Understanding the Role of Erythrocyte Adenosine Deaminase in the Ribosomopathies

Diamond Blackfan anemia (DBA) is congenital bone marrow failure syndrome characterized by red cell aplasia and a predisposition to cancer. It was the first disease linked to ribosomal dysfunction with 70% of patients having haploinsufficiency of a ribosomal protein (RP) gene with RPS19 being the most frequently mutated. The 5q- syndrome is a subtype of myelodysplastic syndrome (MDS) also characterized by a severe anemia that is caused by heterozygous loss of RPS14 on chromosome 5q. These patients also have a predisposition to cancer. The reciprocal relationship between these two diseases, which are now collectively known as the ribosomopathies, has spurred interest in how we may be able to better understand the pathophysiology of these ribosomopathies to broaden therapeutic options, and to improve diagnosis.

Erythrocyte adenosine deaminase (eADA) levels have been used for last three decades in the diagnosis of Diamond Blackfan anemia based on the finding in 1983 that eADA enzyme levels are significantly elevated in patients with DBA. It is now known the eADA levels are elevated in >75% of patients with DBA. Furthermore, it has a sensitivity of 84%, specificity of 95% and positive and negative predictive values of 91% for the diagnosis of DBA compared with other inherited bone marrow failure syndromes. Our goal was to study the levels of eADA in patients with the 5q- syndrome to determine whether they were elevated (suggesting that eADA may be specific to ribosomal haploinsufficiency in general) or normal (suggesting that eADA may be specific to DBA).

Under a Stanford approved IRB, we are testing adult patients with the 5q syndrome who have not been transfused in the previous 3 months (which would affect the results of the test) and who have a confirmed deletion of the 5q- region by cytogenetics. To date, all of the 4 MDS samples, sent to us from collaborating hematologists, have had a normal eADA level. These findings suggest that elevation of eADA may be specific to DBA and not a general feature of ribosomal haploinsufficiency although our sample size is small and we plan to test additional samples.