Severe Combined Immunodeficiency
Disease (SCID)
By June Swinburne PhD and Matthew Binns PhD
Severe Combined Immunodeficiency Disease (SCID) is an inherited
disease specifically seen in pure and part-bred Arab horses.
Foals afflicted with this condition have an enhanced susceptibility
to infection and first show signs of disease at between two
days and eight weeks of age. Clinical diagnosis of the disease
is not straightforward as the symptoms, such as raised temperature,
respiratory complications and diahorrea, are typical of new-born
foals with a range of infections. SCID affected foals always
die within the first six months of life, regardless of the
level of veterinary care administered. SCID is therefore a
distressing condition both for the animals involved and the
owners and carers of the horses, and results in financial
loss due to dead foals and veterinary expenses.
SCID is an inherited disease
Although SCID has probably been present in Britain for approximately
100 years, it was not until the 1970's that it was identified
as a specific disease. This is mainly due to the fact that,
as outlined above, the symptoms are not unique to SCID. This
difficulty in diagnosis has hindered the control of the disease;
if affected foals are not identified as SCID victims their
parents will continue to be used for unrestricted breeding.
SCID is unlike other genetically inherited defects of the
horse such as cryptorchidism, parrot mouth or clubfoot, in
that there is no visible defect at birth. SCID is rather a
deficiency of the immune system which predisposes the new-born
foal to infection. The immune system has two major defence
systems, the B-lymphocytes which produce antibodies, and the
T-lymphocytes which are responsible for cell-mediated immunity.
The SCID defect, or mutation, results in an inability to produce
either B- or T-lymphocytes, so the affected foal effectively
has no immune system, leaving it susceptible to infective
pathogens.
Mode of Inheritance
The mode of inheritance of SCID was studied in test coverings
during the 1970s. It was shown that SCID is caused by an 'autosomal
recessive mutation'. Offspring inherit one copy of all genes
from their mother and another complete copy from their father.
With a recessive mutation, one gene copy in the individual
may be defective, but providing the second copy inherited
from the other parent is normal, it will function and the
animal will appear perfectly normal. In SCID this means that
foals which inherit only one copy of the defective gene (inherited
from either their dam or sire) do not show any symptoms of
the disease, but do carry it and can pass it on to their offspring.
This is where the problem arises; 'carriers' appear perfectly
normal and cannot be identified by appearance. Until now carrier
horses could only be identified in the breeding population
once they produced affected offspring - affected foals can
result only from breeding two carriers, so an affected foal
proves that both of its parents are carriers. However, if
a carrier is never bred with another carrier (or if affected
offspring have not been identified as SCID victims), it would
not be identified as a carrier, although 50% of the offspring
will themselves be carriers. In this way the disease is propagated.
It is worth noting that only one quarter of offspring resulting
from the breeding of two carriers will be affected foals and
none of the offspring from a normal-carrier mating will be
affected. A string of healthy offspring cannot therefore prove
that an animal is not a carrier. Finally, the disease is not
sex-linked, i.e. males and females are equally likely to be
affected.
Methods of diagnosis
Before the characterisation of the mutation which causes
SCID, affected foals were identified by clinical means involving
blood lymphocyte and immunoglobulins counts. However SCID
could only be definitively diagnosed during post-mortem; the
major physical characteristic of a SCID foal is hypoplasia
- defective development of the lymph tissues - which is conclusively
diagnosed under the microscope.
The major new development in SCID testing, which has been
developed during the last few months, has been a DNA test
for carriers. These individuals, who are responsible for the
propagation of the disease and have been hitherto impossible
to identify directly, can now be quickly identified by an
inexpensive blood test. The creation of this test results
from the recent identification of the precise cause of SCID.
Combined immunodeficiencies occur in other animals and it
was postulated that the same gene could be affected in both
the horse and mouse versions of the disease. This proved to
be the case. The gene affected in SCID (DNA-dependent kinase,
catalytic subunit) is required to manufacture B- and T-lymphocytes
and is totally inactivated by the mutation. This explains
the total lack of immunity in the affected foals. By determining
the sequence of the defective gene in an affected foal, it
was shown that the mutation was a loss (or deletion) of five
nucleotides from the DNA.
The new test for SCID carriers
The new test is DNA based and requires a small blood sample
to be taken from the horse in question - only five millilitres
(one teaspoonful) is needed. A molecular biology technique
known as the polymerase chain reaction (PCR) is then used
to specifically amplify only the tiny region of the DNA which
is affected by SCID. The samples are then run on a diagnostic
apparatus which determines the length of the DNA fragments
generated during PCR. If the horse is normal the length will
be 163, if the horse is affected the length will be 158, and
if the horse is a carrier both of these lengths will be present.
An example of these results is shown in Figure 2.
The test can also be used to confirm cases where an ill foal
is suspected to be a SCID case.
Incidence of SCID
There have been a number of studies during recent years which
attempt to estimate the true frequency of SCID carriers in
the Arab horse population. Most sources speculate that the
percentage of Arab foals which die of SCID is 2-3%. If coverings
are random this would imply that 28-35% of Arab horses are
carriers. Selective breeding ensures that covering is not
random however, so the true frequency of carriers in the population
may fall outside this range.
The most recent study, involves the testing of 106 'random',
anonymous Arab horses which have been submitted for blood
typing to the Animal Health Trust during the latter half of
1997 and early 1998. Of these 106, only three are carriers.
Assuming random mating, the chances of producing a SCID affected
foal from these sampled horses would be as low as 0.0225%.
Reducing the incidence of SCID
There are two aspects to examine when considering the reduction
of SCID. The first is the removal of SCID from the Arab horse
population as a whole and the second is the prevention of
the conception of affected foals.
The ultimate aim for the future would be the complete elimination
of the SCID gene from the Arab horse breeding population.
This would require the gradual withdrawal of all carrier horses
from breeding. If the percentage of carriers in the population
turns out to be high this would take a number of years, but
would eventually remove the need to test any further individuals
for SCID. Realistically, preventing the breeding of carriers
may in fact be undesirable, particularly if highly acclaimed
animals prove to be carriers. The SCID defect is only one
aspect of a carrier's genetic make-up and the desirable characteristics
carried may outweigh this fault. One advantage which the new
carrier test provides is that carriers can now be confidently
used in breeding programmes with no fear of producing an affected
foal. If carriers are only bred with normal horses, there
is no possibility of generating a SCID foal. The progeny of
all carriers will however need to be tested to determine whether
they are normal or are carriers. The use of carriers in breeding
should therefore carry no stigma, but responsible breeders
will now ensure that they do not pair a carrier with a carrier.
In the long term, the aim for the breed should be to reduce
the frequency of carrier-normal matings to lead to the eventual
elimination of SCID whilst maintaining desirable genes.
To find out more about the AHT why not visit their website
www.aht.org.uk
