Severe combined immunodeficiency disease

Low levels or absence of adenosine deaminase (ADA) is associated with one form of severe combined immunodeficiency disease (SCID) characterized by B-andT-lymphocyte dysfunction due to toxic effects of deoxyadenosine (HI9). Most patients present as infants with failure to thrive, repeated infections, severe lymphopenia, and defective cellular and humoral immunity. Disease severity is correlated with the degree of deoxyadenosine nucleotide pool expansion and inactivation of S-adenosylhomocysteine hydrolase in red blood cells. Up to now, more than 40 mutations have been identified (A4, H20, S5, S6). The majority of the basic molecular defects underlying ADA deficiency of all clinical phenotypes are missense mutations. Nonsense mutations, deletions ranging from very large to single nucleotides, and splicing mutations have also been reported. It is likely that severe... 

Currently, there is stUl a gap for the potential of gene therapy to be fulfilled. Gene therapy clinical trials have been conducted for diseases such as severe combined immunodeficiency disease (SCID, bubble baby syndrome), sickle cell anemia, cystic fibrosis, familial hypercholesterolemia, and Gaucher disease. 

Severe combined immunodeficiency disease The enzyme adenosine deaminase degrades deoxyadenosine which is produced during DNA degradation (Chapter 10). Deficiency of the enzyme results in accumulation of deoxyadenosine which is a substrate for adenosine kinase and leads to production of deoxyadenosine and deoxyquanosine triphosphates, which reach high concentrations. This disturbs the balance of deoxy nucleotides which results in failure of DNA replication. This enzyme is normally present in lymphocytes so that a deficiency prevents proliferation of the lymphocytes, which is essential in combatting an infection. Consequently, patients are very susceptible to infections. This is one disease that is effectively treated by gene therapy. 

Familial hypercholesterolemia Severe combined immunodeficiency diseases... 

Indications Enzyme replacement therapy for adenosine deaminase (ADA) deficiency in patients with severe combined immunodeficiency disease (SCID) who are not suitable candidates for—or who have failed— bone marrow transplantation... 

E. Therapeutic response Adagen has been effective in reversing biochemical abnormalities in children with adenosine deaminase deficiency and severe combined immunodeficiency disease (SCID). It is... 

Dunbar, C., L. Chang, C. Mullen, et al.. Amendment to Clinical Research Project. Project 90-C-195. April 1,1993. Treatment of severe combined immunodeficiency disease (SCID) due to adenosine deaminase deficiency with autologous lymphocytes transduced with a human ADA gene. Hum Gene Ther, 1999.10(3) 477-88. 

As an example, at least one of the trials was criticized after a volunteer died following poor clinical practices. In another trial three patients were successfully treated for an x-linked severe combined immunodeficiency disease but 2 years after the treatment two of the patients developed T-cell acute lymphoblast leukemia. The FDA promptly placed a ban on any further similar clinical studies. 

The use of HLA-non-identical T-cell-depleted marrow transplants for correction of severe combined immunodeficiency disease. O Reilly, R.J., Keever, C.A., Small, T.N., Brochstein, J. (1989). Immunodefic Rev, 1 (4) 273-309. 

Adenosine deaminase deficiency results in an accumulation of adenosine, which is converted to its ribonucleotide or deoxyribonucleotide forms by cellular kinases. As dATP levels rise, they inhibit ribonucleotide reductase, thus preventing the production of deoxyribonucleotides, so that the cell cannot produce DNA and divide. This causes severe combined immunodeficiency disease, involving a lack of T cells and B cells. 

Adagen (adenosine deaminase) approved for treatment of severe combined immunodeficiency disease. 

B-4) Adenosine deamina.se deficiency. This is associated with low numbers of lymphocytes, severe combined immunodeficiency disease, and sometimes liver disease. There is an overproduction of ATP and dATP, which leads to an imbalance that upsets the proliferatimi of immune cells. Gene replacement for this enzyme is under investigation. 

Adenosine deaminase (ADA EC 3.5.4.4) is the enzyme of the purine metabolism that deaminates adenosine and l deoxyadenosme to inosine and 2 -deoxymosine, respectively. ADA deficiency, which leads to severe combined immunodeficiency disease (SCID), is associated with a decrease in RBC adenosine deaminase activity, without hemolysis. ADA deficiency will not be discussed here. 

Mutations in the tyrosine phosphatase CD45 gene in a child with severe combined immunodeficiency disease. Nat Med 6 343-345... 

Antitumor activity of Fab and IgG-anti-CD22 immunotoxins in disseminated human B lymphomas grown in mice with severe combined immunodeficiency disease effect on tumor cells in extranodal sites. Cancer Res. 51,5876-5880. 

Infants with severe combined immunodeficiency disease (SCID, bubble boy syndrome) have a gene defect that leads to a complete lack of white blood cells. Without treatment, these infants die from complications of infectious diseases during the first few years of life. The only treatment currently approved for this condition is a bone marrow transplant. 

Gout Severe combined immunodeficiency disease (SCiD) Multiple causes Adenosine deaminase (purine salvage pathway) Uric acid Deoxyadenosine and derivatives thereof Painful joints Loss of immune system, including no T or B cells... 

In X-linked severe combined immunodeficiency disease (SCID), the most common form of SCID, circulating T lymphocytes are not formed, and B lymphocytes are not active. The affected gene encodes the gamma chain of the interleukin 2 receptor. Mutant receptors are unable to activate JAK3, and the cells are unresponsive to the cytokines that stimulate growth and differentiation. Recall also that adenosine deaminase deficiency (see Chapter 41), which is not X-linked, also leads to a form of SCID, but for different reasons. 

Biochemical Connections Severe combined immunodeficiency disease (SCID) is characterized by the complete lack of an immune system. Strains of mice have been developed that have SCID. When SCID mice that carry genetic predisposition to prion diseases are infected with PrP , they do not develop prion diseases. How do these facts relate to the transmission of prion diseases ... 

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