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Severe combined immune deficiency (SCID) represents a heterogenous group of hereditary diseases. Mutations in the common gamma-chain (gamma c), which is part of several cytokine receptors including those for interleukin (IL)-2, IL-4, IL-7, IL-9 and IL-15, are responsible for X-linked SCID, which is usually associated with a lack of circulating T cells and the presence of B lymphocytes (T- B+ SCID). The gene(s) responsible for autosomal recessive T- B+ SCID is still unknown. The Jak-3 protein kinase has been found to associate with the gamma c-chain-containing cytokine receptors. Therefore Jak-3 or other STAT proteins with which it interacts are candidate genes for autosomal recessive T- B+ SCID. Here we investigate two unrelated T- B+ SCID patients (both from consanguineous parents) who have homozygous mutations in the gene for Jak-3. One patient carries a mutation (Tyr100-->Cys) in a conserved tyrosine residue in the JH7 domain of Jak-3 which is absent in more than 150 investigated chromosomes. The other patient carries a homozygous 151-base-pair deletion in the kinase-like domain, leading to a frameshift and premature termination. Both mutations resulted in markedly reduced levels of Jak-3. These findings show that abnormalities in the Jak/STAT signalling pathway can account for SCID in humans.

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...