Inflammation has been advocated as a possible common central mechanism for developmental cognitive impairment. Rett syndrome (RTT) is a devastating neurodevelopmental disorder, mainly caused by de novo loss-of-function mutations in the gene encoding MeCP2. Here, we investigated plasma acute phase response (APR) in stage II (i.e., “pseudo-autistic”) RTT patients by routine haematology/clinical chemistry and proteomic 2-DE/MALDI-TOF analyses as a function of four major MECP2 gene mutation types (R306C, T158M, R168X, and large deletions). Elevated erythrocyte sedimentation rate values (median 33.0？mm/h versus 8.0？mm/h, ) were detectable in RTT, whereas C-reactive protein levels were unchanged ( ). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive ( spots) or negative ( spots), and to a lesser extent as proteins involved in the immune system ( spots), with some proteins having overlapping functions on metabolism ( spots). The number of protein changes was proportional to the severity of the mutation. Our findings reveal for the first time the presence of a subclinical chronic inflammatory status related to the “pseudo-autistic” phase of RTT, which is related to the severity carried by the MECP2 gene mutation. 1. Introduction RTT (OMIM ID: 312750) occurs with a frequency of up to 1？:？10,000 live female births. Causative mutations in the X linked methyl-CpG binding protein 2 gene (MECP2) are detectable in up to 95% of cases, although a wide genetical and phenotypical heterogeneity is well established [1]. Approximately 80% of RTT clinical cases show the so-called “typical” clinical picture; after an apparently normal development for 6–18 months, RTT girls lose their acquired cognitive, social, and motor skills in a typical 4-stage neurological regression [2]. It has become apparent that there is a spectrum of severity in RTT, as some patients may present with atypical features, sometimes overlapping with those suggestive of autism spectrum disorders (ASDs) [3–5]. Autistic features are typically transient in RTT, although this condition has long been considered as a genetic/epigenetic model of ASDs [6, 7], RTT has been recently distinct from the ASDs group [8, 9]. Recently, the gene sequence analysis indicates that several hundreds of gene mutations appear to be associated with the MECP2 gene mutation and, therefore, are to be considered as potential disease modifiers [10], although the genetic mechanisms of RTT have been explored to an extraordinary extent, to
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