L-2-HGA Hydroxyglutaric Aciduria
In the past few years a small number of Staffords have been diagnosed
with a metabolic disorder, its clinical name is L2 hydroxyglutaric
aciduria or L-2-HGA. L-2-HGA affects the central nervous system, with
clinical signs usually apparent between 6 months and one year (although
they can appear later). Symptoms include epileptic seizures, "wobbly"
gait, tremors, muscle stiffness as a result of exercise or excitement
and altered behaviour.
Dogs from totally different bloodlines have been found to be sufferers
and the number of affected dogs diagnosed has risen. The disorder has an
autosomal recessive method of inheritance, which means that both parents
must be carriers of the affected gene to produce affected offspring.
The mutation, or change to the structure of the gene, probably
occurred spontaneously in a single dog but once in the population has
been inherited from generation to generation like any other gene. The
disorder shows an autosomal recessive mode of inheritance: two copies of
the defective gene (one inherited from each parent) have to be present
for a dog to be affected by the disease. Individuals with one copy of
the defective gene and one copy of the normal gene - called carriers -
show no symptoms but can pass the defective gene onto their offspring.
When two apparently healthy carriers are crossed, 25% (on average) of
the offspring will be affected by the disease, 25% will be clear and the
remaining 50% will themselves be carriers
The mutation responsible for the disease has recently been identified at
the Animal Health Trust. Using the information from this research, we
have developed a DNA test for the disease. This test not only diagnoses
dogs affected with this disease but can also detect those dogs which are
carriers, displaying no symptoms of the disease but able to produce
affected pups. Carriers could not be detected by the tests previously
available, which involved either a blood or urine test detecting
elevated levels of L-2-hydroxyglutarate or magnetic resonance imaging.
Under most circumstances, there will be a much greater number of
carriers than affected animals in a population. It is important to
eliminate such carriers from a breeding population since they represent
a hidden reservoir of the disease that can produce affected dogs at any
The test is available now and information on submitting samples is
Breeders will be sent results identifying their dog as belonging to one
of three categories:
CLEAR: the dog has 2 copies of the normal gene and will neither
develop L-2-HGA, nor pass a copy of the L-2-HGA gene to any of its
CARRIER: the dog has one copy of the normal gene and one copy of
the mutant gene that causes L-2-HGA. It will not develop L-2-HGA but
will pass on the L-2-HGA gene to 50% (on average) of its offspring.
AFFECTED: the dog has two copies of the L-2-HGA mutation and is
affected with L-2-HGA. It will develop L-2-HGA at some stage during its
lifetime, assuming it lives to an appropriate age.
Carriers can still be bred to clear dogs. On average, 50% of such a
litter will be clear and 50% carriers; there can be no affecteds
produced from such a mating. Pups which will be used for breeding can
themselves be DNA tested to determine whether they are clear or carrier.
This test requires 3mls of whole blood in EDTA tube or cheek swab
samples (swab kits available free of charge from the address below or
e-mail (email@example.com)) can be sent. L-2-hydroxyglutaric
aciduria (L2HGA) and Hereditary Cataracts (HC) - DNA Testing for
Staffordshire Bull Terriers
www.aht.org.uk. DNA testing forms can
be downloaded by
SOME FREQUENTLY ASKED QUESTIONS AND ANSWERS
WHAT ARE THE SYMPTOMS OF L-2?
Symptoms can vary from dog to dog but basically there may be seizures of
an epileptic style or you may see a change in the way the dog moves.
Often after or during exercise (exercise intolerance), or in stressful
situations the dog’s muscles begin to seize up and you would notice
stiffness around the hind legs and an arching of the back, resulting in
the dog being unable to walk normally. This can range from slight
incapacity to almost total loss of co-ordination and the dog having
full-blown seizures. There are other possible symptoms you may notice:
an apparent loss of recognition of normal surroundings, staring at walls,
appearing to have altered behaviour.
MY DOG`S BACK LEGS SHAKE WHEN HE`S STANDING STILL OR HE IS STIFF
AFTER EXERCICE - DOES HE HAVE L-2?
Lots of Staffords have `muscle tremble` when they are standing - this
isn’t indicative of L-2. If your dog is stiff after exercise ask
yourself, has this always been the case or has it happened as he has
become older (simple ageing) or following an injury (possible arthritis
of a joint).
MY DOG APPEARS NORMAL - SHOULD HE BE TESTED FOR L-2?
If you have no concerns that your dog may have L-2 from the classic
symptoms there is NO need to test unless the dog is going to be bred
from. ALL breeding stock should be tested prior to the mating to
determine it’s genetic status. You may think that as your dog has no
clinical signs of L-2 that you don’t need to test but it is impossible
to know whether or not your dog is a carrier of the rogue gene without
the DNA test.
IS THIS A PROBLEM IN ONLY SOME BREEDING LINES?
ABSOLUTELY WRONG! This is a problem in Staffordshire Bull Terriers,
within the breed as a whole, not within any particular breeding line.
The reason that initially only certain lines were showing the problem is
because, having produced affected pups, responsible breeders within
those lines joined the research for the DNA test. As testing is becoming
more commonplace L-2 carriers are showing up across the broad in various
`lines`. It is thought that this problem goes back probably over at
least eight generations of Staffords - look at the majority of Stafford
pedigrees and you will find common ancestry when you start delving back.
WHAT IS THE PROGNOSIS FOR AN L-2 AFFECTED DOG?
L-2 can vary from dog to dog, so in the worst case scenario the severity
of the seizures can be so awful that the owner decides the best course
of action for the dog is to have it put to sleep to save further
suffering. The medication necessary to control the condition is
anti-convulsant (phenobarbitone) and therefore strong and powerful, as
well as expensive! It also needs to be administered at very regular
intervals to have the correct effect. A dog on such medication needs a
VERY regular routine to be able to live a normal life. Some more mildly
affected dogs have lived without medication, owners dealing with the
symptoms by keeping out of stressful conditions, maintaining an even
keel so as not to stimulate seizures. Herbal tranquillisers have had
effect. Similar to epilepsy, it can be progressive and have spells where
the dog remains the same for a period of time, to later deteriorate.
WHAT IS THE DNA TEST?
The DNA test is a one-off test that will determine the genetic status of
your dog. There are three possible outcomes of the test. It will be:
CLEAR (UNAFFECTED or NORMAL)-that is NOT affected by L-2,nor a carrier
of the mutant gene which produces L-2
CARRIER - that is not affected by L-2 but carrying one copy of the
mutant gene, which will be passed on to, on average, 50% of it’s
AFFECTED - affected by the L-2 condition and carrying two copies of the
HOW DO I GET MY DOG TESTED?
Testing is now simple - your vet needs to take 3mls of blood (this can
be done while you are at the vets for any other routine procedure) and
send it to the Animal Health Trust at Newmarket for DNA testing. When
research was underway urine samples were used to determine whether or
not the dog was affected (not for carrier status) - this is no longer
HOW LONG DOES TESTING TAKE?
Testing can take around six weeks for results to come back so make sure
you have submitted blood samples long before you plan your matings.
WHAT WILL THE RESULT MEAN FOR ME WHEN I AM BREEDING FROM THE DOG?
The result will mean that you can breed responsibly with the knowledge
that by making sure you only ever breed clear to clear, or clear to
carrier that you NEVER produce affected puppies. If you have a carrier
dog and decide to breed from it, the mating MUST be to a clear dog and
then you must test all puppies to determine their genetic status. It is
sensible to then endorse the registration papers of the carrier pups so
that progeny of these pups cannot be registered with the KC and explain
the importance to their new owners that they should NOT be bred on from
without serious consideration and the responsibility (ie. mating only to
a tested clear dog and then testing and endorsing pups). Some breeders
may chose to ensure that any subsequent carrier pups will be neutered
when they are old enough
Combination of Dogs
Combination of Dogs Acceptable
Clear x Clear
All puppies will be clear
No need to test puppies
Clear x Carrier
50% of puppies will be clear
50% of puppies will be affected
Test all puppies for breeding
Clear x Affected
All puppies will be carriers
No need to test puppies
Carrier x Carrier
25% of puppies will be clear
25% of puppies will be affected
50% of puppies will be carriers
Carrier x Affected
50% of puppies will be affected
50% of puppies will be carriers
Affected x Affected
ALL PUPPIES WILL BE AFFECTED
HOW CAN PUPPIES BE TESTED?
Puppies can be tested by submitting 3ml of blood in the same way as
adults. Obviously pups will have to be old enough to have blood taken,
probably around 4 weeks, and it will be necessary to be totally accurate
about identifying the individual puppy. It is proposed to begin testing
by taking a buccal (cheek cell) swab in the near future. This may be an
easier and less traumatic way of testing puppies, again the pup would
need to be 4 weeks old to swab
WILL THE RESULT BE ACKNOWLEDGED ON DOCUMENTATION?
The Kennel Club has been approached by the SBT Breed Council to ensure
that future KC registration documents will results of L-2 HGA tests. The
results will also be published in the Breeds Record Supplement. This
should be effective from the beginning of 2006
COMBINED GENETIC TESTING
The genetic test for Hereditary Cataract is now available to the public.
For anyone who has already submitted blood for L-2 testing, the same
blood sample can be able to be used by the AHT for HC testing. It is
possible to test for both HC and L-2 HGA from one blood sample and using
one combined form, paying £100 for both tests
DNA profiling has been underway for quite a while now as a means of
identifying beyond dispute an individual dog’s parentage. Although the
DNA for any dog profiled will be recorded it is not possible to use this
for genetic testing. Each test requires specific differing methods of
extracting the DNA, therefore separate swabs would need to be used
It is advisable to ensure that individual dogs are microchipped, then
when samples are taken for genetic testing, whether by blood or swab,
the details of the microchip can be entered on the accompanying form.
Although it will be possible for swab kits to be sent out to individuals
for `home use` it may be best if the swabs are actually used under
veterinary supervision for third party integrity and also to ensure that
the swabs are used correctly. If the swabs aren’t handled properly you
will find they are returned - another length of time before you will get
your results!. It will be essential that any litters of puppies DNA
tested are identified accurately. If pups aren’t obviously different by
their coat markings they could wear differing coloured collars, have
differing coloured nail varnishes applied to nails on one foot or
perhaps cut a small piece of fur from differing areas of the coat
In an ideal world we should all use DNA testing on all our breeding
stock from now on, mate only clear to clear or clear to carrier then
test pups. It is unlikely that many people will choose to mate carrier
dogs, partly because of the expense involved in testing a whole litter
(£60 per pup). In this way within a few generations the condition will
become self-limiting and carriers would be phased out. It must be
accepted that only responsible breeders will use the test, leaving the
rogue gene still out there unseen
In the future once the Kennel Club registration documents contain the
result of L-2 testing it will be accepted that pups from two L-2 tested
clear parents will be hereditarily clear and recorded as such without
need for further testing