Immune-system - effects on a cellular level
The dominant consequences of ADA deficiency are on the immune system, causing severe depletion of T- and B-lymphocytes and NK cells, resulting in impaired cellular and humoral immunity. High levels of ADA are expressed in lymphoid tissues due to the high levels of cell turnover, particularly in the thymus, likely accounting for the resulting severe lymphocytotoxic effects of deficiency [
10]. The underlying mechanisms responsible for the deleterious effects on the immune system have been elucidated with the use of ADA-deficient experimental models. There are pronounced effects on thymocyte development, although the precise stage at which this occurs is unknown. Apasov et al. demonstrated extensive apoptosis in the thymi of ADA(−/−) murine models but not in the peripheral lymph nodes and spleen, demonstrating the detrimental effect on developing thymocytes. Apoptosis in the thymi was evident predominantly at the cortico-medullary junction and particularly affected double positive thymocytes. Peripheral T-lymphocytes were also abnormal, with aberrant distribution in secondary lymphoid tissues and expression of cell markers, as well as defective T-lymphocyte signaling through the TCR [
11]. It is thought that the combination of both intracellular accumulation of toxic substrates and defective T-lymphocyte signaling contribute to the depletion of developing thymocytes.
The B-lymphocyte compartment is also affected in ADA-deficiency with patients exhibiting severe B-lymphocytopaenia and hypogammaglobulinaemia, although, in contrast to T-lymphocytes, early B-lymphocyte development does not appear to be disturbed [
12]. Abnormal splenic germinal centre architecture is observed suggesting impaired antigen-dependent B-lymphocyte maturation, and B-lymphocytes also displayed reduced proliferative abilities, increased apoptosis and impaired signaling upon activation [
12]. This suggests that the B-lymphocyte defect is more likely to be related to impaired differentiation due to an intrinsic defect rather than solely due lack of appropriate CD4+ T-lymphocyte help. Impaired V(D)J recombination due to increased dATP levels may also negatively affect B-lymphocyte diversity and function [
13].
Immune system - clinical manifestations
As a result of severely defected cellular and humoral immunity, the typical presentation of ADA-deficiency occurs early in life with severe infections and failure to thrive, and affected individuals will normally succumb within the first or second year of life without intervention. The clinical picture of ADA-deficient SCID is similar to other genetic forms of SCID, with persistent diarrhoea, dermatitis, and serious infections, often caused by opportunistic pathogens such as Pneumocystis jiroveci, being characteristic. Physical findings include absent thymus gland on thoracic-radiographs and absence of lymphoid tissues.
Non-immune manifestations
The ubiquitous nature of ADA also means that consequences of deficiency are not limited to lymphocytes, and many other systemic non-immunological features are also observed, with known impact on the nervous, auditory, skeletal, pulmonary, hepatic and renal systems as well as cognitive and behavioural abnormalities. Non-immunological manifestations have become more apparent in recent years as survival and immune reconstitution improves following stem cell transplantation, and awareness and identification of involvement of multiple organ systems is essential to allow timely optimal management.
Children with ADA-deficiency have been shown to exhibit a range of behaviour abnormalities, including attention deficits, hyperactivity, aggression and social problems, which appear to develop independently of the influences associated with HSCT [
14,
15]. IQ levels are lower in children with ADA-deficient SCID compared to the population average and compared to children with other forms of SCID [
15]. High levels of ADA expression found in the brain [
10], and the finding that the total IQ scores correlate with the level of dATP at diagnosis [
14], further support the theory that cognitive impairment is both a consequence of the metabolic disturbance in ADA-deficiency and dependent on the degree of deficiency.
Bilateral sensorineural hearing loss was first reported in two patients with ADA-deficiency who had been successfully treated with HSCT. Structural and infectious causes were excluded and both patients did not receive any conditioning prior to HSCT, precluding that as a potential cause and implicating the underlying metabolic defect [
16]. A high prevalence of bilateral sensorineural hearing loss (58%) was reported in a cohort of 12 patients with ADA-deficiency who had been treated with HSCT [
17]. In this study, no relationship was found between deafness and dATP levels.
The metabolic role of adenosine deaminase and consequences of toxic substrate accumulation in the lungs has been demonstrated in experimental models, with ADA(−/−)mice displaying severe pulmonary inflammation, with accumulation of activated macrophages and eosinophils, and airway remodeling, reversible upon initiation of ERT [
5]. Mouse models have also shown that prolonged exposure to high concentrations of adenosine in the lung due to treatment with low dose ERT leads to development of pulmonary fibrosis, but these changes were reversed upon reducing pulmonary adenosine levels [
18]. In ADA-deficient patients, similar pulmonary manifestations are seen, and non-infectious pulmonary disease, including pneumonitis and pulmonary alveolar proteinosisis (PAP), is found more frequently than in other genetic forms of SCID [
19]. 43.8% of patients with ADA-deficient SCID had PAP in one study that rapidly resolved (in all but one patient) following commencement of ERT [
20].
Skeletal abnormalities such as involving the costochondral joints are widely reported, possibly related to an imbalance between nuclear factor-κB ligand (RANKL) and osteoprotegerin (OPG), disturbing the interaction between osteoblasts and osteoclasts and subsequent bone formation, although abnormalities are mainly only apparent on radiological imaging without dysmorphic consequences [
21‐
24]. The effect of toxic metabolites on bone marrow may play a role in the ‘auto-conditioning’ evident in ADA-deficient SCID, with the creation of stem cell niches, facilitating donor hematopoietic stem cell engraftment. However, skeletal abnormalities have also been reported in other immunodeficiencies and complete correction following therapy is not seen suggesting other factors involved in the pathogenesis.
Hepatic involvement in ADA-deficiency appears to differ between mice and humans. Murine ADA(−/−) models display severe hepatocellular degeneration that is fatal in the perinatal period [
25]. In comparison, a severe degree of hepatic impairment is not normally seen in ADA-deficient patients, although there is a case report of a patient with ADA-deficient SCID who developed rapid fatal hepatic failure which could not be attributed to infection [
26], and a neonate with ADA-deficient SCID with hepatitis and hyperbilirubinaemia which resolved with ERT [
27]. Reports of renal involvement in ADA-deficiency include the occurrence of mesangial sclerosis found in 7/8 autopsies of ADA-deficient patients, with 6/8 also demonstrating cortical sclerosis of the adrenal glands [
22]. Atypical haemolytic uraemic syndrome was reported in 4 patients with ADA-deficiency, 2 who recovered with mild or no residual renal impairment following supportive management and initiation of ERT [
28]. Dermatofibrosarcoma protuberans is a rare malignant skin tumour, which has been reported to occur with greater frequency in patients with ADA-deficiency, but the mechanism behind this is unclear [
29].
While ADA-deficiency is widely accepted as a systemic metabolic disorder, it is important to consider that certain systemic manifestations have only been reported in a small number of patients. Other contributing factors such as infectious agents may be involved and further investigation into the underlying pathogenesis of these manifestations is needed. Nevertheless, awareness of multi-organ involvement is essential for optimal patient care.