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

Aisha V Sauer,Patrizia D’Adamo,Antonella Tabucchi,Manuela Cominelli,Pietro Luigi Poliani ,Maria Sessa,Chiara Dallatomasina,Filippo Carlucci,Cristina Baldoli,Letizia Leocani,Francesca Fumagalli,Maurizio Casiraghi ,S Medaglini ,Sabrina Canale,Giancarlo Comi,Giancarlo La Marca,Carlo Alberto Forcellini,Federica Barzaghi,Lucia Dora Notarangelo ,Raisa Jofra Hernández ,Chiara Azzari,Veronica Bianchi,Letterio S Politi,Francesca Ferrua,Nicola Carriglio,Elisa Riboni,Fabio Minicucci,Alessandro Aiuti

doi:10.1038/srep40136

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.

Highlights

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates
Treated patients were divided into two groups according to their age: 8 patients with less than 3 years of age (3yrs, mean age: 13.1 years)
In order to dissect the cellular or metabolic mechanisms contributing to neurological and behavioral alterations in ADA-deficiency, we studied the Ada−/−mouse model that retains many features associated with ADA deficiency in humans, including systemic metabolic alterations and immunodeficiency[22]

Summary

Introduction

Adenosine Deaminase (ADA) deficiency is an autosomal recessive variant of severe combined immunodeficiency (SCID) caused by systemic accumulation of ADA substrates. We found significant neurological and cognitive alterations in untreated ADA-SCID patients as well as in two groups of patients after shortand long-term enzyme replacement therapy with PEG-ADA. 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. Previous studies were unable to identify transplantation-related or SCID-specific factors correlating with this neurologic outcome Their pathogenesis or the underlying metabolic and molecular mechanisms remained unknown and insufficient data were available to assess whether treatment is efficient in preventing or controlling these alterations. The effects of PEG-ADA on immune reconstitution and the metabolic alterations in ADA-SCID are well described, but its long-term effect on the neurological manifestations remained unclear. The high affinity Adora[1] and Adora2a are the most abundant in the nervous system and the most relevant under physiologic conditions[21]

Methods

Results

Conclusion