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

作者：Sauer Aisha V; Hernandez Raisa Jofra; Fumagalli Francesca; Bianchi Veronica; Poliani Pietro L; Dallatomasina Chiara; Riboni Elisa; Politi Letterio S; Tabucchi Antonella; Carlucci Filippo; Casiraghi Miriam; Carriglio Nicola; Cominelli Manuela; Forcellini Carlo Alberto; Barzaghi Federica; Ferrua Francesca; Minicucci Fabio; Medaglini Stefania; Leocani Letizia; La Marca Giancarlo; Notarangelo Lucia D; Azzari Chiara; Comi Giancarlo; Baldoli Cristina; C****e Sabrina

来源：Scientific Reports, 2017, 7(1): 40136.

DOI：10.1038/srep40136

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.

• 出版日期2017-1-11