Treatment with valproic acid ameliorates ADHD symptoms in fragile X syndrome boys
Abstract
Fragile X syndrome (FXS) is the leading cause of inherited mental retardation, due to expansion and methylation of the CGG sequence at the 5′ UTR of the FMR1 gene. Around 90% of affected boys present with attention deficit hyperactivity disorder (ADHD), while this percentage is lower in FXS girls (35–47%). Treatment of these behavioral symptoms is critical for many families. In an attempt at identifying drugs capable of restoring the activity of the FMR1 gene, we investigated the use of valproic acid (VPA), a well‐known antiepileptic drug, also used as a mood stabilizer and in migraine therapy. It is described as an inhibitor of histone deacetylase (HDAC) and, possibly, as a DNA demethylating agent. In an in vitro study we observed that treatment of lymphoblastoid cells from FXS patients with VPA caused a modest reactivation of FMR1 transcription and increased levels of histone acetylation, confirming the histone hyperacetylating effect, but not its putative DNA demethylating activity. On the basis of these findings, we decided to evaluate the in vivo efficacy of VPA on ADHD symptoms in FXS patients. We observed an improvement in the adaptive behavior, defined as the performance of daily activities required for personal and social competence, due to a significant reduction in hyperactivity after VPA treatment. This treatment could be considered as an alternative to that with stimulants, whose efficacy in patients with FXS needs to be confirmed by further studies. © 2010 Wiley‐Liss, Inc.
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In a small open-label safety trial of 10 boys with fragile X syndrome, valproic acid resulted in general improvement in hyperactivity and attention deficit.
“On a small, open-label trial of 10 boys with FXS, essentially meant to be a safety trial, treatment with valproic acid resulted in a general improvement in hyperactivity and attention deficit (104).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [104]
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Tabolacci, E., & Neri, G. (2016) · Elsevier eBooks · doi:10.1016/b978-0-12-800226-1.00006-x · Cited by 1 · see citing works
Self-citationEpigenetics of attention-deficit hyperactivity disorder
Peedicayil, J. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-18516-8.00003-x · Cited by 1 · see citing works
Epigenetic causes of intellectual disability—the fragile X syndrome paradigm
Tabolacci, E., & Neri, G. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-18516-8.00007-7 · Cited by 1 · see citing works
Self-citationHemmings, C. P., & Bouras, N. (2015) · Cambridge University Press eBooks · doi:10.1017/cbo9781107588714.014 · Cited by 1 · see citing works
Response to “Valproic Acid and ADHD Symptoms in Fragile X Syndrome: More Evidence Is Needed”
Snape, M., & Neri, G. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33606
Self-citationValproic acid and ADHD symptoms in Fragile X syndrome: More evidence is needed
Sahu, J. K. (2010) · American Journal of Medical Genetics Part A · doi:10.1002/ajmg.a.33607
What Mechanisms Induce Methylation of FMR1 Gene Full Mutation? A Still Unanswered Question
Tabolacci, E., & Neri, G. (2016) · Epigenetics and human health · doi:10.1007/978-3-319-27186-6_8
Self-citationTabolacci, E., & Chiurazzi, P. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-804461-2.00017-2
Self-citationDonzelli, A. (2013) · Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) · doi:10.13130/donzelli-andrea_phd2013-01-16
Microrrearranjos cromossômicos em síndromes craniofaciais complexas
de Souza, R. M. C. (2019) · doi:10.11606/t.61.2019.tde-17032020-141304
Steenbergen, A. V., Minhas, A., Lin, T. R., Kaur, M., & Bolduc, F. V. (2023) · Research Square · doi:10.21203/rs.3.rs-3439158/v1
- Authors
- Torrioli, M., Vernacotola, S., Setini, C., Bevilacqua, F., Martinelli, D., Snape, M., Hutchison, J. A., Di Raimo, F. R., Tabolacci, E., & Neri, G.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- Corresponding author
- Neri, Giovanni
- Venue
- American Journal of Medical Genetics Part A
- Publisher
- Wiley
- Published
- 2010-05-14
- Volume
- 152A
- Issue
- 6
- Pages
- 1420-1427
- ISSN
- 1552-4825 (ISSN-L)
- 1552-4833
- OpenAlex
- W2087468279
- Cited by
- 71
- References
- 41
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 3 · 2019: 1 · 2018: 5 · 2017: 8 · 2016: 9 · 2015: 3 · 2014: 6 · 2013: 10 · 2012: 9
- FWCI
- 5.03
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Medical Genetics Part A (publishedVersion)
- PubMed (publishedVersion)
- Funders
- FRAXA Research Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Attention Deficit Hyperactivity Disorder
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- valproic acid, fragile X syndrome, attention deficit hyperactivity disorder, FMR1 gene, histone deacetylase inhibition, histone acetylation, CGG repeat expansion, hyperactivity, adaptive behavior
- MeSH terms
- Adolescent, Anticonvulsants, Attention Deficit Disorder with Hyperactivity, Child, Female, Fragile X Syndrome, Humans, Male, Valproic Acid, Histone Deacetylase Inhibitors
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