This is the first article in a series that addresses the
disease found in the Bichon Frise called Primary Ciliary Dyskinesia.
The purpose of the series is to bring awareness to breeders so that
they can recognize the disease, identify and effectively treat
affected puppies and hopefully prevent the disease. Only by
eliminating affected dogs from the breeding population and by
limiting the breeding of suspected carriers to non-carriers can this
goal be accomplished. We also hope the information will lead to
interest in breed specific research to identify the mode of
inheritance and provide answers to so many questions about the
disease. The information presented in this paper was obtained from
three published papers, research presented on the Internet and from
interviews with the authors and other veterinarians.
Introduction
Talk to breeders of the Bichon Frise and you’ll hear stories of
‘snorkeling’ puppies. While most puppies are born healthy, there are
some that have a rattling, raspy sound coming from their noses.
Search further and you’ll hear reports of puppies born with
pneumonia, others with a nasal discharge that often turns green or
yellow and other forms of respiratory distress.
Naturally, breeders turn to their veterinarians for help. The usual
prescribed treatment is a course of antibiotics for a suspected
respiratory infection. Fortunately, the drugs usually clear up the
symptoms. Unfortunately, the problem is not solved and the symptoms
return.
While the puppies tend to outgrow the symptoms of snorkeling, as
older dogs they may have recurring episodes of sinus infections,
upper respiratory problems and chest infections that are not
identified as symptoms of the same malady. Again, the antibiotic
regimen targets only the symptoms and not the cause.
Thus, the questions presented are: What is the cause of snorkeling?
Does it correct itself over time or do the symptoms only change? Are
there other physical affects and problems? And, of course, breeders
want to know how they can avoid the ailment all together. This paper
explains what the condition is, how it’s diagnosed, its treatment,
outcome, and how to prevent it.
Primary Ciliary Dyskinesia, Kartagener Syndrome and Immotile
Cilia Syndrome
The search for a diagnosis of what causes a Bichon puppy to snorkel
leads in many directions. The condition is found not only in other
breeds of dogs but also in other species, including humans.
Fortunately for the Bichon, the condition has been accurately
diagnosed as Primary Ciliary Dyskinesia (PCD). Unfortunately, the
symptoms can dissipate or become less frequent which has led
breeders to believe the problem is not serious. This has helped to
mask its identification and consequently has contributed to its
perpetuation. A basic understanding of the disease is necessary for
further discussion.
In 1933, Manes Kartagener first described the three symptoms common
to the illness, situs inversus, bronchiectasis and chronic
sinusitis, as a distinct congenital syndrome and thus, it was named
after him, Kartagener Syndrome (KS). During the next four decades,
researchers further discovered that the cilia (the hair-like
structures on the mucus membranes lining such areas as the nose and
lungs) involved in all these cases were abnormal, poorly mobile and
deformed. Thus, in 1977, the descriptive phrase Immotile Cilia
Syndrome was used to characterize the same condition.
Four years later, however, it was found that not all the cilia were
immotile, they were however, uncoordinated and inefficient, and thus
the name Primary Ciliary Dyskinesia (PCD) was coined to describe all
ciliary disorders.
A distinction in a case of KS is what is called situs inversus.
Situs inversus is when some organs in the body are mirrored
left-right, or found on the opposite side of where they’re normally
found. A patient with a ciliary disorder and situs inversus is
considered as having KS. Kartagener Syndrome is a part of the larger
group of disorders, PCD.
The theory why the organs are reversed is that the ciliary movement
is abnormal during embryonic development. Approximately one half of
patients with PCD has situs inversus and, thus, is classified as
having KS. In patients with PCD, organ rotation occurs as a random
event; therefore, half the patients have situs inversus (KS) and the
other half have normal situs (PCD).
As mentioned, cilia are the hair-like structures on the mucus
membranes lining such areas as the nose and lungs. When properly
formed, the cilia move in a wave-like fashion to move fluids through
the system and protect the respiratory system from inhaled pathogens
(infectious agents that cause illness) such as dust, dirt, and
microbes. The cilia are also responsible for the transporting these
particles out of the lungs. The beating of the cilia transports the
fluid upwards until it can be coughed out.
However, when the cilia are deformed both in structure and in the
way they are anchored, they cannot move in unison (dyskinesia) so
fluids and pathogens collect and become trapped in the airways. The
result is chronic respiratory infections leading to bronchitis and
pneumonia.
Cilia are also present in the male and female reproductive tracts.
The tail of a sperm itself is a very long cilium. A consequence of
the deformed cilia in these areas is that it can lead to
infertility.
Cilia are also responsible for moving the cerebrospinal fluid in the
brain. Consequently, a small proportion of affected Bichons have
hydrocephalus. Hydrocephalus is the abnormal buildup of
cerebrospinal fluid in the ventricles (cavities) of the brain. The
form of hydrocephalus seen in the Bichon does not cause any clinical
signs and does not impair the dog’s quality of life.
It is important to note, however, there are forms of PCD in humans
that are also associated with hydrocephalus. This observation
strengthens the theory that we are truly dealing with PCD in the
Bichon and not, as previously thought an immune disease. The Irish
Wolfhound study through the University of Pennsylvania further
investigated this important distinction.
The study concluded that Irish Wolfhound Rhinitis, or PCD, is not
caused by an immune system defect. The main reason Wolfhound
Rhinitis was thought to be caused by an immune defect was because,
in the past, the immune systems of affected dogs were always
examined during phases of severe illness; the immune system is never
normal in very sick or dying individuals. For their studies, they
treated the affected dogs and waited until they were clinically
healthy to examine their immune systems. After an exhaustive
examination and comparison of the immune system of affected dogs and
their normal littermates they found no differences, thus dispelling
the immune system defect.
It is understandable why more cases of PCD are not diagnosed. The
usual problems of misdiagnoses are apparent. Newly whelped puppies
may be incorrectly diagnosed as ‘fading puppies,’ or as having
pneumonia due to inhalation of maternal fluid or having neonatal
respiratory virus infection. Furthermore, carriers of PCD may be
less fertile and thus produce fewer puppies than unaffected and
carrier dogs. Finally, affected puppies may die before birth or
shortly thereafter and are thus not seen by a veterinarian. The
breeder has no reason to suspect an underlying genetic disease.
The Symptoms and Diagnosis
PCD normally presents itself in the neonatal period or prior to
three months of age. As previously discussed, a breeder’s first
glimpse of the problem is the puppy that has a rattling, snorkeling
sound coming from its nose. It’s a reasonable conclusion for the
breeder to suspect the amniotic fluid has not been cleared from the
puppy’s airway. There may also be a nasal discharge. It is common
for the affected puppies to lay with their heads up the wall of the
whelping box after birth in order to catch their breaths.
As the puppies get older, the snorkeling becomes chronic. It may
disappear for a few days but will return. As the puppies continue to
age, they may become completely symptom-free around the age of one
and one half years. Some breeders and owners report the symptoms
persist but recur less often and are easier to manage.
The symptoms of the adult dog are harder to recognize. These Bichons
have repeated bouts of sinus infections, upper respiratory problems
and pneumonia. Antibiotics are generally prescribed but the
infections are difficult to treat. It is reasonable to suspect PCD
as the cause of these recurring infections.
Recognition of the signs of PCD is the first step in diagnosing the
disease. However, only an electron microscope or Gama-ray
examination of the suspected cilia can make a firm diagnosis.
Moreover, samples cannot be taken from a puppy until it is five
weeks old.
In addition to the deformed cilia, a radiographic examination
(dorsal- ventral or ventral-dorsal and not lateral) will find about
fifty percent of the dogs’ hearts to be on the right instead of the
left side of the chest. In some cases, other internal organs may
also be transposed.
The male sperm are also adversely affected because the tail of the
sperm is formed from cilia. Consequently, the affected males are
sub- or infertile with a large number of the sperm being immotile.
In bitches, the reproductive organs are likely to be immature.
A radiograph may show evidence of bronchitis, bronchiectasis and
bronchopneumonia. These findings are responsible for a large number
of misdiagnoses of canine distemper viral infection. Other organs
can also be affected by PCD. The dog may develop middle ear
infections (otitis media), the kidneys may acquire lesion leading to
the need for dialysis or kidney transplantation (renal fibrosis),
there may be abnormal bone growth (sternum, vertebrae, and ribs)
and, as mentioned earlier, the brain may develop hydrocephalus.
Research
The breeder, scientist and veterinarian look forward to the day when
PCD has been eradicated. In that direction, research continues to
find the gene mutation that affects the cilia. Despite the advances
in science, the process is slow. The dog has a complicated genome
with 78 chromosomes. Fortunately, the human genome is widely mapped
and is fairly similar to the canine genome.
The mutation is likely to affect one of the proteins present in the
cilia. Therefore, if the genes known to be related to ciliary
proteins are examined first, only 1 – 200 genes need investigation,
not 80,000 – 100,000. The advent of a canine genome map has made
this type of research much quicker.
What researches are looking for is a genetic marker, which is a gene
or DNA sequence that has a known location on a chromosome and is
associated with a particular gene or trait. Genetic markers
associated with certain diseases can be detected in the blood and
used to determine whether an individual is at risk for developing a
disease.
These markers can be used to identify groups of genes, and if an
individual inherits a particular marker with a genetic disease, the
gene responsible must lie close to the marker on the same
chromosome. The nearer a marker lies to the mutated gene, the more
likely they are to be inherited together. Once a close marker has
been identified, the mutated gene becomes easier to find.
Once the mutated gene responsible for a genetic disease has been
identified, a simple, reliable test can be developed which will
identify the presence of that gene on an affected individual’s ‘DNA
fingerprint’, or in a carrier. This means that a blood sample or
cheek swab can identify carriers before they are bred. The
disadvantages with this type of DNA test are that it can only be
performed in specialist centers and each test is usually specific to
only one disease in one breed.
Mode of Inheritance / Breeding
For the breeder, it is most important to know the mode of
inheritance in order to avoid producing puppies with PCD. At this
time the mode of inheritance is not known. It is currently believed
to be Autosomal Recessive as it is in humans and some other breeds
of dogs. However more in depth breed specific studies on the Bichon
Frise need to be done to be able to accurately state the mode of
inheritance. It is thought by some researchers to be based on more
than one gene which would not then be a simple autosomal recessive
inheritance but a complex mode of inheritance with the major
contribution being autosomal recessive. This means that a dog that
has PCD has gotten two defective genes: one (or more) from its sire
and one (or more) from its dam. Most alarming for the breeder is
that the parents show no signs of PCD and are physically healthy.
Despite the fact they are healthy, they are in fact carriers of the
gene that causes PCD and can pass it on to their get.
Currently, there is no reasonable way to distinguish carriers from
normal dogs because they look the same and do not have the disease.
To eliminate PCD from the breeding population, a DNA-based test
would be extremely valuable, but the marker is not known, and thus
no scientific test exists.
At this time, there are only two ways to know if potential parents
are carriers. The first scenario is to breed them and wait to see if
puppies with PCD are born. The second way is to breed a known
carrier of the PCD gene to a suspected non-carrier. If more than 11
normal pups are born, the suspected non-carrier parent is most
likely not a carrier. Clearly, this is a crude method of "genetic
testing" and is unacceptable to most breeders.
However if there was a PCD affected pup in a litter it can be
assumed that approximately 50% of the pup’s litter mates would be
carriers of the gene/s.
Long Term Care of an Affected Dog
In general, dogs with this condition can live long and in relative
comfort if they are maintained properly and have the right
combination of antibiotics. If the symptoms are severe, other
treatment may be necessary, such as frequent inhalation of steam.
Another effective treatment is ‘coupage,’ patting the affected dog
on the side of the chest for several minutes on each side, which
helps loosen any mucous that is stuck in the deeper airways,
allowing the dog to breathe more easily.
As noted, Bichon puppies may actually improve as they get older.
Some are completely symptom free at or around the age of one and a
half years. Others have symptoms that are easier to manage but still
recur. In either case, proper care is necessary when respiratory
ailments are present. ■
The next article in the series will address how to care for
puppies/dogs that have PCD.
Shelly Vaden, DVM, Charles Henrikson, PhD, Michael Metcalf,
DVM, Leah Cohn, DVM and William Craig, Jr., MA, Primary Ciliary
Dyskinesia in Bichon Frise Litter Mates, Journal of the American
Animal Hospital Association, November/December 1991 Vol. 27; David
Edwawrds, DVM, Clark Patton, MS, DBM, and John Kennedy, PhD, Primary
Ciliary Dyskinesia in the Dog, Problems in Veterinary Medicine,
April-June 1992, Vol 3, No. 2; W. Jean Dodds, DVM, Steven Craft, DVM,
Mark Kopit, DVM, Lon Rich, DVM, PhD, Dennis Wilson, DVM, PhD,
Kartagener’s (Immotile Cilia) Syndrome in Bichon Frise.
Wolfhound Rhinitis/Primary Ciliary Dyskinesia, Margret L. Casal,
med. vet, Phd, http://www.irishwolfhoundstudy.com/pcd/casal.htm
Ibid.
Genome: The ordering of genes in a haploid set of chromosomes of a
particular organism
A genome map identifies where particular genes lie on each
chromosome.
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