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Sci Rep. 2017 Jan 11;7:40136. doi: 10.1038/srep40136.

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

Author information

1
San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.
2
Neurology Unit, Neurology Department, IRCCS San Raffaele Hospital, Milan, Italy.
3
Dulbecco Telethon Institute at Division of Neuroscience, IRCCS San Raffaele Scientific Institute, Milan, Italy.
4
Department of Pathology, University of Brescia, Brescia, Italy.
5
Psychological Service, Neurological Department, IRCCS San Raffaele Hospital, Milan, Italy.
6
Imaging Core and Neuroradiology Unit, Head and Neck Department, IRCCS San Raffaele Hospital, Milan, Italy.
7
Department of Medical Biotechnologies, University of Siena, Italy.
8
Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Hospital, Milan, Italy.
9
Vita-Salute San Raffaele University, Milan, Italy.
10
Neurophysiology Center, IRCCS San Raffaele Scientific Institute, Milan, Italy.
11
Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
12
Department of Molecular and Translational Medicine, Pathology Unit, University of Brescia, Brescia, Italy.
13
Neuroradiology Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy.
14
Multimedica hospital, Neurological Rehabilitation, Limbiate, Italy.

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.

PMID:
28074903
PMCID:
PMC5225479
DOI:
10.1038/srep40136
[Indexed for MEDLINE]
Free PMC Article

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