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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Adenosine Deaminase
Adenosine
Severe Combined Immunodeficiency
Brain
Enzyme Replacement Therapy
Phenotype
Purinergic P1 Receptors
Stem Cell Transplantation
Cell- and Tissue-Based Therapy
Genetic Therapy
Electroencephalography
Anxiety
Mouse Ada protein

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Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. / Sauer, AV; Hernandez, RJ; Fumagalli, F.; Bianchi, V; Poliani, PL; Dallatomasina, C; Riboni, E; Politi, LS; Tabucchi, Antonella; Carlucci, Filippo; Casiraghi, M; Carriglio, N; Cominelli, M; Forcellini, CA; Barzaghi, Federica; Ferrua, F; Minicucci, F; Medaglini, S; Leocani, L; la Marca, Giancarlo; Notarangelo, Lucia Dora; Azzari, C; Comi, G; Baldoli, C; Canale, S; Sessa, M; D'Adamo, P; Aiuti, A.

In: Scientific Reports, Vol. 7, No. 9, 40136, 2017.

Research output: Contribution to journalArticle

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, la Marca, G, Notarangelo, LD, Azzari, C, Comi, G, Baldoli, C, Canale, S, Sessa, M, D'Adamo, P & Aiuti, A 2017, 'Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients', Scientific Reports, vol. 7, no. 9, 40136. https://doi.org/10.1038/srep40136
Sauer, AV ; Hernandez, RJ ; Fumagalli, F. ; Bianchi, V ; Poliani, PL ; Dallatomasina, C ; Riboni, E ; Politi, LS ; Tabucchi, Antonella ; Carlucci, Filippo ; Casiraghi, M ; Carriglio, N ; Cominelli, M ; Forcellini, CA ; Barzaghi, Federica ; Ferrua, F ; Minicucci, F ; Medaglini, S ; Leocani, L ; la Marca, Giancarlo ; Notarangelo, Lucia Dora ; Azzari, C ; Comi, G ; Baldoli, C ; Canale, S ; Sessa, M ; D'Adamo, P ; Aiuti, A. / Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients. In: Scientific Reports. 2017 ; Vol. 7, No. 9.
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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. {\circledC} 2017 The Author(s).",
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T1 - Alterations in the brain adenosine metabolism cause behavioral and neurological impairment in ADA-deficient mice and patients

AU - Sauer, AV

AU - Hernandez, RJ

AU - Fumagalli, F.

AU - Bianchi, V

AU - Poliani, PL

AU - Dallatomasina, C

AU - Riboni, E

AU - Politi, LS

AU - Tabucchi, Antonella

AU - Carlucci, Filippo

AU - Casiraghi, M

AU - Carriglio, N

AU - Cominelli, M

AU - Forcellini, CA

AU - Barzaghi, Federica

AU - Ferrua, F

AU - Minicucci, F

AU - Medaglini, S

AU - Leocani, L

AU - la Marca, Giancarlo

AU - Notarangelo, Lucia Dora

AU - Azzari, C

AU - Comi, G

AU - Baldoli, C

AU - Canale, S

AU - Sessa, M

AU - D'Adamo, P

AU - Aiuti, A

PY - 2017

Y1 - 2017

N2 - 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).

AB - 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).

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JO - Scientific Reports

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