fatal, and devastating to the dogs and their
families, we would recommend that every breeding animal be DNA
tested for this disease. Additionally, all pups that are
waiting to be placed in permanent homes should be considered
for testing, to spare their new owners a great deal of anguish
and anxiety. Any non-breeding animal that is under three years
of age may be a candidate for testing to identify if it is
affected and will develop clinical signs. However it must be
mentioned that there is no treatment for this disease, hence
testing of such animals is probably useful only to relieve the
anxiety of owners who know that their pet is at risk, i.e. an
animal whose parents are known to be carriers.
How soon can I get my dog tested and how much does testing
cost?
Submissions will be accepted beginning April 1st, 2003.
Testing will cost $75/dog. To encourage testing we will offer
a reduced price for the first two month's submissions. This
reduced rate will be $50/per dog and will be available to all
submissions postmarked by July 1st, 2003. There is not a
reduced fee for bulk submission, or for litter submissions.
This rate for DNA testing in dogs is among the lowest
available for any disease.
How soon can I expect to get results back?
Results will be available in 3-4 weeks from the time of
receipt of samples. Because DNA testing is usually for planned
breedings, we do not have a policy of accepting rush
diagnostics for genetic diseases, unless it is an animal with
clinical signs of disease for which there is a treatment
available, which is not the case for MPS IIIB. Please do not
contact the Laboratory to inquire whether samples have
arrived. If you wish to be able to confirm that samples have
been delivered we suggest that you use a delivery/mail service
that allows you to track the shipments progress, arrange for a
return receipt which acknowledges delivery, or include a
stamped self addressed card for the acknowledgement of receipt
of samples. Because we are in the first stages of diagnosing
this disease with a DNA test, there may arise an overwhelming
response to the testing in the first few months, which may
delay the reporting of results. If such a situation occurs, we
will keep the Schipperke Club of America's Health and Genetics
Chairperson appraised of any change in the normal turnaround
on test results.
What do I do if I have pups waiting to go to homes?
Another consequence of offering a new DNA test is that there
may be cases where breedings are in progress or where pups are
on the ground, and parents have either not been tested, or
perhaps are known to be carriers. In a situation such as this
where the breeder has a concern about placing an affected pup,
we will make a priority of testing parents of such pups.
Please submit these parental samples together, with sire and
dam of litter in the same submission. If both parents are
found to be or known to be carriers, pups that are waiting or
due to be placed in homes will also be tested on a priority
basis. By pups waiting to go to homes we mean young pups going
to their first home from the breeder. On the submission form
there is a place to note the reason for screening, there is a
box marked "other". Check that box, and write
"puppy waiting for placement" or "sire and dam
of litter waiting to be placed". Please do not abuse this
privilege. The turn around on such samples is not rush, but
will be the normal 3-4 week turn around. This provision will
be in effect for any breeding conducted before April 1, 2003.
What do I do if I am planning a breeding?
As we anticipate much of our
initial testing is to be done on breeding animals, we feel it
impractical to offer a priority testing because a breeding is
eminent. In cases were a breeding is eminent, we must
regretfully recommend that the planned breeding take place
after a diagnosis is provided. We regret the delay this may
cause, but in a worse case scenario, it will only delay
breeding by one heat cycle of a bitch.
What should I do if I have
an affected dog?
Unfortunately there is no
treatment for this disease. Once an animal has begun to show
clinical signs, all that can be done is to provide a safe
environment, such as one without stairs, or obstacles, which
might lead to falls or make getting around difficult. The
decision of when to elect euthanasia for a sick pet is a
difficult one, and must be made by balancing the importance of
the bond between the owner and their pet, and the quality of
life of their pet. Under no circumstances can we recommend
that non-symptomatic animals be euthanized. Although the
lifespan of dogs with this disease is much shorter than
normal, until they become clinically affected, they are
absolutely normal, and depending on the clinical course of the
disease in the individual, they can have many months of
quality life after clinical signs appear. The difference
between owning an affected versus and unaffected dog, is that
the owner has a very good idea of when and why they may face
the decision to elect euthanasia for their pet. If you are a
breeder and find that you have an unplaced affected pup, or if
you are an owner of an affected dog, and you would like to
know how you can help to further our efforts to find a
treatment and a cure for this devastating disease, we
encourage you to contact us via FAX (215-573-2162), or regular
mail (Dr. N.M. Ellinwood, 3900 Delancey Street, Philadelphia,
PA 19104-6010.
Questions:
Please submit any questions
you may have regarding MPS IIIB in Schipperkes Dr. N.M. Ellinwood,
3900 Delancey Street, Philadelphia, PA 19104-6010. Such
questions will be helpful in constructing a frequently asked
questions resource.
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