CORRESPONDENCE

Valproic Acid and ADHD Symptoms in Fragile XSyndrome: More Evidence Is NeededJitendra Kumar Sahu*Department of Neurology, All India Institute of Medical Sciences, New Delhi, India

Received 2 June 2010; Accepted 23 June 2010

TO THE EDITOR:

I read with interest the recent article in Am J Med Genet Part A (June

2010) by Torrioli et al. on ‘‘Treatment with valproic acid ameli-

orates ADHD symptoms in Fragile X Syndrome boys’’ [Torrioli

et al., 2010]. Authors observed an improvement in the adaptive

behavior in patients with fragile X syndrome treated with valproic

acid, although the in vitro transcriptional reactivating effect on

FMR-1 gene was minimal. While there is discrepancy between

clinical correlation and applying pathological principles, I suggest

that there are important potential limitations in the study.

First, although the authors kept epilepsy as one of the exclusion

criteria, they failed to perform electroencephalogram (EEG) at

baseline. Patients with fragile X syndrome have high susceptibility

to epilepsy and up to 20% may have epilepsy [Musumeci et al., 1999;

Berry-Kravis, 2002]. Complex partial seizures are the most com-

mon seizure type in fragile X patients, and parents can miss them, if

they are subtle in presentation. Valproic acid, as an effective

antiepileptic may be indirectly beneficial in such cases. I had an

experience with a 12-year-old boy with fragile X syndrome who had

marked hyperactive behavior with no clinical seizures and abnor-

mal centro-temporal spikes on EEG. He had significant improve-

ment in behavioral function and disappearance of abnormal

discharges in EEG after valproic acid treatment. Thus, baseline

EEG should be performed.

Second, overestimation of results could occur due to Hawthorne

and placebo effects as these are inherent limitations of an open label

trial. Third, Conner’s Teacher Rating Scale score may have possible

ceiling effect, which may underestimate the results in severely

affected patients. Fourth, a major flaw in the study design, also

mentioned by the authors, was the small sample size. With such

small sample size the possibility of type II error cannot be excluded.

The authors may provide more details of the sample size

calculation.

Torrioli and colleagues are to be congratulated for performing a

practical clinical study that is the first of its kind on effect of valproic

acid treatment on ADHD symptoms in patients with fragile X

syndrome. Clinicians should interpret this study with caution as there

are important shortcomings in the study. Hopefully, other centers will

continue to address this issue, and may be in time we will have the

perfect study with long follow-up and pertinent clinical outcome

parameters to satisfy our colleagues in evidence-based medicine.

REFERENCES

Berry-Kravis E. 2002. Epilepsy in fragile X syndrome. Dev Med ChildNeurol 44:724–728.

Musumeci SA, Hagerman RJ, Ferri R, Bosco P, Dalla Bernardina B,Tassinari CA, De Sarro GB, Elia M. 1999. Epilepsy and EEG findingsin males with fragile X syndrome. Epilepsia 40:1092–1099.

Torrioli MG, Vernacotola S, Setini C, Bevilacqua F, Martinelli D, Snape M,Hutchison JA, Di Raimo FR, Tabolacci E, Neri G. 2010. Treatment withvalproic acid ameliorates ADHD symptoms in fragile X syndrome boys.Am J Med Genet Part A 152A:1420–1427.

*Correspondence to:

Jitendra Kumar Sahu, MD, DM, Department of Neurology, All India

Institute of Medical Sciences, New Delhi, India.

E-mail: jsh2003@gmail.com

Published online 23 August 2010 in Wiley Online Library

(wileyonlinelibrary.com).

DOI 10.1002/ajmg.a.33607

How to Cite this Article:Sahu JK. 2010. Valproic acid and ADHD

symptoms in fragile X syndrome: More

evidence is needed.

Am J Med Genet Part A 152A:2681.

� 2010 Wiley-Liss, Inc. 2681