This case adds to our current knowledge of spontaneous reversion of mutations in ADA deficiency and shows that the effects of the ERT may vary among these patients, suggesting that it could depend on the cell and type in which the somatic mosaicism is established upon reversion. Autosomal recessive severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID, OMIM #102700) is characterized by severe and recurrent

early-onset infections, profound lymphopenia, absent cellular and humoral immunity and failure to thrive [1]. Its incidence is estimated between 1: 200,000 and 1: 1,000,000 live births and is the second most prevalent form of SCID, accounting for up to 20% of all cases. ADA is involved LY2157299 nmr in the metabolism of purine nucleosides,

and its deficiency causes excessive accumulation Vismodegib datasheet of Ado and dAdo and preferential conversion of the latter to the toxic compound dATP, leading to its accumulation in plasma, red blood cells (RBC) and lymphoid tissues, where it impairs lymphocyte development and function throughout different mechanisms (reviewed in [2]). More than 65 different mutations have been described in the ADA gene in humans, from which nearly 70% are missense and the rest non-sense and splicing mutations [3, 4]. Interestingly, these mutations usually correlate with the residual enzymatic activity as well as the extent of substrate accumulation and are reflected in a spectrum of clinical Glutamate dehydrogenase phenotypes [1, 3], being the most frequent the early onset or fatal infantile onset (ADA-SCID), characterized by the absence of enzyme activity and total dAXP increased by 300- to 2000-fold in RBC. Other less frequent variants include delayed or late onset and late or adult onset in some patients, as well as a partial ADA deficiency in a few healthy relatives of ADA-deficient patients [3–5]. ADA-SCID is commonly fatal within the first year of life, unless the immune system is reconstituted by haematopoietic stem cell transplantation (HSCT)

or gene therapy (GT) [6]. Yet another option of treatment for patients who lack an immediate HLA-matched stem cell donor is enzyme replacement therapy (ERT) with pegylated bovine ADA (PEG-ADA) [6]. Continued administration of PEG-ADA eliminates dAXP and protects lymphocytes, restoring the immune function within 2 to 4 months in most patients [1]; however, in some patients, long-term treatment leads to lower lymphocyte counts as well as abnormalities in lymphocyte function [7,8]. In recent years, a small number of ADA-deficient patients have shown spontaneous and partial clinical remission with increasing numbers of peripheral blood (PB) lymphocytes, as a result of reversion of inherited mutations to wild type (ADA deficiency with somatic mosaicism) [9–13]. This phenomenon is being recognized in other primary immunodeficiencies (PID) as well, and it might provide a model for the process of development of cell and gene therapy in these diseases [14].