title: Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation.
abstract: BACKGROUND
  Mutations in the cyclin-dependent kinase-like 5 gene cause a clinical variant of Rett syndrome (CDKL5-RTT). A role for the acute-phase response (APR) is emerging in typical RTT caused by methyl-CpG-binding protein 2 gene mutations (MECP2-RTT). No information is, to date, available on the inflammatory protein response in CDKL5-RTT. We evaluated, for the first time, the APR protein response in CDKL5-RTT.
  
  
  METHODS
  Protein patterns in albumin- and IgG-depleted plasma proteome from CDKL5-RTT patients were evaluated by two-dimensional gel electrophoresis/mass spectrometry. The resulting data were related to circulating cytokines and compared to healthy controls or MECP2-RTT patients. The effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) were evaluated.
  
  
  RESULTS
  CDKL5-RTT mutations resulted in a subclinical attenuated inflammation, specifically characterized by an overexpression of the complement component C3 and CD5 antigen-like, both strictly related to the inflammatory response. Cytokine dysregulation featuring a bulk increase of anti-inflammatory cytokines, predominantly IL-10, could explain the unchanged erythrocyte sedimentation rate and atypical features of inflammation in CDKL5-RTT. Omega-3 PUFAs were able to counterbalance the pro-inflammatory status.
  
  
  CONCLUSIONS
  For the first time, we revealed a subclinical smouldering inflammation pattern in CDKL5-RTT consisting in the coexistence of an atypical APR coupled with a dysregulated cytokine response.
authors.affiliation: Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, 53100, Siena, Italy. alessio.cortelazzo@biologo.onb.it.|Department of Medical Biotechnologies, University of Siena, Via A. Moro 2, 53100, Siena, Italy. alessio.cortelazzo@biologo.onb.it.|Clinical Pathology Laboratory Unit, University Hospital AOUS, Viale M. Bracci 16, 53100, Siena, Italy. alessio.cortelazzo@biologo.onb.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Cortelazzo
authors.affiliation: Neonatal Intensive Care Unit, University Hospital AOUS, Viale M. Bracci 16, 53100, Siena, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: de Felice
authors.affiliation: Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, 53100, Siena, Italy.|Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 6, 53100, Siena, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Leoncini
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 6, 53100, Siena, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Signorini
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via A. Moro 2, 53100, Siena, Italy.|Clinical Pathology Laboratory Unit, University Hospital AOUS, Viale M. Bracci 16, 53100, Siena, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Guerranti
authors.affiliation: Department of Medical Biotechnologies, University of Siena, Via A. Moro 2, 53100, Siena, Italy.|Clinical Pathology Laboratory Unit, University Hospital AOUS, Viale M. Bracci 16, 53100, Siena, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Leoncini
authors.affiliation: Department of Life Sciences, University of Siena, Via A. Moro 2, 53100, Siena, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Armini
authors.affiliation: Department of Life Sciences, University of Siena, Via A. Moro 2, 53100, Siena, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bini
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 6, 53100, Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Ciccoli
authors.affiliation: Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, 53100, Siena, Italy.
authors.forename: Joussef
authors.initials: J
authors.lastname: Hayek
mesh_terms: D000210:Acute-Phase Reaction / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000293:Adolescent; D001798:Blood Proteins / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D019587:Dietary Supplements; D000073376:Epileptic Syndromes; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology; D005260:Female; D006801:Humans; D007223:Infant; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013036:Spasms, Infantile / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D001798:Blood Proteins; D016207:Cytokines; D015525:Fatty Acids, Omega-3; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human
keywords: Acute-phase proteins; Cyclin-dependent kinase-like 5; Cytokines; Polyunsaturated fatty acids; Rett syndrome; Subclinical inflammation