![]() ![]() Experiences with HSCT with matched unrelated donors (MUD) or haploidentical donors have shown lower success rates ( Hassan et al. Another option that has been shown to correct for the absence of ADA is ex vivo-modified autologous hematopoietic stem cell gene therapy (HSC-GT) ( Kohn et al. ![]() To date, hematopoietic stem cell transplantation (HSCT) is the treatment of choice when a human leukocyte antigen (HLA)-matched related donor (MRD) is available ( Griffith et al. Thus, it is considered a bridging modality before curative treatment is initiated. The bovine-derived ADA product was replaced in 2019 by a recombinant form of the enzyme (elapegademase) which has shown similar in-vitro and possibly better in-vivo activity compared to its predecessor ( Murguia-Favela et al. In either case, measurement of ADA enzyme activity and associated levels of ADA substrates/metabolites (adenosine, 2′deoxyadenosine (dAXP), deoxyadenosine triphosphate) is often the first step in identifying ADA deficiency.ĮRT using polyethylene glycol-modified bovine ADA has proved to be effective in correcting the immune and some non-immune abnormalities conferred by ADA deficiency, however, in some patients immune function declined over time ( Booth et al. Those with incomplete (partial) deficiency may present with milder but gradually worsening manifestations, associated with reduced populations of T, B, and NK cells ( Santisteban et al. Skeletal abnormalities, cognitive impairment, and hearing loss are common ( Albuquerque and Gaspar 2004 Titman et al. Prior to the advent of newborn screening, patients with complete ADA deficiency traditionally presented during infancy with recurrent bacterial, viral and fungal infections and failure to thrive, while laboratory evaluations revealed severe lymphopenia, hypogammaglobulinemia, and neutropenia. By contrast, hypomorphic mutations result in somewhat reduced ADA activity and are associated with less severe or late-onset phenotypes. Genotype-phenotype correlations have revealed greater metabolic disturbance in those with more severe biallelic defects in ADA ( Arredondo-Vega et al. Without treatment it is usually fatal within the first year of life. ![]() The detrimental effects are most pronounced in pathways regulating lymphocyte maturation and function, although non-immunological organ systems, including the hepatic, renal, pulmonary, skeletal, peripheral and central nervous systems, can also be affected (reviewed by( Whitmore and Gaspar (2016)).ĪDA deficiency affects 1:200 000 live births ( Blackburn and Kellems 2005), with a higher frequency reported in Canadian Inuit and Mennonite populations ( Grunebaum et al. The toxic accumulation of ADA substrates and metabolites interferes with downstream metabolic pathways, including inhibition of ribonucleotide reductase and subsequent blockade of DNA synthesis, as well as S-adenosylhomocysteine hydrolase-dependent transmethylation ( Flinn and Gennery 2018). Deficiency of ADA, caused by mutations in the ADA gene and subsequent impairment of ADA activity, leads to an autosomal recessive form of severe combined immunodeficiency (SCID) ( Sauer et al. It is essential for normal lymphoid development, with particularly high levels found in the thymus ( Adams and Harkness 1976 Poliani et al. Adenosine deaminase (ADA) is a ubiquitously expressed enzyme of the purine salvage pathway which catalyzes the irreversible deamination of adenosine and deoxyadenosine. ![]()
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