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 Deaminase Deficiency).
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 to develop
alternative methods of treatment that would change the genotypes of ADA deficient humans.
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.
References

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, New Jersey.
P699-700.

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