Deaminase Deficiency

Myoadenylate deaminase (or AMP deaminase) deficiency is a relatively benign muscle disorder characterized by fatigue and exercise-induced muscle aches. This disorder is presumably inherited as an autosomal recessive trait. The relationship between the exercise-induced skeletal muscle dysfunction and AMP deaminase deficiency is explained by an interruption of the purine nucleotide cycle. 

During muscle contraction AMP deaminase activity increases. Nucleoside triphosphates are negative modulators, whereas nucleoside di- and monophosphates are positive modulators of the enzyme. The increased AMP deaminase activity prevents accumulation of AMP so that the adenylate kinase reaction favors the formation of ATP ADP - -ADP ATP -k AMP. 

The NH3 produced in the AMP deaminase reaction and the decreased levels of ATP as a result of exercise stimulate phosphofructokinase to enhance the rate of glycolysis (Chapter 13). 

The increased concentration of IMP may activate glycogen phosphorylase and further enhance glycolysis. 

The formation of IMP may provide a means by which the intracellular purine nucleotide pool is maintained. AMP deaminase deficiency disrupts the purine 

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The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Adenosine deaminase deficiency is associated with an immunodeficiency disease in which both thymus-derived lymphocytes (T cells) and bone marrow-derived lymphocytes (B cells) are sparse and dysfunctional. Purine nucleoside phosphorylase deficiency is associated with a severe deficiency of T cells but apparently normal B cell function. Immune dysfunctions appear to result from accumulation of dGTP and dATP, which inhibit ribonucleotide reductase and thereby deplete cells of DNA precursors. 

Adenosine deaminase 20q13-qter Adenosine deaminase deficiency... 

H3. Hershfield, M. S Chaffee, S., and Sorensen, R. U., Enzyme replacement therapy with polyethylene glycol-adenosine deaminase in adenosine deaminase deficiency Overview and case reports of three patients, including two now receiving gene therapy. Pediatr. Res. 33 (Suppl.), S42-S48 (1993). 

H4. Hershfield, M. S., and Mitchell, B. S., Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In Metabolic and Molecular Bases of Inherited Disease, 7th ed. (C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, eds.), pp. 1725-1768. McGraw-Hill, New York, 1995. 

Hershfield MS (1995) PEG-ADA an alternative to haploidentical bone marrow transplantation and an adjunct to gene therapy for adenosine deaminase deficiency. Hum Mutat 5 107-112... 

Sabina, R. L. Myoadenylate deaminase deficiency. A common inherited defect with heterogeneous clinical presentation. Neurol. Clin. 18 185-194,2000. 

Gene engineering is the basis of gene therapy where genes are removed, replaced, or altered producing new proteins for the treatment of diseases such as muscular dystrophy, some cancers, adenosine deaminase deficiency, cystic fibrosis, and emphysema. 

The answer is D. Impaired immune function in severe combined immunodeficiency (SCID) is the direct result of blocked DNA synthesis due to inadequate supplies of de-oxyribonucleotides in B and T cells. This effect arises by dATP-induced allosteric inhibition of ribonucleotide reductase, which catalyzes reduction of the 2 -hydroxyl groups on ADP and GDP to form dADP and dCDP. The ultimate cause of many cases of SCID is adenosine deaminase deficiency, which leads to accumulation of dATP and consequent inhibition of ribonucleotide reductase. Although the other enzymes mentioned are also involved in purine nucleotide metabolism, their deficiencies do not lead to SCID. 

Mutation in the adenosine deaminase gene on chromosome 20 can cause severe combined immunodeficiency due to absence of T cells, B cells, and natural killer cells (T cell-negative, B cell-negative, natural killer cell-negative autosomal recessive SCID). The lack of the enzyme adenosine deminase results in the accumulation of adenosine and toxic deoxyadenosine nucleotides. The latter can cause apoptosis of lymphocytes. Lymphocyte counts can be as low as 0.5 x 10 /L, affecting primarily T cells which are absent (105). While therapy of missing enzyme has been shown to effect improvement, bone marrow transplantation is the preferred treatment. Milder forms of adenosine deaminase deficiency have been reported (116). 

Adenosine deaminase deficiency Mutation in chromosome 20 results in T cell—negative,... 

Giblett, E.R., J.E. Anderson, F. Cohen, B. Pollara, and H.J. Meuwissen, Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet, 1972. 2(7786) 1067-9. 

Hirschliorn, R., Overview of biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res, 1993. 33(1 Suppl) S35-41. 

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... 

F. Role in therapy According to Micromedex, the goal of therapy with Adagen is to correct immune function by reversal of the biochemical abnormalities caused by adenosine deaminase deficiency. Adagen s role in therapy at this time would appear to be as an alternative when bone marrow transplantation is not feasible or has been unsuccessful. It may also be considered in lieu of transplantation in milder cases of adenosine deaminase deficiency. Adagen is preferable to red cell transfusions in these patients. While regular administration of Adagen can improve immune function and reduce the incidence of opportunistic infections in patients with ADA-deficient SCID, it is of no value in patients with immunodeficiency due to other causes. 

Hershfield, M.S., R.H. Buckley, M.L. Greenberg, A.L. Melton, R. Schiff) C. Hatem, J. Kurtzberg, M.L. Markert, R.H. Kobayashi, A.L. Kobayashi, et al., Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N Engl J Med, 1987. 316(10) 589-96. 

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. 

Gene therapy holds great promise for the treatment of many diseases (e.g., cancer, AIDS, cystic fibrosis, adenosine deaminase deficiency, cardiovascular diseases, Gaucher disease, a 1-antitrypsin deficiency, rheumatoid arthritis, and several others) (1,2). Advances in genomics and molecular biology have revealed that almost all diseases have a genetic component. In some cases, such as cystic fibrosis or hemophilia,... 

Individuals affected with porphyria present with acute attacks, skin lesions, or both. The onset of these attacks rarely occurs before puberty. An attack usually consists of severe abdominal pain and often neurological sequelae. During and after such attacks, excessive amounts of aminolevulinic acid and PBG are excreted in the urine. The most common porphyria is PBG deaminase deficiency (acute intermittent porphyria), which primarily affects liver function. A positive result coupled with a clinical indication of hepatosplenomegaly suggests that evaluation for tyrosine metabolites in the urine should be pursued (using the nitrosonaphthol test). 

Volume III, Pharmacology and Therapy, addresses developments in basic science, translational and clinical research that are underway to bring stem cell research to therapy, particularly for the treatment of Batten s diseases, graft-versus-host disease and adenosine deaminase deficiency. This volume covers the importance of stem cell research for the understanding of drug activities and design. It also addresses the ethical issues and constraints involved in stem cell research, and its commercial applications. 

San Raffaele Telethon Institute for Gene Therapy is developing an adenosine deaminase transduced hematopoietic stem cell therapy for the potential intravenous treatment of adenosine deaminase deficiency in severe combined immunocompromised individuals (ADA-SCID). 

Successful peripheral T-lymphocyte-directed gene transfer for apatient with severe combined immune deficiency caused by adenosine deaminase deficiency. Onodera, M., Ariga, T., Kawamura, N., Kobayashi, I., Ohtsu, M., Yamada, M., Tame, A., Furuta, H., Okano, M., Matsumoto, S., Kotani, H. et al. (1998). Blood, 91 (1) 30-36. 

Gene therapy for adenosine-deaminase-deficient severe combined immunodeficiency. Aiuti, A. (2004). Best Pract Res Clin Hematol, 17 (3) 505-516. 

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