title: Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients.
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.
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Aisha V
authors.initials: AV
authors.lastname: Sauer
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Raisa Jofra
authors.initials: RJ
authors.lastname: Hernandez
authors.affiliation: Neurology Unit, Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fumagalli
authors.affiliation: Dulbecco Telethon Institute at Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Bianchi
authors.affiliation: Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: Pietro L
authors.initials: PL
authors.lastname: Poliani
authors.affiliation: Psychological Service, Neurological Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Dallatomasina
authors.affiliation: Psychological Service, Neurological Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Riboni
authors.affiliation: Imaging Core and Neuroradiology Unit, Head and Neck Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Letterio S
authors.initials: LS
authors.lastname: Politi
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Tabucchi
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Italy.
authors.forename: Filippo
authors.initials: F
authors.lastname: Carlucci
authors.affiliation: Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Casiraghi
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Carriglio
authors.affiliation: Department of Pathology, University of Brescia, Brescia, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Cominelli
authors.affiliation: Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Carlo Alberto
authors.initials: CA
authors.lastname: Forcellini
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.|Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Barzaghi
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.|Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ferrua
authors.affiliation: Neurophysiology Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Minicucci
authors.affiliation: Neurophysiology Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Medaglini
authors.affiliation: Neurophysiology Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Letizia
authors.initials: L
authors.lastname: Leocani
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: la Marca
authors.affiliation: Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy.
authors.forename: Lucia D
authors.initials: LD
authors.lastname: Notarangelo
authors.affiliation: Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Azzari
authors.affiliation: Psychological Service, Neurological Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.affiliation: Neuroradiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Baldoli
authors.affiliation: Multimedica hospital, Neurological Rehabilitation, Limbiate, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Canale
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.|Neurology Unit, Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Sessa
authors.affiliation: Dulbecco Telethon Institute at Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: D'Adamo
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.|Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy.|Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000243:Adenosine Deaminase / Q000172:deficiency*; D000818:Animals; D001519:Behavior; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009422:Nervous System Diseases / Q000473:pathology / Q000503:physiopathology*
chemical_list: C548482:ADA protein, human; C548483:Ada protein, mouse; D000243:Adenosine Deaminase; D000241:Adenosine