Whitmore, Kathryn Victoria; (2020) Understanding the neurological defects in adenosine deaminase (ADA) deficiency. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Adenosine deaminase (ADA) deficiency is one of the most prevalent forms of severe combined immunodeficiency (SCID). Patients present primarily with severe immunodeficiency but neurological abnormalities are also reported, including auditory, cognitive, behavioural, and motor abnormalities. Current treatments do not prevent the generation or development of these. Little is known about ADA deficiency in the brain and a greater understanding of the pathogenic mechanism(s) will allow treatment optimisation to effectively target the neurological abnormalities. Absence of ADA activity, characteristic of ADA deficiency, leads to an increase in metabolic substrates adenosine and 2’deoxyadenosine. The hypothesis underlying this thesis was that substrate accumulation was directly responsible for the neurological abnormalities. ADA deficiency was modelled in vitro using a neuroblastoma cell line which showed that cytotoxicity was induced through ADA inhibition and substrate accumulation. This cytotoxicity may occur via multiple pathways but 2’deoxyadenosine is most likely to act via an intracellular mechanism following conversion to dATP. Scoping investigations were carried out in vivo to investigate the effect of ADA deficiency by comparing age-matched wildtype murine brains with brains from an ADA deficient mouse model at two different ages. ADA protein and enzyme activity was absent from brains of this model but transcripts of the ADA gene were increased. Further transcriptomic analyses identified multiple genes and pathways that were differentially regulated between wildtype and ADA deficient brains. Accumulation of adenosine was observed in ADA deficient brains at both ages analysed but accumulation of 2’deoxyadenosine was only observed in the younger cohort. The impact of this accumulation was investigated using stereology and immunohistochemistry but no specific effects were identified. This thesis presents novel work in the field, and confirms that the neurological abnormalities in ADA are likely to be caused by substrate accumulation. However, the mechanism is not elucidated and further work is needed.

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