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Combined familial adenosine deaminase and purine nucleoside phosphorylase deficiencies
A Shanon1, S Levin, F Holtzman
1Department of Paediatrics, Kaplan Hospital, Rehovot, Israel.
Insights
Severe combined immunodeficiency (SCID) in an Arab family was linked to adenosine deaminase (ADA) deficiency. Even partial enzyme activity protected against SCID, highlighting the importance of residual enzyme function.
Area of Science:
- Immunology
- Biochemistry
- Genetics
Background:
- Severe combined immunodeficiency (SCID) is a group of rare genetic disorders characterized by profound defects in both T-cell and B-cell immune functions.
- Adenosine deaminase (ADA) deficiency and purine nucleoside phosphorylase (PNP) deficiency are known causes of SCID, impacting purine metabolism and lymphocyte development.
Observation:
- A consanguineous Arab family presented with multiple infant deaths due to infections, suggestive of SCID.
- Affected infants exhibited severe combined immunodeficiency, with one also showing reduced purine nucleoside phosphorylase (PNP) activity.
- Clinical manifestations included hyperpigmented skin lesions preceding death in some infants.
Findings:
- Complete absence of adenosine deaminase (ADA) in white blood cells was directly correlated with the development of severe combined immunodeficiency.
- Heterozygous carriers (parents and healthy siblings) displayed varying degrees of partial ADA and PNP deficiencies.
- Minimal residual ADA and/or PNP activity in affected individuals was sufficient for immune system maturation and normal immune function, despite partial enzyme deficiencies.
Implications:
- This study underscores the critical role of ADA and PNP in immune system development and function.
- Understanding the genotype-phenotype correlation in ADA and PNP deficiencies can aid in genetic counseling and potential therapeutic strategies.
- The findings suggest that even low levels of residual enzyme activity may confer significant protection against severe immunodeficiency, offering hope for milder forms of the disease.
Abstract:
We studied an Arab family in which two infants died of severe combined immunodeficiency caused by adenosine deaminase (ADA) deficiency. One infant had purine nucleoside phosphorylase (PNP) activity in the leucocytes only half that of normal. Four other infant siblings had previously died from infections before the age of 2 months. Hyperpigmented skin lesions preceded death in three cases. The healthy parents and three healthy siblings aged 4-9 years had varying degrees of both ADA and PNP deficiencies in both white and red cells. ADA deficiency was pronounced in two siblings, and mild in the third and in the parents, and PNP activity was severely deficient in one sibling, and moderately deficient in the parents and other two siblings, who were all well. Complete absence of ADA from white cells lead to the development of severe combined immunodeficiency, but even minimal residual ADA and PNP activity allowed maturation of the immune system with normal immune function.