Chapter 109

## Abstract

1. Adenosine deaminase (ADA)and purine nucleoside phosphorylase (PNP) catalyze sequential steps in the metabolism of purine ribo- and deoxyribonucleosides. They are expressed at very high levels in lymphoid cells. In patients with heritable deficiency of ADA or PNP, actions of their substrates or related metabolites impair lymphocyte differentiation, viability, and function, resulting in lymphopenia and immunodeficiency. Most patients with ADA deficiency lack both cell-mediated (T cell) and humoral (B cell) immunity, resulting in severe combined immunodeficiency disease (SCID). PNP-deficient children have defective cell-mediated immunity but may have normal, hyperactive, or reduced humoral immunity. Most patients with these disorders are severely affected and present during infancy and early childhood with recurrent infections involving pathogens and opportunistic organisms. Autoimmunity and neurologic abnormalities may occur with either enzyme deficiency, and hepatic dysfunction occurs in some patients with ADA deficiency.

2. ADA deficiency (MIM 102700) has been identified in several hundred families, and PNP deficiency in less than 50. Increasingly, enzyme-deficient patients with later onset and milder or atypical clinical presentations are being recognized. These diagnoses should be considered in patients with unexplained T-cell lymphopenia and late manifestations of immunodeficiency, such as chronic pulmonary insufficiency, sometimes with a history of autoimmunity and neurologic abnormalities, during the first two decades of life and even later. Diagnosis is made by finding absent or very low enzyme activity in erythrocytes or in nucleated blood cells. Heterozygotes have normal immune function and approximately half the normal erythrocyte enzyme levels. Prenatal diagnosis can be established by measuring enzyme activity in amniotic cells or chorionic villi.

3. Both conditions are inherited in an autosomal-recessive manner. Structural genes are located on chromosomes 20q13.11 (ADA) and 14q13 (PNP). Over 60 ADA gene mutations have been identified in immune-deficient patients. Several others have been found in a small group of individuals with so-called partial ADA deficiency, who are clinically unaffected owing to significant ADA activity in nucleated cells despite nearly absent levels in erythrocytes. There is a good correlation between the ADA activity expressed in vitro by mutant ADA alleles and clinical severity. Fourteen PNP mutations have been identified. The developmental and tissue-specific expression of ADA and PNP genes have been investigated, and the three-dimensional crystal structures of murine ADA and human PNP have been determined.

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