Rett syndrome (RTT) is a devastating neurodevelopmental disorder with a 300-fold increased risk rate for sudden cardiac death. A subclinical myocardial biventricular dysfunction has been recently reported in RTT by our group and found to be associated with an enhanced oxidative stress (OS) status. Here, we tested the effects of the naturally occurring antioxidants ω-3 polyunsaturated fatty acids (ω-3 PUFAs) on echocardiographic parameters and systemic OS markers in a population of RTT patients with the typical clinical form. A total of 66 RTT girls were evaluated, half of whom being treated for 12 months with a dietary supplementation of ω-3 PUFAs at high dosage (docosahexaenoic acid ~71.9 ± 13.9？mg/kg b.w./day plus eicosapentaenoic acid ~115.5 ± 22.4？mg/kg b.w./day) versus the remaining half untreated population. Echocardiographic systolic longitudinal parameters of both ventricles, but not biventricular diastolic measures, improved following ω-3 PUFAs supplementation, with a parallel decrease in the OS markers levels. No significant changes in the examined echocardiographic parameters nor in the OS markers were detectable in the untreated RTT population. Our data indicate that ω-3 PUFAs are able to improve the biventricular myocardial systolic function in RTT and that this functional gain is partially mediated through a regulation of the redox balance. 1. Introduction Rett syndrome (RTT) is a genetically determined, neurodevelopmental disorder with autistic features [1, 2]. Although relatively rare, RTT represents the second most common cause of severe intellective disability in the female gender. To date, the disease has been classified into a typical form and three main atypical variants, that is, preserved speech, early seizure, and congenital. In up to 95% of cases, RTT is caused by de novo mutation in the X-linked gene encoding MeCP2, a protein known to either activate or repress several transcriptional genes [3, 4]. Cumulating evidence indicates that RTT, for a long time considered exclusively a disease of the brain, is actually a systemic disease with involvement of several organs besides the brain, including autonomic nervous system, lung, bone, and heart [5–8]. Girls affected by typical RTT show a 300-fold increased risk for sudden cardiac death as compared to general population (about 26% of all deaths are sudden and of unknown cause [9]), although a satisfactory explanation for the association is still missing. In the lack of evidence for an increased prevalence of congenital heart defects, the attention of several authors has been focused
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