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European Child & Adolescent Psychiatry

, Volume 27, Issue 2, pp 241–252 | Cite as

Potential for diagnosis versus therapy monitoring of attention deficit hyperactivity disorder: a new epigenetic biomarker interacting with both genotype and auto-immunity

  • Walter Adriani
  • Emilia Romano
  • Mariangela Pucci
  • Esterina Pascale
  • Luca Cerniglia
  • Silvia Cimino
  • Renata Tambelli
  • Paolo Curatolo
  • Oleg Granstrem
  • Mauro Maccarrone
  • Giovanni Laviola
  • Claudio D’Addario
Original Contribution

Abstract

In view of the need for easily accessible biomarkers, we evaluated in ADHD children the epigenetic status of the 5′-untranslated region (UTR) in the SLC6A3 gene, coding for human dopamine transporter (DAT). We analysed buccal swabs and sera from 30 children who met DSM-IV-TR criteria for ADHD, assigned to treatment according to severity. Methylation levels at six-selected CpG sites (among which, a CGGCGGCGG and a CGCG motif), alone or in combination with serum titers in auto-antibodies against dopamine transporter (DAT aAbs), were analysed for correlation with CGAS scores (by clinicians) and Conners’ scales (by parents), collected at recruitment and after 6 weeks. In addition, we characterized the DAT genotype, i.e., the variable number tandem repeat (VNTR) polymorphisms at the 3′-UTR of the gene. DAT methylation levels were greatly reduced in ADHD patients compared to control, healthy children. Within patients carrying at least one DAT 9 allele (DAT 9/x), methylation at positions CpG2 and/or CpG6 correlated with recovery, as evident from delta-CGAS scores as well as delta Conners’ scales (‘inattentive’ and ‘hyperactive’ subscales). Moreover, hypermethylation at CpG1 position denoted severity, specifically for those patients carrying a DAT 10/10 genotype. Intriguingly, high serum DAT-aAbs titers appeared to corroborate indications from high CpG1 versus high CpG2/CpG6 levels, likewise denoting severity versus recovery in DAT 10/10 versus 9/x patients, respectively. These profiles suggest that DAT 5′UTR epigenetics plus serum aAbs can serve as suitable biomarkers, to confirm ADHD diagnosis and/or to predict the efficacy of treatment.

Keywords

Auto-antibodies (aAbs) to neuro-receptors Epigenetics in neuro-psychiatry Conners’ scales CGAS scale Dopamine transporter (DAT) 10-Repeat allele 9-Repeat allele OCD Tourette’s 

Notes

Acknowledgements

Research performed under the young-investigator “ADHD-sythe” project (“under 40” call 2007) and the EU “NeuroGenMRI” project (ERAnet “PrioMedChild”), both from Italian Ministry of Health (for Italian partner, to W. A.); in part, supported under Grant Agreements ref. 278367 “EMTICS—European Multicentre Tics In Children Studies” and ref. 603016 “MATRICS—Multidisciplinary Approaches to Translational Research In Conduct Syndromes” by European Seventh Framework Programme (FP7) 2007–2013 (for Italian partner, to G. L.). We acknowledge Dr Nadia Francia and Dr Viola Cardia for their precious help with all management and patenting issues. There are only two items for potential conflict of interest to be disclosed: (1) Adriani W, Laviola G, Pascale E, D’Addario C “Metodo Per Determinare Il Deficit Di Attenzione Con Iperattività (Method to determine attention deficit and hyperactivity disorder)”; Patent Application, deposit in ITALY at No. 102016000129938 (22-DECEMBER-2016). (2) Granstrem O, Adriani W, Laviola G, Porfirio MC, Curatolo P “Biomarkers for validation of A.D.H.D. diagnosis and monitoring of therapy efficacy”; Full Patent No. PN810701WO; Int.l Application No. PCT/EP2013/066845; Publication number WO/2014/023852 (10-AUGUST-2013).

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Walter Adriani
    • 1
    • 2
  • Emilia Romano
    • 1
  • Mariangela Pucci
    • 3
  • Esterina Pascale
    • 4
  • Luca Cerniglia
    • 2
  • Silvia Cimino
    • 5
  • Renata Tambelli
    • 5
  • Paolo Curatolo
    • 6
  • Oleg Granstrem
    • 7
  • Mauro Maccarrone
    • 8
    • 9
  • Giovanni Laviola
    • 1
  • Claudio D’Addario
    • 3
    • 9
  1. 1.Center for Behavioural Sciences and Mental HealthIstituto Superiore di SanitàRomeItaly
  2. 2.Faculty of PsychologyUniversità Telematica Internazionale “Uninettuno”RomeItaly
  3. 3.Faculty of Bioscience and Technology for Food, Agriculture and EnvironmentUniversity of TeramoTeramoItaly
  4. 4.Medico-Surgical Sciences and Biotechnologies“Sapienza” University of RomeRomeItaly
  5. 5.Dynamic and Clinical Psychology Department“Sapienza” University of RomeRomeItaly
  6. 6.Pediatric Neurology Unit, Department of System Medicine“Tor Vergata” University of RomeRomeItaly
  7. 7.NBioService LtdSaint-PetersburgRussia
  8. 8.Department of Medicine“Campus Bio-Medico” University of RomeRomeItaly
  9. 9.European Center for Brain ResearchIRCCS “Santa Lucia”RomeItaly

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