Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients

AV Sauer, RJ Hernandez, F. Fumagalli, V Bianchi, PL Poliani, C Dallatomasina, E Riboni, LS Politi, Antonella Tabucchi, Filippo Carlucci, M Casiraghi, N Carriglio, M Cominelli, CA Forcellini, Federica Barzaghi, F Ferrua, F Minicucci, S Medaglini, L Leocani, Giancarlo la MarcaLucia Dora Notarangelo, C Azzari, G Comi, C Baldoli, S Canale, M Sessa, P D'Adamo, A Aiuti

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Abstract

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. Neurological and behavioral abnormalities observed in ADA-SCID patients surviving after stem cell transplantation or gene therapy represent an unresolved enigma in the field. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after short-and long-Term enzyme replacement therapy with PEG-ADA. These included motor dysfunction, EEG alterations, sensorineural hypoacusia, white matter and ventricular alterations in MRI as well as a low mental development index or IQ. Ada-deficient mice were significantly less active and showed anxiety-like behavior. Molecular and metabolic analyses showed that this phenotype coincides with metabolic alterations and aberrant adenosine receptor signaling. PEG-ADA treatment corrected metabolic adenosine-based alterations, but not cellular and signaling defects, indicating an intrinsic nature of the neurological and behavioral phenotype in ADA deficiency. © 2017 The Author(s).
Original languageEnglish
Article number40136
JournalScientific Reports
Volume7
Issue number9
DOIs
Publication statusPublished - 2017

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Sauer, AV., Hernandez, RJ., Fumagalli, F., Bianchi, V., Poliani, PL., Dallatomasina, C., Riboni, E., Politi, LS., Tabucchi, A., Carlucci, F., Casiraghi, M., Carriglio, N., Cominelli, M., Forcellini, CA., Barzaghi, F., Ferrua, F., Minicucci, F., Medaglini, S., Leocani, L., ... Aiuti, A. (2017). Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. Scientific Reports, 7(9), [40136]. https://doi.org/10.1038/srep40136