Adenosine Deaminase Deficiency
by Chris Marting
Adenosine Deaminase Deficiency, commonly called ADA deficiency, is a very
rare genetic disorder, documented as occurring in only a few dozen humans.
This disease is also quite lethal, leading to death in virtually all those
afflicted if not treated. The disease is an autosomal recessive disease
caused by receiving a deficient ADA gene from both parents. The ADA gene
codes for the enzyme Adenosine Deaminase which is essential for the proper
functioning of the human body's immune system. People afflicted with this
disease often have to live in a sheltered or enclosed environment, so that
they're not exposed to infectious agents. One of the more commonly known
cases of ADA deficiency was "The Boy in the Bubble" in which a
little boy had to live his life in a enclosed bubble structure that shielded
him from the outside world (Klug, Concepts of Genetics). ADA deficiency
causes an increase of dATP, which inhibits S-adenosylhomocysteine hydrolase,
causing an increase in S-adenosylhomocysteine. Both dATP and S-adenosylhomocysteine
have toxic affects on lymphocytes, causing them to be functionally defective.
The defective function is caused by a depletion of all of the dNTP pools.
This causes a breakdown in DNA synthesis and repair of breaks occurring
in the DNA.
There have been many attempts to try to relieve symptoms, as well as the
disease itself, in those afflicted. Since ADA is carried in the blood, early
attempts were made to relieve symptoms by transfusing blood from ADA positive
humans into ADA deficient individuals. However, this procedure was quickly
abandoned as ineffective, as well as
toxic. Since ADA has a half-life of a few minutes, transfusions would need
to be given constantly to be an effective treatment. Obviously this in itself
is quite impractical. In addition, intracellular iron concentrations would
increase with continuous transfusions, eventually leading to a toxic reaction.
Another method has been devised to allow ADA to stay in the bloodstream
longer. Polyethylene glycol, commonly called PEG, forms a conjugation with
ADA and has been experimentally tested for its effects. Most patients treated
with a transfusion of PEG-ADA show dramatic results in ADA activity. There
is a marked increase in AXP concentrations (AXP=ATP+ADP+AMP), and a decrease
in dAXP concentrations, which would explain the reversal of the toxic effects
associated with ADA deficiency. The immune systems of people that show positive
results for PEG-ADA treatment have been shown to be relatively normal, although
people receiving treatment of PEG-ADA with a serious infection have never
been studied. Receiving weekly transfusions of PEG-ADA can have the effect
of sustaining the immune system in an ADA deficient patient, thus this treatment
has allowed an increase in the ADA half-life from minutes to weeks. Although
this treatment does not change the genotype of ADA deficient humans and
only changes the phenotype for a period of time, this treatment is the most
commonly used because of its high percentage of positive effects and its
relatively cheap cost. Also, most patients receiving or awaiting other treatments
use this treatment to sustain their life (Hershfield, Treatment of Adenosine
The studies and treatments described above are efforts to correct the phenotypes
of ADA deficient humans and although they work most of the time, they don't
cure the problem (i.e. change the genotype). Thus there was a need for researchers
alternative methods of treatment that would change the genotypes of ADA
Since T cells, responsible for the initiation of the immune response, are
manufactured in the bone marrow of human beings, bone marrow transplants
from normal healthy individuals into ADA deficient humans was an approach
taken to possibly change the genotype of these patients. This treatment
is theoretically effective, but certain considerations must be made. People
that are willing to be a donor must be screened to determine if their bone
marrow is compatible in the patient's body. If marrow is transplanted into
a person without proper screening of body antigens, the body will elicit
an immune response and kill these cells, thus rendering the procedure unsuccessful.
Due to this compatibility factor, patients often have a hard time finding
donors for this procedure. Often the best hope of finding a match is in
a twin, a sibling, a parent, or other close family member. In one case,
a young girl approximately four months of age received a bone marrow transplant
from her father. This produced a positive effect inside her marrow, where
the functioning marrow cells, with the proper enzymes, reproduced and populated
her bone marrow. This allowed the little girl to develop her immune system
to a functional level, although her status as of now is not known.
With the advent of recombinant genetics, new approaches in the treatment
of ADA deficiency have been devised. These procedures use retroviruses to
introduce synthetically made DNA into target tissues in the body, thus changing
the genotype of the patient. The retroviruses are made avirulent, so that
only the target gene, or ADA gene, is allowed to be transcribed and translated
inside of the host's cells, thus preventing an infection from occurring.
This procedure was been tested in various ways on the various tissues or
cells that are affected along the pathway. In a particular case, a girl
named Shelly underwent treatment with an ADA positive avirulent retrovirus
on the mature T cells that had been separated from her blood plasma. After
treatment, these cells were injected into her body, and a positive effect
was shown in stimulating her immune system. A drawback to this treatment
is that it needs to be done every few weeks, thus it only changes the genotype
of previously produced T cells, not the cells that are producing them.
The same procedure was repeated on a patient named Todd, except this time
the target cells were immature T cells found in the bone marrow. This procedure
also produced a functioning immune system, although not to full function.
It is believed he will also have to come back for further treatments just
as Shelly does, but not as frequently because the treatment is being administered
to cells in an earlier stage of development.
There are many ethical questions humans must deal with related to this disease.
For instance, should we screen people for the possibility of being carriers
of this disease? Also, should people afflicted with this disease be able
to reproduce and possibly pass on this horrible disease? Since ADA deficiency
is an autosomal recessive trait, it is very hard for an individual to have
it, since both parents would have to have the recessive gene and pass it
on to their offspring. Parents who are both heterozygous for this trait
would have a 25% chance of having a child with this disease. A parent who
was homozygous and a parent that was heterozygous would have a 50% chance
of having a child with this disease. Parents who were both homozygous for
the trait would have a 100% chance of having a child with this disease,
so people like Shelly and Todd couldn't have children who would be normally
healthy. Also, in people who are treated for the disease and cured, only
their somatic cells are cured, not their reproductive cells, so one's original
genotype must be considered when determining the chance of passing the disease
on to one's offspring.
Although this disease is incurable to date, treatments are able to maintain
a person so they can lead a somewhat normal life. As experimentation continues
in this and other related fields, such as AIDs, which is an agonist of ADA
deficiency, there will likely be new ways found to treat patients and quite
possibly even a cure.
Hershfield, Michael. Treatment of Adenosine Deaminase Deficiency with Polyethylene
Glycol-Modified Adenosine Deaminase. New England Journal of Medicine, March
5, 1987. p589-596.
Klug, William., Cummings, Michael. Concepts of Genetics. Prentice Hall,
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