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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?
Create a login here, and request the sample information https://netapps.vet.upenn.edu/PennGen/SampleTesting/default.aspx .
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 June 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?
Create a login here: https://netapps.vet.upenn.edu/PennGen/SampleTesting/default.aspx . Select the MPSIIIB test. 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. For testing needs, testing
materials (swabs and submission forms) can
be requested by emailing penngen@vet.upenn.edu.
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 June 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 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 e-mail: penngen@vet.upenn.edu.
Questions:
Please
submit any questions you may have regarding
MPS IIIB in Schipperkes to the SCA's
Heath and Genetics Chair or e-mail: penngen@vet.upenn.edu.. Such questions will be helpful
in constructing a frequently asked questions
resource.
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