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Am J Med Genet A. 2010 Jun;152A(6):1420-7. doi: 10.1002/ajmg.a.33484.

Treatment with valproic acid ameliorates ADHD symptoms in fragile X syndrome boys.

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Università Cattolica del Sacro Cuore, Cattedra di Neuropsichiatria Infantile, Rome, Italy.


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.

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