Publications by authors named "Claudio De Felice"

136 Publications

Protective role of mirtazapine in adult female Mecp2 mice and patients with Rett syndrome.

J Neurodev Disord 2020 09 28;12(1):26. Epub 2020 Sep 28.

Department of Life Sciences, University of Trieste, Via Licio Giorgieri, 5 - 34127, Trieste, Italy.

Background: Rett syndrome (RTT), an X-linked neurodevelopmental rare disease mainly caused by MECP2-gene mutations, is a prototypic intellectual disability disorder. Reversibility of RTT-like phenotypes in an adult mouse model lacking the Mecp2-gene has given hope of treating the disease at any age. However, adult RTT patients still urge for new treatments. Given the relationship between RTT and monoamine deficiency, we investigated mirtazapine (MTZ), a noradrenergic and specific-serotonergic antidepressant, as a potential treatment.

Methods: Adult heterozygous-Mecp2 (HET) female mice (6-months old) were treated for 30 days with 10 mg/kg MTZ and assessed for general health, motor skills, motor learning, and anxiety. Motor cortex, somatosensory cortex, and amygdala were analyzed for parvalbumin expression. Eighty RTT adult female patients harboring a pathogenic MECP2 mutation were randomly assigned to treatment to MTZ for insomnia and mood disorders (mean age = 23.1 ± 7.5 years, range = 16-47 years; mean MTZ-treatment duration = 1.64 ± 1.0 years, range = 0.08-5.0 years). Rett clinical severity scale (RCSS) and motor behavior assessment scale (MBAS) were retrospectively analyzed.

Results: In HET mice, MTZ preserved motor learning from deterioration and normalized parvalbumin levels in the primary motor cortex. Moreover, MTZ rescued the aberrant open-arm preference behavior observed in HET mice in the elevated plus-maze (EPM) and normalized parvalbumin expression in the barrel cortex. Since whisker clipping also abolished the EPM-related phenotype, we propose it is due to sensory hypersensitivity. In patients, MTZ slowed disease progression or induced significant improvements for 10/16 MBAS-items of the M1 social behavior area: 4/7 items of the M2 oro-facial/respiratory area and 8/14 items of the M3 motor/physical signs area.

Conclusions: This study provides the first evidence that long-term treatment of adult female heterozygous Mecp2 mice and adult Rett patients with the antidepressant mirtazapine is well tolerated and that it protects from disease progression and improves motor, sensory, and behavioral symptoms.
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http://dx.doi.org/10.1186/s11689-020-09328-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7523042PMC
September 2020

OPERA: a novel method to reduce ghost and aliasing artifacts.

MAGMA 2020 Aug 12. Epub 2020 Aug 12.

AOUS, Neonatal Intensive Care Unit, S.M. Alle Scotte General Hospital, Siena, Italy.

Objective: A method for Orthogonal Phase Encoding Reduction of Artifact (OPERA) was developed and tested.

Materials And Methods: Because the position of ghosts and aliasing artifacts is predictable along columns or rows, OPERA combines the intensity values of two images acquired using the same parameters, but with swapped phase-encoding directions, to correct the artifacts. Simulations and phantom experiments were conducted to define the efficacy, robustness, and reproducibility. Clinical validation was performed on a total of 1003 images by comparing the OPERA-corrected images and the corresponding image standard in terms of Signal-to-Noise Ratio (SNR) and Contrast-to-Noise Ratio (CNR). The method efficacy was also rated using a Likert-type scale response by two experienced independent radiologists using a single-blinded procedure.

Results: Simulations and phantom experiments demonstrated the robustness and effectiveness of OPERA in reducing artifacts strength. OPERA application did not significantly change the SNR [+ 4.16%; inter-quartile range (IQR): 2.72-5.01%] and CNR (+ 4.30%; IQR: 2.86-6.04%) values. The two radiologists observed a total of 893 original images with artifacts (89.03% of the total images), a reduction in the perceived artifacts of 82.0% and 83.9% (p < 0.0001), and an improvement in the perceived SNR (82.8% and 88.5%; K = 0.714) and perceived CNR (86.9-88.9%; K = 0.722).

Discussion: The study demonstrated that OPERA reduces MR artifacts and improves the perceived image quality.
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http://dx.doi.org/10.1007/s10334-020-00881-1DOI Listing
August 2020

Defective proteasome biogenesis into skin fibroblasts isolated from Rett syndrome subjects with MeCP2 non-sense mutations.

Biochim Biophys Acta Mol Basis Dis 2020 07 8;1866(7):165793. Epub 2020 Apr 8.

Dept of Clinical Sciences and Translational Medicine, University of Rome Tor Vergata, Rome, Italy. Electronic address:

Rett Syndrome (RTT) is a rare X-linked neurodevelopmental disorder which affects about 1: 10000 live births. In >95% of subjects RTT is caused by a mutation in Methyl-CpG binding protein-2 (MECP2) gene, which encodes for a transcription regulator with pleiotropic genetic/epigenetic activities. The molecular mechanisms underscoring the phenotypic alteration of RTT are largely unknown and this has impaired the development of therapeutic approaches to alleviate signs and symptoms during disease progression. A defective proteasome biogenesis into two skin primary fibroblasts isolated from RTT subjects harbouring non-sense (early-truncating) MeCP2 mutations (i.e., R190fs and R255X) is herewith reported. Proteasome is the proteolytic machinery of Ubiquitin Proteasome System (UPS), a pathway of overwhelming relevance for post-mitotic cells metabolism. Molecular, transcription and proteomic analyses indicate that MeCP2 mutations down-regulate the expression of one proteasome subunit, α7, and of two chaperones, PAC1 and PAC2, which bind each other in the earliest step of proteasome biogenesis. Furthermore, this molecular alteration recapitulates in neuron-like SH-SY5Y cells upon silencing of MeCP2 expression, envisaging a general significance of this transcription regulator in proteasome biogenesis.
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http://dx.doi.org/10.1016/j.bbadis.2020.165793DOI Listing
July 2020

Effect of Dietary -3 Source on Rabbit Male Reproduction.

Oxid Med Cell Longev 2019 16;2019:3279670. Epub 2019 Dec 16.

Department of Molecular and Developmental Medicine, University of Siena, Policlinico Santa Maria alle Scotte, Viale Bracci 14, 53100 Siena, Italy.

In the last two decades, the human sperm count linearly decreased in Western countries. Health problems, lifestyle, pollutants, and dietary behaviours are considered as the main risk factors, and the unbalance of dietary -6/-3 fatty acids is one of the most relevant. The aim of the present research is to study the effect of different dietary sources of -3 polyunsaturated fatty acids (PUFA) on reproductive traits using rabbit buck as the animal model. Fifteen rabbit bucks were assigned to three experimental groups: the control group, the FLAX group fed 10% extruded flaxseed, and the FISH group fed 3.5% fish oil for 110 days (50-day adaptation and 60-day experimental periods). Semen samples were collected weekly, whereas blood was collected every two weeks for the analytical determination of semen traits, oxidative status, fatty acid profiles, isoprostanes, neuroprostanes, and the immunocytochemistry of docosahexaenoic acid (DHA) and eicosapentaenoic (EPA) acid. At the end of the trial, the rabbits were killed and the testes were removed and stored for the analysis of fatty acid profile and immunocytochemistry. Results showed that dietary administration of -3 PUFA improved the track speed of the sperm and increased the -3 long-chain PUFA mainly confined in the sperm tail. Seminal plasma increased the thiobarbituric reactive substances (TBARs) by three times in the groups fed supplemental -3, whereas the F-isoprotanes (F-IsoPs) and F-neuroprostanes (F-NeuroPs) were lower and higher, respectively, in both supplemented groups than in the control. The testes and sperm showed a higher DHA and EPA distribution in rabbits from the -3 supplemented groups compared with the control. In conclusion, supplemental dietary -3 PUFA improved sperm motion traits and resulted in an enrichment of membrane fatty acid in the sperm and testes of the rabbits. However, such an increased amount of PUFA negatively affected the sperm oxidative status, which was mainly correlated with the generation of F-NeuroPs with respect to F-IsoPs. Accordingly, the latter cannot be considered a good marker of oxidation when diets rich in -3 PUFA are provided.
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http://dx.doi.org/10.1155/2019/3279670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011472PMC
June 2020

Brain protein changes in Mecp2 mouse mutant models: Effects on disease progression of Mecp2 brain specific gene reactivation.

J Proteomics 2020 01 16;210:103537. Epub 2019 Oct 16.

Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy.

Rett syndrome (RTT) is a leading cause of severe intellectual disability in females, caused by de novo loss-of function mutations in the X-linked methyl-CpG binding protein 2 (MECP2). To better investigate RTT disease progression/pathogenesis animal models of Mecp2 deficiency have been developed. Here, Mecp2 mouse models are employed to investigate the role of protein patterns in RTT. A proteome analysis was carried out in brain tissue from i) Mecp2 deficient mice at the pre-symptomatic and symptomatic stages and, ii) mice in which the disease phenotype was reversed by Mecp2 reactivation. Several proteins were shown to be differentially expressed in the pre-symptomatic (n = 18) and symptomatic (n = 20) mice. Mecp2 brain reactivated mice showed wild-type comparable levels of expression for twelve proteins, mainly related to proteostasis (n = 4) and energy metabolic pathways (n = 4). The remaining ones were found to be involved in redox homeostasis (n = 2), nitric oxide regulation (n = 1), neurodevelopment (n = 1). Ten out of twelve proteins were newly linked to Mecp2 deficiency. Our study sheds light on the relevance of the protein-regulation of main physiological process in the complex mechanisms leading from Mecp2 mutation to the RTT clinical phenotype. SIGNIFICANCE: We performed a proteomic study of a Mecp2 mouse model for Rett syndrome (RTT) at the pre-symptomatic and symptomatic Mecp2 deficient mice stage and for the brain specific reactivated Mecp2 model. Our results reveal major protein expression changes pointing out to defects in proteostasis or energy metabolic pathways other than, to a lesser extent, in redox homeostasis, nitric oxide regulation or neurodevelopment. The Mecp2 mouse rescued model provides the possibility to select target proteins more susceptible to the Mecp2 gene mutation, potential and promising therapeutical targets.
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http://dx.doi.org/10.1016/j.jprot.2019.103537DOI Listing
January 2020

Increased isoprostanoid levels in brain from murine model of Krabbe disease - Relevance of isoprostanes, dihomo-isoprostanes and neuroprostanes to disease severity.

Free Radic Biol Med 2019 08 15;139:46-54. Epub 2019 May 15.

Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy; Neonatal Intensive Care Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy. Electronic address:

Krabbe disease (KD) is a rare and devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. The disease leads to impaired myelin formation and extensive myelin damage in the brain. Oxidative stress is implicated in the pathogenesis of KD but insofar few information is available. The gray and white matter of the brain are rich in docosahexaenoic acid and adrenic acid respectively and under non-enzymatic oxidative stress, release isoprostanoids, i.e. F-neuroprostanes (F-NeuroPs) and F-dihomo-isoprostanes (F-dihomo-IsoPs). In this study, the formation of isoprostanoids in brain tissue was investigated in a well-established KD mouse model (twitcher) that recapitulates the human pathology. According to the genotype determinations, three groups of mice were selected: wild-type control mice (n = 13), heterozygotes mice (carriers of GALC mutations, n = 14) and homozygous twitcher mice (n = 13). Measurement of F-dihomo-IsoP and F-NeuroP levels were performed on whole brain tissue obtained at day 15 and day 35 of the life cycle. Brain isoprostanoid levels were significantly higher in the twitcher mice compared to the heterozygous and wild-type control mice. However, F-dihomo-IsoP and F-NeuroP levels did not differ in brain of day 15 compared to day 35 of the heterozygote mice. Interestingly, isoprostanoid levels were proportionally enhanced with disease severity (F-dihomo-IsoPs, rho = 0.54; F-NeuroPs, rho = 0.581; P values ≤ 0.05; n = 13). Our findings are the first to show the key role of polyunsaturated fatty acid oxidative damage to brain grey and white matter in the pathogenesis and progression of KD. This shed new insights on the biochemical indexes of KD progression, and potentially provide information for novel therapeutic targets.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.05.014DOI Listing
August 2019

Isoprostanoids in Clinical and Experimental Neurological Disease Models.

Antioxidants (Basel) 2018 Jul 11;7(7). Epub 2018 Jul 11.

School of Biological Sciences, The University of Hong Kong, Hong Kong, China.

Isoprostanoids are a large family of compounds derived from non-enzymatic oxidation of polyunsaturated fatty acids (PUFAs). Unlike other oxidative stress biomarkers, they provide unique information on the precursor of the targeted PUFA. Although they were discovered about a quarter of century ago, the knowledge on the role of key isoprostanoids in the pathogenesis of experimental and human disease models remains limited. This is mainly due to the limited availability of highly purified molecules to be used as a reference standard in the identification of biological samples. The accurate knowledge on their biological relevance is the critical step that could be translated from some mere technical/industrial advances into a reliable biological disease marker which is helpful in deciphering the oxidative stress puzzle related to neurological disorders. Recent research indicates the value of isoprostanoids in predicting the clinical presentation and evolution of the neurological diseases. This review focuses on the relevance of isoprostanoids as mediators and potential biomarkers in neurological diseases, a heterogeneous family ranging from rare brain diseases to major health conditions that could have worldwide socioeconomic impact in the health sector. The current challenge is to identify the preferential biochemical pathways that actually follow the oxidative reactions in the neurological diseases and the consequence of the specific isoprostanes in the underlying pathogenic mechanisms.
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http://dx.doi.org/10.3390/antiox7070088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071265PMC
July 2018

Intestinal Candida parapsilosis isolates from Rett syndrome subjects bear potential virulent traits and capacity to persist within the host.

BMC Gastroenterol 2018 May 2;18(1):57. Epub 2018 May 2.

Department of Biology, University of Florence, Via Madonna del Piano 6, 50019, Sesto Fiorentino, Florence, Italy.

Background: Rett syndrome (RTT) is a neurological disorder mainly caused by mutations in MeCP2 gene. It has been shown that MeCP2 impairments can lead to cytokine dysregulation due to MeCP2 regulatory role in T-helper and T-reg mediated responses, thus contributing to the pro-inflammatory status associated with RTT. Furthermore, RTT subjects suffer from an intestinal dysbiosis characterized by an abnormal expansion of the Candida population, a known factor responsible for the hyper-activation of pro-inflammatory immune responses. Therefore, we asked whether the intestinal fungal population of RTT subjects might contribute the sub-inflammatory status triggered by MeCP2 deficiency.

Methods: We evaluated the cultivable gut mycobiota from a cohort of 50 RTT patients and 29 healthy controls characterizing the faecal fungal isolates for their virulence-related traits, antifungal resistance and immune reactivity in order to elucidate the role of fungi in RTT's intestinal dysbiosis and gastrointestinal physiology.

Results: Candida parapsilosis, the most abundant yeast species in RTT subjects, showed distinct genotypic profiles if compared to healthy controls' isolates as measured by hierarchical clustering analysis from RAPD genotyping. Their phenotypical analysis revealed that RTT's isolates produced more biofilm and were significantly more resistant to azole antifungals compared to the isolates from the healthy controls. In addition, the high levels of IL-1β and IL-10 produced by peripheral blood mononuclear cells and the mixed Th1/Th17 cells population induced by RTT C. parapsilosis isolates suggest the capacity of these intestinal fungi to persist within the host, being potentially involved in chronic, pro-inflammatory responses.

Conclusions: Here we demonstrated that intestinal C. parapsilosis isolates from RTT subjects hold phenotypic traits that might favour the previously observed low-grade intestinal inflammatory status associated with RTT. Therefore, the presence of putative virulent, pro-inflammatory C. parapsilosis strains in RTT could represent an additional factor in RTT's gastrointestinal pathophysiology, whose mechanisms are not yet clearly understood.
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http://dx.doi.org/10.1186/s12876-018-0785-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930502PMC
May 2018

Clinical biomarkers for cancer recognition and prevention: A novel approach with optical measurements.

Cancer Biomark 2018 ;22(2):179-198

Department of Medical Biotechnologies, University of Siena, Siena, Italy.

Cancer is the most important cause of death worldwide, and early cancer detection is the most fundamental factor for efficacy of treatment, prognosis, and increasing survival rate. Over the years great effort has been devoted to discovering and testing new biomarkers that can improve its diagnosis, especially at an early stage. Here we report the potential usefulness of new, easily applicable, non-invasive and relatively low-cost clinical biomarkers, based on abnormalities of oral mucosa spectral reflectance and fractal geometry of the vascular networks in several different tissues, for identification of hereditary non-polyposis colorectal cancer carriers as well for detection of other tumors, even at an early stage. In the near future the methodology/technology of these procedures should be improved, thus making possible their applicability worldwide as screening tools for early recognition and prevention of cancer.
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http://dx.doi.org/10.3233/CBM-170050DOI Listing
October 2018

Relevance of 4-F-neuroprostane and 10-F-neuroprostane to neurological diseases.

Free Radic Biol Med 2018 02 9;115:278-287. Epub 2017 Dec 9.

Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

F-neuroprostanes (F-NeuroPs) are non-enzymatic oxidized products derived from docosahexaenoic acid (DHA) and are suggested to be oxidative damage biomarkers of neurological diseases. However, 128 isomers can be formed from DHA oxidation and among them, 4(RS)-4-F-NeuroP (4-F-NeuroP) and 10(RS)-10-F-NeuroP (10-F-NeuroP) are the most studied. Here, we report the identification and the clinical relevance of 4-F-NeuroP and 10-F-NeuroP in plasma of four different neurological diseases, including multiple sclerosis (MS), autism spectrum disorders (ASD), Rett syndrome (RTT), and Down syndrome (DS). The identification and the optimization of the method were carried out by gas chromatography/negative-ion chemical ionization tandem mass spectrometry (GC/NICI-MS/MS) using chemically synthesized 4-F-NeuroP and 10-F-NeuroP standards and in oxidized DHA liposome. Both 4-F-NeuroP and 10-F-NeuroP were detectable in all plasma samples from MS (n = 16), DS (n = 16), ASD (n = 9) and RTT (n = 20) patients. While plasma 10-F-NeuroP content was significantly higher in patients of all diseases as compared to age and gender matched healthy control subjects (n = 61), 4-F-NeuroP levels were significantly higher in MS and RTT as compared to healthy controls. Significant positive relationships were observed between relative disease severity and 4-F-NeuroP levels (r = 0.469, P <0.0001), and 10-F-NeuroP levels (r = 0.757, P < 0.0001). The study showed that the plasma amount ratio of 10-F-NeuroP to 4-F-NeuroP and the plasma amount as individual isomer can be used to discriminate between different brain diseases. Overall, by comparing the different types of disease, our plasma data indicates that 4-F-NeuroP and 10-F -NeuroP: i) are biologically synthesized in vivo and circulated, ii) are related to clinical severity of neurological diseases, iii) are useful to identify shared pathogenetic pathways in distinct brain diseases, and iv) appears to be distinctive for different neurological conditions, thus representing potentially new biological disease markers. Our data strongly suggest that in vivo DHA oxidation follows preferential chemical rearrangements according to different brain diseases.
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http://dx.doi.org/10.1016/j.freeradbiomed.2017.12.009DOI Listing
February 2018

Dysphagia in Rett Syndrome: A Descriptive Study.

Ann Otol Rhinol Laryngol 2017 Sep 2;126(9):640-645. Epub 2017 Aug 2.

1 Department of Medicine, Surgery and Neuroscience, ENT Clinic, University Hospital of Siena, Viale Bracci 14, 53100 Siena, Italy.

Objectives: Rett syndrome (RS) is a neurodevelopmental disorder and the second major cause of mental retardation in females. The aim of this study was to evaluate swallowing problems of RS patients by endoscopic assessment and compile a list of suggestions for managing feeding and preventing complications.

Methods: The sample consisted of 61 female patients (mean age = 13.6 years, range, 2-33 years) admitted to the Department of Neuropsychiatry, where they had previously been diagnosed with RS. Speech evaluation associated with observation during mealtimes was useful to formulate suggestions for caregivers.

Results: Progressive deterioration of feeding was commonly noted by caregivers. Fifty-four patients had a history of recurrent episodes of bronchitis. Oral apraxia, dyskinetic tongue movements, prolonged oral stage, and poor bolus formation were the most common findings in all patients.

Conclusions: Dysphagia was primarily limited to oral preparatory phases, while the pharyngeal phase was normal in most patients. The high percentage of dysphagia suggests the need to accurately monitor the feeding capability of RS children. It is critical to correctly inform caregivers about safe swallowing procedures to reduce the incidence of fatal complications.
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http://dx.doi.org/10.1177/0003489417723033DOI Listing
September 2017

Persistent Unresolved Inflammation in the -308 Female Mutated Mouse Model of Rett Syndrome.

Mediators Inflamm 2017 16;2017:9467819. Epub 2017 May 16.

Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, 53100 Siena, Italy.

Rett syndrome (RTT) is a rare neurodevelopmental disorder usually caused by mutations in the X-linked gene (). Several mutant mouse lines have been developed recapitulating part of the clinical features. In particular, -308 female heterozygous mice, bearing a truncating mutation, are a validated model of the disease. While recent data suggest a role for inflammation in RTT, little information on the inflammatory status in murine models of the disease is available. Here, we investigated the inflammatory status by proteomic 2-DE/MALDI-ToF/ToF analyses in symptomatic -308 female mice. Ten differentially expressed proteins were evidenced in the -308 mutated plasma proteome. In particular, 5 positive acute-phase response (APR) proteins increased (i.e., kininogen-1, alpha-fetoprotein, mannose-binding protein C, alpha-1-antitrypsin, and alpha-2-macroglobulin), and 3 negative APR reactants were decreased (i.e., serotransferrin, albumin, and apolipoprotein A1). CD5 antigen-like and vitamin D-binding protein, two proteins strictly related to inflammation, were also changed. These results indicate for the first time a persistent unresolved inflammation of unknown origin in the -308 mouse model.
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http://dx.doi.org/10.1155/2017/9467819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5448068PMC
March 2018

New evidences on the altered gut microbiota in autism spectrum disorders.

Microbiome 2017 02 22;5(1):24. Epub 2017 Feb 22.

Institute of Agriculture Biology and Biotechnology, National Research Council (CNR), Via Moruzzi 1, 56124, Pisa, Italy.

Background: Autism spectrum disorders (ASDs) are neurodevelopmental conditions characterized by social and behavioural impairments. In addition to neurological symptoms, ASD subjects frequently suffer from gastrointestinal abnormalities, thus implying a role of the gut microbiota in ASD gastrointestinal pathophysiology.

Results: Here, we characterized the bacterial and fungal gut microbiota in a cohort of autistic individuals demonstrating the presence of an altered microbial community structure. A fraction of 90% of the autistic subjects were classified as severe ASDs. We found a significant increase in the Firmicutes/Bacteroidetes ratio in autistic subjects due to a reduction of the Bacteroidetes relative abundance. At the genus level, we observed a decrease in the relative abundance of Alistipes, Bilophila, Dialister, Parabacteroides, and Veillonella in the ASD cohort, while Collinsella, Corynebacterium, Dorea, and Lactobacillus were significantly increased. Constipation has been then associated with different bacterial patterns in autistic and neurotypical subjects, with constipated autistic individuals characterized by high levels of bacterial taxa belonging to Escherichia/Shigella and Clostridium cluster XVIII. We also observed that the relative abundance of the fungal genus Candida was more than double in the autistic than neurotypical subjects, yet due to a larger dispersion of values, this difference was only partially significant.

Conclusions: The finding that, besides the bacterial gut microbiota, also the gut mycobiota contributes to the alteration of the intestinal microbial community structure in ASDs opens the possibility for new potential intervention strategies aimed at the relief of gastrointestinal symptoms in ASDs.
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http://dx.doi.org/10.1186/s40168-017-0242-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5320696PMC
February 2017

Oxygen exchange and energy metabolism in erythrocytes of Rett syndrome and their relationships with respiratory alterations.

Mol Cell Biochem 2017 Feb 7;426(1-2):205-213. Epub 2017 Jan 7.

Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.

Rett syndrome (RTT) is a neurodevelopmental disorder, mainly affecting females, which is associated to a mutation on the methyl-CpG-binding protein 2 gene. In the pathogenesis and progression of classic RTT, red blood cell (RBC) morphology has been shown to be an important biosensor for redox imbalance and chronic hypoxemia. Here we have evaluated the impact of oxidation and redox imbalance on several functional properties of RTT erythrocytes. In particular, we report for the first time a stopped-flow measurement of the kinetics of oxygen release by RBCs and the analysis of the intrinsic affinity of the hemoglobin (Hb). According to our experimental approach, RBCs from RTT patients do not show any intrinsic difference with respect to those from healthy controls neither in Hb's oxygen-binding affinity nor in O exchange processes at 37 °C. Therefore, these factors do not contribute to the observed alteration of the respiratory function in RTT patients. Moreover, the energy metabolism of RBCs, from both RTT patients and controls, was evaluated by ion-pairing HPLC method and related to the level of malondialdehyde and to the oxidative radical scavenging capacity of red cells. Results have clearly confirmed significant alterations in antioxidant defense capability, adding important informations concerning the high-energy compound levels in RBCs of RTT subjects, underlying possible correlations with inflammatory tissue alterations.
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http://dx.doi.org/10.1007/s11010-016-2893-9DOI Listing
February 2017

Proteomic analysis of the Rett syndrome experimental model mecp2 mutant zebrafish.

J Proteomics 2017 02 3;154:128-133. Epub 2017 Jan 3.

Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy.

Rett syndrome (RTT) is a severe genetic disorder resulting from mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene. Recently, a zebrafish carrying a mecp2-null mutation has been developed with the resulting phenotypes exhibiting defective sensory and thigmotactic responses, and abnormal motor behavior reminiscent of the human disease. Here, we performed a proteomic analysis to examine protein expression changes in mecp2-null vs. wild-type larvae and adult zebrafish. We found a total of 20 proteins differentially expressed between wild-type and mutant zebrafish, suggesting skeletal and cardiac muscle functional defects, a stunted glycolysis and depleted energy availability. This molecular evidence is directly linked to the mecp2-null zebrafish observed phenotype. In addition, we identified changes in expression of proteins critical for a proper redox balance, suggesting an enhanced oxidative stress, a phenomenon also documented in human patients and RTT murine models. The molecular alterations observed in the mecp2-null zebrafish expand our knowledge on the molecular cascade of events that lead to the RTT phenotype.

Biological Significance: We performed a proteomic study of a non-mammalian vertebrate model (zebrafish, Danio rerio) for Rett syndrome (RTT) at larval and adult stages of development. Our results reveal major protein expression changes pointing out to defects in energy metabolism, redox status imbalance, and muscle function, both skeletal and cardiac. Our molecular analysis grants the mecp2-null zebrafish as a valuable RTT model, triggering new research approaches for a better understanding of the RTT pathogenesis and phenotype expression. This non-mammalian vertebrate model of RTT strongly suggests a broad impact of Mecp2 dysfunction.
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http://dx.doi.org/10.1016/j.jprot.2016.12.010DOI Listing
February 2017

Skeletal dysplasia with bowing long bones: Proposed flowchart for prenatal diagnosis with case demonstration.

Taiwan J Obstet Gynecol 2016 Dec;55(6):771-776

Department of Obstetrics, Paulista School of Medicine - Federal University of São Paulo (EPM-UNIFESP), São Paulo, Brazil.

Objective: Skeletal dysplasia with bowing long bones is a rare group of multiple characterized congenital anomalies.

Materials And Methods: We introduce a simple, practical diagnostic flowchart that may be helpful in identifying the appropriate pathway of obstetrical management.

Results: Herein, we describe four fetal cases of bent bony dysplasia that focus on ultrasound findings, phenotype, molecular tests, distinctive X-ray features, and chondral growth plate histology. The first case was a typical campomelic dysplasia resulting from a de novo mutation in the SOX9 gene. The second fetus was affected by osteogenesis imperfecta Type II carrying a mutation in the COLA1 gene. The third case was a rare presentation of campomelic dysplasia, Cumming type, in which SOX9 examination was normal. Subsequently, a femoral hypoplasia unusual facies syndrome is also discussed.

Conclusion: Targeted molecular tests and genetic counseling are required for supplementing ultrasound imaging in order to diagnose the correct skeletal disorders.
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http://dx.doi.org/10.1016/j.tjog.2015.10.027DOI Listing
December 2016

Inflammatory protein response in CDKL5-Rett syndrome: evidence of a subclinical smouldering inflammation.

Inflamm Res 2017 Mar 29;66(3):269-280. Epub 2016 Nov 29.

Child Neuropsychiatry Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, 53100, Siena, Italy.

Background: Mutations in the cyclin-dependent kinase-like 5 gene cause a clinical variant of Rett syndrome (CDKL5-RTT). A role for the acute-phase response (APR) is emerging in typical RTT caused by methyl-CpG-binding protein 2 gene mutations (MECP2-RTT). No information is, to date, available on the inflammatory protein response in CDKL5-RTT. We evaluated, for the first time, the APR protein response in CDKL5-RTT.

Methods: Protein patterns in albumin- and IgG-depleted plasma proteome from CDKL5-RTT patients were evaluated by two-dimensional gel electrophoresis/mass spectrometry. The resulting data were related to circulating cytokines and compared to healthy controls or MECP2-RTT patients. The effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) were evaluated.

Results: CDKL5-RTT mutations resulted in a subclinical attenuated inflammation, specifically characterized by an overexpression of the complement component C3 and CD5 antigen-like, both strictly related to the inflammatory response. Cytokine dysregulation featuring a bulk increase of anti-inflammatory cytokines, predominantly IL-10, could explain the unchanged erythrocyte sedimentation rate and atypical features of inflammation in CDKL5-RTT. Omega-3 PUFAs were able to counterbalance the pro-inflammatory status.

Conclusion: For the first time, we revealed a subclinical smouldering inflammation pattern in CDKL5-RTT consisting in the coexistence of an atypical APR coupled with a dysregulated cytokine response.
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http://dx.doi.org/10.1007/s00011-016-1014-2DOI Listing
March 2017

Increased non-protein bound iron in Down syndrome: contribution to lipid peroxidation and cognitive decline.

Free Radic Res 2016 Dec 23;50(12):1422-1431. Epub 2016 Nov 23.

e Neonatal Intensive Care Unit , University Hospital, AOUS, Policlinico "S. M. alle Scotte" , Siena , Italy.

Down syndrome (DS, trisomy 21) is the leading cause of chromosomal-related intellectual disability. At an early age, adults with DS develop with the neuropathological hallmarks of Alzheimer's disease, associated with a chronic oxidative stress. To investigate if non-protein bound iron (NPBI) can contribute to building up a pro-oxidative microenvironment, we evaluated NPBI in both plasma and erythrocytes from DS and age-matched controls, together with in vivo markers of lipid peroxidation (F-isoprostanes, F-dihomo-isoprostanes, F-neuroprostanes) and in vitro reactive oxygen species (ROS) formation in erythrocytes. The serum iron panel and uric acid were also measured. Second, we explored possible correlation between NPBI, lipid peroxidation and cognitive performance. Here, we report NPBI increase in DS, which correlates with increased serum ferritin and uric acid. High levels of lipid peroxidation markers and intraerythrocyte ROS formations were also reported. Furthermore, the scores of Raven's Colored Progressive Matrices (RCPM) test, performed as a measure of current cognitive function, are inversely related to NPBI, serum uric acid, and ferritin. Likewise, ROS production, F-isoprostanes, and F-neuroprostanes were also inversely related to cognitive performance, whereas serum transferrin positively correlated to RCPM scores. Our data reveal that increased availability of free redox-active iron, associated with enhanced lipid peroxidation, may be involved in neurodegeneration and cognitive decline in DS. In this respect, we propose chelation therapy as a potential preventive/therapeutic tool in DS.
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http://dx.doi.org/10.1080/10715762.2016.1253833DOI Listing
December 2016

Altered gut microbiota in Rett syndrome.

Microbiome 2016 07 30;4(1):41. Epub 2016 Jul 30.

Institute of Biometeorology (IBIMET), National Research Council (CNR), Via Giovanni Caproni 8, I-50145, Florence, Italy.

Background: The human gut microbiota directly affects human health, and its alteration can lead to gastrointestinal abnormalities and inflammation. Rett syndrome (RTT), a progressive neurological disorder mainly caused by mutations in MeCP2 gene, is commonly associated with gastrointestinal dysfunctions and constipation, suggesting a link between RTT's gastrointestinal abnormalities and the gut microbiota. The aim of this study was to evaluate the bacterial and fungal gut microbiota in a cohort of RTT subjects integrating clinical, metabolomics and metagenomics data to understand if changes in the gut microbiota of RTT subjects could be associated with gastrointestinal abnormalities and inflammatory status.

Results: Our findings revealed the occurrence of an intestinal sub-inflammatory status in RTT subjects as measured by the elevated values of faecal calprotectin and erythrocyte sedimentation rate. We showed that, overall, RTT subjects harbour bacterial and fungal microbiota altered in terms of relative abundances from those of healthy controls, with a reduced microbial richness and dominated by microbial taxa belonging to Bifidobacterium, several Clostridia (among which Anaerostipes, Clostridium XIVa, Clostridium XIVb) as well as Erysipelotrichaceae, Actinomyces, Lactobacillus, Enterococcus, Eggerthella, Escherichia/Shigella and the fungal genus Candida. We further observed that alterations of the gut microbiota do not depend on the constipation status of RTT subjects and that this dysbiotic microbiota produced altered short chain fatty acids profiles.

Conclusions: We demonstrated for the first time that RTT is associated with a dysbiosis of both the bacterial and fungal component of the gut microbiota, suggesting that impairments of MeCP2 functioning favour the establishment of a microbial community adapted to the costive gastrointestinal niche of RTT subjects. The altered production of short chain fatty acids associated with this microbiota might reinforce the constipation status of RTT subjects and contribute to RTT gastrointestinal physiopathology.
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http://dx.doi.org/10.1186/s40168-016-0185-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967335PMC
July 2016

Objective Evaluation of Presbyphonia: Spectroacoustic Study on 142 Patients with Praat.

J Voice 2017 Mar 15;31(2):257.e25-257.e32. Epub 2016 Jul 15.

Department of Neonatology, University Hospital of Siena, Siena, Italy.

Objectives: Presbyphonia is the sequence of physiological events related to the process of senility of the vocal folds. The aim of our analysis was to provide deeper knowledge of presbyphonia, raising awareness of this condition as well as giving basic suggestions on how to treat related vocal alterations.

Study Design: This is a randomized study.

Methods: In 2015, we conducted a study on 182 subjects. Each participant underwent an ENT examination (video-laryngo-stroboscopy and subjective acoustic analysis using the General degree of dysphonia; degree of voice Instability; degree of voice Roughness; degree of voice Breathiness; degree of voice Asthenia; degree of voice Strain (GIRBAS) scale) and a logopedic examination (anamnesis, medical history, and acoustic voice analysis using the free software Praat).

Results: The comparison between the voice of young people and the seniors showed significant differences for the following Praat-analyzed acoustic parameters: modal fundamental frequency (F0) in women (P < 0,0001), fraction of locally unvoiced frames (P < 0,0001), number of voice breaks (P < 0,0001), jitter local (P < 0,0001), jitter local abs (P < 0,0001), jitter rap (P < 0,0001), jitter ppq5 (P < 0,0001), shimmer local (P < 0,0001), shimmer local dB (P < 0,0001), shimmer apq3 (P < 0,0001), shimmer apq5 (P < 0,0001), mean N/H (P < 0,0001), and mean H/N (P < 0,001), for both sexes.

Conclusions: The Praat was confirmed to be a useful tool to detect the existence of the variation of the speech parameters in relation to aging and to quantify statistically significant differences that show a general deterioration in the voice quality, defined numerically. This might lead to a phoniatric treatment or speech therapy, which could improve patients' quality of life, leading to better vocal performance and social and communicative interaction.
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http://dx.doi.org/10.1016/j.jvoice.2016.05.022DOI Listing
March 2017

Expression and oxidative modifications of plasma proteins in autism spectrum disorders: Interplay between inflammatory response and lipid peroxidation.

Proteomics Clin Appl 2016 Nov 27;10(11):1103-1112. Epub 2016 Jun 27.

Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy.

Purpose: A role for inflammation and oxidative stress is reported in autism spectrum disorders (ASDs). Here, we tested possible changes in expression and/or oxidative status for plasma proteins in subjects with ASDs.

Experimental Design: To evaluate protein expression and protein adducts of lipid peroxidation-derived aldehyde, analysis of plasma proteins was performed in 30 subjects with ASDs and compared with 30 healthy controls with typical development, using a proteomic approach.

Results: Significant changes were evidenced for a total of 12 proteins. Of these, ten were identified as proteins involved in the acute inflammatory response including alpha-2-macroglobulin, alpha-1-antitrypsin, haptoglobin, fibrinogen, serum transferrin, prealbumin, apolipoprotein A-I apolipoprotein A-IV, apolipoprotein J, and serum albumin. In addition, significant changes occurred for two immunoglobulins alpha and gamma chains.

Conclusions And Clinical Relevance: Our present data indicate that an inflammatory response, coupled with increased lipid peroxidation, is present in subjects with ASDs. This information can provide new insight into the identification of potential plasma protein biomarkers in autism.
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http://dx.doi.org/10.1002/prca.201500076DOI Listing
November 2016

MECP2 Duplication Syndrome: Evidence of Enhanced Oxidative Stress. A Comparison with Rett Syndrome.

PLoS One 2016 1;11(3):e0150101. Epub 2016 Mar 1.

Child Neuropsychiatry Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

Rett syndrome (RTT) and MECP2 duplication syndrome (MDS) are neurodevelopmental disorders caused by alterations in the methyl-CpG binding protein 2 (MECP2) gene expression. A relationship between MECP2 loss-of-function mutations and oxidative stress has been previously documented in RTT patients and murine models. To date, no data on oxidative stress have been reported for the MECP2 gain-of-function mutations in patients with MDS. In the present work, the pro-oxidant status and oxidative fatty acid damage in MDS was investigated (subjects n = 6) and compared to RTT (subjects n = 24) and healthy condition (subjects n = 12). Patients with MECP2 gain-of-function mutations showed increased oxidative stress marker levels (plasma non-protein bound iron, intraerythrocyte non-protein bound iron, F2-isoprostanes, and F4-neuroprostanes), as compared to healthy controls (P ≤ 0.05). Such increases were similar to those observed in RTT patients except for higher plasma F2-isoprostanes levels (P < 0.0196). Moreover, plasma levels of F2-isoprostanes were significantly correlated (P = 0.0098) with the size of the amplified region. The present work shows unique data in patients affected by MDS. For the first time MECP2 gain-of-function mutations are indicated to be linked to an oxidative damage and related clinical symptoms overlapping with those of MECP2 loss-of-function mutations. A finely tuned balance of MECP2 expression appears to be critical to oxidative stress homeostasis, thus shedding light on the relevance of the redox balance in the central nervous system integrity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150101PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773238PMC
July 2016

Rett syndrome: An autoimmune disease?

Autoimmun Rev 2016 Apr 22;15(4):411-6. Epub 2016 Jan 22.

Child Neuropsychiatry Unit, University Hospital, Siena, Italy.

Rett syndrome (RTT) is a devastating neurodevelopmental disease, previously included into the autistic spectrum disorders, affecting almost exclusively females (frequency 1:10,000). RTT leads to intellective deficit, purposeful hands use loss and late major motor impairment besides featuring breathing disorders, epilepsy and increased risk of sudden death. The condition is caused in up to 95% of the cases by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Our group has shown a number of previously unrecognized features, such as systemic redox imbalance, chronic inflammatory status, respiratory bronchiolitis-associated interstitial lung disease-like lung disease, and erythrocyte morphology changes. While evidence on an intimate involvement of MeCP2 in the immune response is cumulating, we have recently shown a cytokine dysregulation in RTT. Increasing evidence on the relationship between MeCP2 and an immune dysfunction is reported, with, apparently, a link between MECP2 gene polymorphisms and autoimmune diseases, including primary Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis. Antineuronal (i.e., brain proteins) antibodies have been shown in RTT. Recently, high levels of anti-N-glucosylation (N-Glc) IgM serum autoantibodies [i.e., anti-CSF114(N-Glc) IgMs] have been detected by our group in a statistically significant number of RTT patients. In the current review, the Authors explore the current evidence, either in favor or against, the presence of an autoimmune component in RTT.
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http://dx.doi.org/10.1016/j.autrev.2016.01.011DOI Listing
April 2016

Abnormal N-glycosylation pattern for brain nucleotide pyrophosphatase-5 (NPP-5) in Mecp2-mutant murine models of Rett syndrome.

Neurosci Res 2016 Apr 20;105:28-34. Epub 2015 Oct 20.

Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy.

Neurological disorders can be associated with protein glycosylation abnormalities. Rett syndrome is a devastating genetic brain disorder, mainly caused by de novo loss-of-function mutations in the methyl-CpG binding protein 2 (MECP2) gene. Although its pathogenesis appears to be closely associated with a redox imbalance, no information on glycosylation is available. Glycoprotein detection strategies (i.e., lectin-blotting) were applied to identify target glycosylation changes in the whole brain of Mecp2 mutant murine models of the disease. Remarkable glycosylation pattern changes for a peculiar 50kDa protein, i.e., the N-linked brain nucleotide pyrophosphatase-5 were evidenced, with decreased N-glycosylation in the presymptomatic and symptomatic mutant mice. Glycosylation changes were rescued by selected brain Mecp2 reactivation. Our findings indicate that there is a causal link between the amount of Mecp2 and the N-glycosylation of NPP-5.
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http://dx.doi.org/10.1016/j.neures.2015.10.002DOI Listing
April 2016

Scavenger Receptor B1 oxidative post-translational modifications are responsible for its loss in Rett syndrome.

Free Radic Biol Med 2014 Oct 10;75 Suppl 1:S10-1. Epub 2014 Dec 10.

CNR (IRCCS Neuromed, Pozzilli, Italy), Institute of Bioscience and BioResources UOS, Italy.

The modulation of the HDL receptor scavenger receptor B1 (SRB1) was evaluated in skin fibroblasts isolated from Rett syndrome (RTT) patients, a rare neurodevelopmental disorder affecting almost exclusively females associated in up to 95% of cases to de novo loss-of-function mutations in the X-chromosome-linked gene encoding the methyl-CpG-binding protein 2 (MeCP2). Patients showed an altered plasma lipid profile, while their skin fibroblasts showed a dramatic reduction in SRB1 (immunogold, Western blot and immunohistochemistry). The decreased SRB1 levels were demonstrated to be the consequence of its binding with 4-hydroxy-2-nonenal (4HNE), a product of lipid peroxidation, and its increased ubiquitination. Therefore the loss of SRB1 in RTT cells is a consequence of the chronic oxidative stress status present in RTT. In addition RTT fibroblast presented high intracellular levels of H2O2 and 4HNE protein adducts. This finding was correlated with the constitutive activation of NADPH oxidase (NOX) and was reverted by DPI (NOX inhibitor) or Desferal (Iron chelator) pre-treatment. To confirm the alteration of status redox in RTT cells, the activity of several enzymes involved in protecting the cell from OS was also evaluated. Glutathione peroxidase (GPx), Supeoxide dismutase and Glucose-6-phosphate dehydrogenase (G6PDH) activity were decreased respect to control. These data paralleled with a constitutive activation of NRF2 and elevated gene expression of Heme oxigenase-1 (HO-1) and NAD(P)H dehydrogenase quinone 1 (NQO-1). Of note, when NRF2 pathway was stimulated via exogenous oxidants, RTT fibroblast did not respond as the control cells.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.10.855DOI Listing
October 2014

Histopathological Findings in Spontaneous Hematoma of the Umbilical Cord: Severe Hypoxic-Ischemic Encephalopathy in a Term Survived Newborn.

Am J Forensic Med Pathol 2015 Dec;36(4):254-6

From the *Department of Obstetrics and Gynecology, Guastalla Civil Hospital, AUSL Reggio Emilia; †Department of Pathology, IRCCS Arcispedale Santa Maria Nuova Hospital, Reggio Emilia; ‡Neonatal Intensive Care Unit, Policlinic Hospital Santa Maria alle Scotte, Azienda Ospedaliera Universitaria Senese, Siena; §Neuroradiology Service, IRCCS Hospital G. Gaslini, Genoa; and ∥Faculty of Law, University of Parma, Parma, Italy.

Background: Spontaneous hematoma of the umbilical cord is a rare, unpreventable, and dramatic event mainly due to a disruption of the vascular wall, often resulting in adverse perinatal outcome.

Case: We describe a case of a term fetus with acute hemorrhage in the cord occurred intrapartum during spontaneous vaginal delivery. No iatrogenic factors were involved because no drugs, obstetric instruments, or procedures were applied. Umbilical hematoma probably developed in a time frame of 90 seconds, when the electronic fetal monitoring tracing detected a loss of fetal heart rate. At birth, the baby was in serious conditions with a low Apgar score (always 3 at 1, 5, and 10 minutes) and severe mixed acidosis. He was intubated, was ventilated, and underwent therapeutic hypothermia. Although all standard emergency procedures had been immediately applied, hypoxic-ischemic encephalopathy ensued within 24 hours postnatal. Placental examination revealed in the cord disruption of the elastic fibers in the vessels walls. Moreover, myofibroblasts in the Wharton's jelly appeared reduced in number and blunted, instead of their usual stellate shape. Chorioamnionitis but no funisitis was also present.Clinical follow-up of the child, aged 4 years, showed spastic tetraplegia, seizures, central deafness, and blindness.

Conclusions: Intrinsic anomalies of the cord favored vascular rupture, hematoma of the cord, and acute fetal hypoxia. Placental examination played a key role in excluding medical malpractice because hematoma of the cord was a damaging, not otherwise preventable, event.
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http://dx.doi.org/10.1097/PAF.0000000000000195DOI Listing
December 2015

Cytokine Dysregulation in MECP2- and CDKL5-Related Rett Syndrome: Relationships with Aberrant Redox Homeostasis, Inflammation, and ω-3 PUFAs.

Oxid Med Cell Longev 2015 8;2015:421624. Epub 2015 Jul 8.

Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), Policlinico "S. M. alle Scotte", 53100 Siena, Italy.

An involvement of the immune system has been suggested in Rett syndrome (RTT), a devastating neurodevelopmental disorder related to oxidative stress, and caused by a mutation in the methyl-CpG binding protein 2 gene (MECP2) or, more rarely, cyclin-dependent kinase-like 5 (CDKL5). To date, it is unclear whether both mutations may have an impact on the circulating cytokine patterns. In the present study, cytokines involved in the Th1-, Th2-, and T regulatory (T-reg) response, as well as chemokines, were investigated in MECP2- (MECP2-RTT) (n = 16) and CDKL5-Rett syndrome (CDKL5-RTT) (n = 8), before and after ω-3 polyunsaturated fatty acids (PUFAs) supplementation. A major cytokine dysregulation was evidenced in untreated RTT patients. In MECP2-RTT, a Th2-shifted balance was evidenced, whereas in CDKL5-RTT both Th1- and Th2-related cytokines (except for IL-4) were upregulated. In MECP2-RTT, decreased levels of IL-22 were observed, whereas increased IL-22 and T-reg cytokine levels were evidenced in CDKL5-RTT. Chemokines were unchanged. The cytokine dysregulation was proportional to clinical severity, inflammatory status, and redox imbalance. Omega-3 PUFAs partially counterbalanced cytokine changes, as well as aberrant redox homeostasis and the inflammatory status. RTT is associated with a subclinical immune dysregulation as the likely consequence of a defective inflammation regulatory signaling system.
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http://dx.doi.org/10.1155/2015/421624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510261PMC
April 2016

Red blood cells in Rett syndrome: oxidative stress, morphological changes and altered membrane organization.

Biol Chem 2015 Nov;396(11):1233-40

In this review, we summarize the current evidence on the erythrocyte as a previously unrecognized target cell in Rett syndrome, a rare (1:10 000 females) and devastating neurodevelopmental disorder caused by loss-of-function mutations in a single gene (i.e. MeCP2, CDKL5, or rarely FOXG1). In particular, we focus on morphological changes, membrane oxidative damage, altered membrane fatty acid profile, and aberrant skeletal organization in erythrocytes from patients with typical Rett syndrome and MeCP2 gene mutations. The beneficial effects of ω-3 polyunsaturated fatty acids (PUFAs) are also summarized for this condition to be considered as a 'model' condition for autism spectrum disorders.
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http://dx.doi.org/10.1515/hsz-2015-0117DOI Listing
November 2015

Alteration of serum lipid profile, SRB1 loss, and impaired Nrf2 activation in CDKL5 disorder.

Free Radic Biol Med 2015 Sep 22;86:156-65. Epub 2015 May 22.

Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Department of Food and Nutrition, Kyung Hee University, Seoul, South Korea. Electronic address:

CDKL5 mutation is associated with an atypical Rett syndrome (RTT) variant. Recently, cholesterol homeostasis perturbation and oxidative-mediated loss of the high-density lipoprotein receptor SRB1 in typical RTT have been suggested. Here, we demonstrate an altered lipid serum profile also in CDKL5 patients with decreased levels of SRB1 and impaired activation of the defensive system Nrf2. In addition, CDKL5 fibroblasts showed an increase in 4-hydroxy-2-nonenal- and nitrotyrosine-SRB1 adducts that lead to its ubiquitination and probable degradation. This study highlights a possible common denominator between two different RTT variants (MECP2 and CDKL5) and a possible common future therapeutic target.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.05.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5572621PMC
September 2015

Immune dysfunction in Rett syndrome patients revealed by high levels of serum anti-N(Glc) IgM antibody fraction.

J Immunol Res 2014 15;2014:260973. Epub 2014 Oct 15.

Child Neuropsychiatry Unit, University Hospital, Azienda Ospedaliera Universitaria Senese (AOUS), 53100 Siena, Italy.

Rett syndrome (RTT), a neurodevelopmental disorder affecting exclusively (99%) female infants, is associated with loss-of-function mutations in the gene encoding methyl-CpG binding protein 2 (MECP2) and, more rarely, cyclin-dependent kinase-like 5 (CDKL5) and forkhead box protein G1 (FOXG1). In this study, we aimed to evaluate the function of the immune system by measuring serum immunoglobulins (IgG and IgM) in RTT patients (n = 53) and, by comparison, in age-matched children affected by non-RTT pervasive developmental disorders (non-RTT PDD) (n = 82) and healthy age-matched controls (n = 29). To determine immunoglobulins we used both a conventional agglutination assay and a novel ELISA based on antibody recognition by a surrogate antigen probe, CSF114(Glc), a synthetic N-glucosylated peptide. Both assays provided evidence for an increase in IgM titer, but not in IgG, in RTT patients relative to both healthy controls and non-RTT PDD patients. The significant difference in IgM titers between RTT patients and healthy subjects in the CSF114(Glc) assay (P = 0.001) suggests that this procedure specifically detects a fraction of IgM antibodies likely to be relevant for the RTT disease. These findings offer a new insight into the mechanism underlying the Rett disease as they unveil the possible involvement of the immune system in this pathology.
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http://dx.doi.org/10.1155/2014/260973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214166PMC
June 2015