Adenosine Deaminase Deficiency ADA deficiency is an inherited condition that occurs in fewer than one in 100,000 live

births worldwide. Individuals with ADA deficiency inherit defective ADA genes and are unable to produce the enzyme adenosine deaminase in their cells. The ADA gene is located on the long arm of chromosome 20. The enzyme adenosine deaminase is needed to break down metabolic byproducts that become toxic to T-cell lymphocytes, and is essential to the proper functioning of the immune system. Most of the body's cells have other means of removing the metabolic byproducts that ADA helps break down and remain unaffected by ADA deficiency. However, T-cell lymphocytes, white blood cells that help fight infection, are not able to remove the byproducts in the absence of ADA. Without ADA, the toxins derived from the metabolic byproducts kill the T cells shortly after they are produced in the bone marrow. Instead of having a normal life span of a few months, T cells of individuals with ADA deficiency live only a few days. Consequently, their numbers are greatly reduced, and the body's entire immune system is weakened. ADA deficiency is the first known cause of a condition known as severe combined immunodeficiency (SCID). Since T cells control B cell activity, the reduction of T cells results in an absence of both T cell and B cell function called severe combined immunodeficiency (SCID). Individuals with SCID are unable to mount resistance to any infection. Therefore, exposures to organisms that normal, healthy individuals easily overcome become deadly infections in SCID patients. Prior to present-day treatments, most ADA-deficient SCID victims died from infections before reaching the age of two. Although SCID is usually diagnosed in the first year of life, approximately one-fifth of ADA deficient patients have delayed onset SCID, which is only diagnosed later in childhood. There are also a few cases of ADA deficiency diagnosed in adulthood. The treatment of choice for ADA deficiency is bone marrow transplantation from a matched sibling donor. If successful, it can relieve ADA deficiency. Unfortunately, only 20–30% of patients with ADA deficiency have a matched sibling donor. Another treatment involves injecting the patient with PEG-ADA, polyethylene glycol-coated bovine ADA derived from cows. The PEG coating helps keep the ADA from being prematurely degraded. Supplying the missing enzyme in this way helps some patients fight infections, while others are helped very little. The latest treatment for ADA deficiency is gene therapy. Gene therapy provides victims with their own T cells into which a normal copy of the human ADA gene has been inserted. ADA deficiency is the first disease to be treated with human gene therapy.

Reticular Dysgenesis

Reticular dysgenesis (RD) is a rare form of severe immunodeficiency that is usually fatal unless a successful stem cell transplant is performed. RD is characterized by combined immunodeficiency and neutropenia. In 1959, de Vaal and Seynhaeve first described and since then, fewer than 30 cases have been described. The genetic basis for RD is not known. Both males and females are affected. Consanguinity has been noted in several families, suggesting an autosomal inheritance. Because of the profound level of immunodeficiency, RD is apparent within the newborn period. The pathology of the lymphoid tissues is similar to that observed in severe combined immunodeficiency (SCID). The thymus is small and dysplastic, containing mainly epithelioid cells but without Hassall corpuscles or thymocytes. Lymph nodes, tonsils, and Peyer patches are absent or small with markedly reduced numbers of lymphocytes. The spleen may be normal in size, but the number of lymphocytes is markedly reduced, and periarterial cuffing is absent. Erythrophagocytosis is observed in the spleen, bone marrow, and liver. The bone marrow may contain normal numbers of erythroid precursors and megakaryocytes; however, cells of the myeloid series are usually not observed. The circulating T lymphocytes are nonfunctional and do not respond to mitogenic stimulation. Langerhans cells are absent in patients with RD. In contrast, macrophages and monocytes are present. These findings suggest that the genetic defect responsible for RD may participate in the expansion of progenitors of the T lymphocytes and neutrophils but not of the B lymphocytes or monocytes. Other extrinsic factors may be responsible for the Langerhans cell defect. RD is an extremely rare disorder and is often classified as a variant of SCID. The frequency of SCID is estimated at 1 case per 100,000 people, and the incidence of patients with RD is estimated at less than 1 case per 3-5 million people. Because of the severity of the immunodeficiency, patients with RD die early in life unless they receive a stem cell transplant.