How I treat ADA deficiency

Abstract

Adenosine deaminase deficiency is a disorder of purine metabolism leading to severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal and requires early intervention. Haematopoietic stem cell transplantation is the major treatment for ADA-SCID, although survival following different donor sources varies considerably. Unlike other SCID forms, 2 other options are available for ADA-SCID: enzyme replacement therapy (ERT) with pegylated bovine ADA, and autologous haematopoietic stem cell gene therapy (GT). Due to the rarity of the condition, the lack of large scale outcome studies, and availability of different treatments, guidance on treatment strategies is limited. We have reviewed the currently available evidence and together with our experience of managing this condition propose a consensus management strategy. IntroductionAdenosine deaminase (ADA) deficiency is a rare inherited disorder of purine metabolism characterized by the accumulation of metabolic substrates that lead to abnormalities of immune system development and function and a variety of systemic defects. The initial and most devastating presentation of the disease is the result of the immune defects; affected infants characteristically present with severe opportunistic infection and failure to thrive and an immunologic profile consistent with severe combined immunodeficiency (ADA-SCID). Without treatment, the condition is fatal in the first year of life and therefore necessitates early intervention. Allogeneic hematopoietic stem cell transplantation (HSCT) has long been considered the mainstay of treatment of ADA-SCID. However, unlike other SCID forms, 2 other treatment options are available for ADA-SCID, namely, enzyme replacement therapy (ERT) with pegylated bovine ADA (Pegadamase, Adagen, or PEG-ADA) and autologous HSC gene therapy (GT).The availability of different treatment modalities presents an opportunity for improved patient care but also presents difficulties in deciding on the specific choice of treatment for individual patients. Making the correct choice is further complicated by the fact that ADA deficiency is not purely an immune defect, unlike other SCID forms, and the systemic manifestations, which can be of major clinical consequence, must also be managed. The rarity of the condition (estimated at anything from 1:200 000 to 1:1 million births) means that any one center has access to only small numbers of patients precluding large-scale prospective studies from which formal and robust outcome data can be accrued. For these reasons, we have gathered experts with experience in management of patients using the different treatment modalities to collect and review the available retrospective data and to construct a consensus management strategy that may be of use to physicians managing this difficult patient population. ADA-SCIDSCID arises from a variety of molecular defects that have profound effects on lymphocyte development and function, including defects in the lymphocyte-specific signaling molecules (comm...

Delayed-onset adenosine deaminase deficiency: Strategies for an early diagnosis

“…However, more favorable results have been reported in other patients. 7 The data from P2 are encouraging, also regarding the lung disease observed in some ADA-deficient patients. 4 We believe that ERT also has an important role in patients diagnosed beyond infancy, mainly to prevent the development of comorbidities that increase the risk for stem cell transplantation.…”

“…5,6 While ERT is a generally accepted treatment in ADA-SCID to stabilize patients prior to stem cell transplantation, its use in patients with a later onset of the disease is less well documented. 7 Although initial immune reconstitution can be observed in most patients receiving ERT, several develop neutralizing antibodies against the bovine-derived ADA, which can completely reverse immune recovery. 8 Fortunately, in P2 and other patients, it has been possible to overcome this problem by increasing the dose.…”

The inclusion of ADA-SCID in expanded newborn screening by tandem mass spectrometry

“…Haematopoietic stem cell transplantation is today the gold standard treatment for ADA-SCID, although it is dependent on a good donor match [9]. ERT with polyethylene glycol-modified bovine adenosine deaminase (PEG-ADA, Adagen ® ) is available and determines the elimination of toxic metabolites and a good reconstitution of the immune system [10].…”

Tandem mass spectrometry, but not T-cell receptor excision circle analysis, identifies newborns with late-onset adenosine deaminase deficiency

“…10,11 We have recently shown that it is possible to identify patients with ADA-SCID using tandem mass spectrometry (tandem-MS) on DBSs collected at birth during routine newborn screening procedures at a low cost (0.01V per test). 12 An expanded newborn screening including more than 40 metabolic diseases is now performed by using tandem-MS in many countries in the world, so that millions of children worldwide are screened each year for those diseases.…”