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

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

Subclinical Inflammatory Status in Rett Syndrome

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, P<0.0001) were detectable in RTT, whereas C-reactive protein levels were unchanged (P=0.63). The 2-DE analysis identified significant changes for a total of 17 proteins, the majority of which were categorized as APR proteins, either positive (n=6 spots) or negative (n=9 spots), and to a lesser extent as proteins involved in the immune system (n=2 spots), with some proteins having overlapping functions on metabolism (n=7 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

Acidi grassi omega-3 nella sindrome di Rett studio clinico al primo stadio della malattia

Rett syndrome (RTT) is a genetic cause of autism, mainly due to mutations in the Xlinked MeCP2 gene or more rarely in the CDKL5 or FOXG1 genes, which affects almost exclusively females, with a frequency of 1:10,000. Although rare, RTT can be considered a natural model for neurodegenerative diseases with high social impact, and represents a paradigm for the complex nutritional issues in pediatric neurodevelopmental disorders. The finding of elevated circulating levels of oxidative stress (OS) markers in RTT patients adds new perspectives to the micronutritional manipulation in these patients. To this regard, an excessive peroxidation of Polyunsaturated fatty acids ω-6 (PUFA) - i.e., F2-isoprostanes from arachidonic acid, or ω-3 PUFAs - i.e., F4-neuroprostanes from docosahexaenoic acid - implicates an excessive consumption of these PUFAs at the cell membrane level. Our prior investigations suggest a positive effect of ω-3 PUFA supplementation to RTT girls in terms of clinical status and OS markers levels. The results of the present study indicates that a high-dosage ω-3 PUFA supplementation (fish oil) in the early stages of RTT is able to partially arrest the natural progression of the disease

Acidi grassi omega-3 nella sindrome di Rett Studio clinico al primo stadio della malattia

International audienceLa sindrome di Rett (RTT) è una causa genetica di autismo, provocata dalla mutazione del gene MeCP2 o più raramente CDKL5 o FOXG1, che colpisce quasi esclusivamente le femmine (frequenza 1:10.000). Per quanto rara, la RTT è un modello per malattie più frequenti e di grande impatto sociale come le malattie neurodegenerative dell'adulto, e rappresenta un paradigma per le problematiche nutrizionali in presenza di disturbi del neurosviluppo. Il riscontro di elevati livelli di prodotti di perossidazione lipidica (stress ossidativo, SO) circolanti nel plasma delle pazienti RTT apre una nuova prospettiva nelle problematiche nutrizionali di questi soggetti. Infatti, un eccesso di prodotti di ossidazione di acidi grassi polinsaturi (PUFA) ω-6 (per esempio F2-isoprostani a partire dall'acido arachidonico) e ω-3 (per esempio F4-neuroprostani a partire dall'acido docosaesanoico) implica la coesistenza di un eccessivo 'consumo' di questi PUFA a livello delle membrane cellulari. Precedenti studi, da noi condotti, suggeriscono che la supplementazione con ω-3 PUFA ha un effetto positivo in termini di condizioni cliniche e di livelli dei marker di SO. I risultati del presente studio indicano che la somministrazione di ω-3 PUFA ad alto dosaggio, sotto forma di olio di pesce di origine naturale nella fase precoce della malattia, è in grado di arrestare, almeno parzialmente, il decorso naturale della malattia in assenza di effetti collaterali

Fatty Acids and Autism Spectrum Disorders: The Rett Syndrome Conundrum

International audienceAutism spectrum disorders (ASDs) are epidemically explosive clinical entities, but their pathogenesis is still unclear and a definitive cure does not yet exist. Rett syndrome (RTT) is a rare genetically determined cause of autism linked to mutations in the X-linked MeCP2 gene or, more rarely, in CDKL5 or FOXG1. A wide phenotypical heterogeneity is a known feature of the disease. Although several studies have focused on the molecular genetics and possible protein changes at different levels, to date very little attention has been paid to fatty acids in this disease, which could be con- sidered as a natural paradigm for the ASDs. To this regard, a quite enigmatic feature of the disease is the evidence in the affected patients of an extensive peroxidation of polyunsaturated fatty acids (arachidonic acid, AA, docosaexahenoic acid, DHA, adrenic acid, AdA and, to a lesser extent, eicosapentaenoic acid, EPA), in contrast with amelioration of the redox changes and phenotypical severity following the supplementation of some of those same fatty acids (DHA + EPA). Therefore, fatty acids may represent a kind of Janus Bifrons in the particular context of RTT. Here, we propose a rational explanation for this apparent "fatty acid paradox" in RTT. A better understanding of this paradox could also be of help to get a better insight into the complex mechanism of action for polyunsaturated fatty acids in health and dis- ease

Fatty Acids and Autism Spectrum Disorders: The Rett Syndrome Conundrum

International audienceAutism spectrum disorders (ASDs) are epidemically explosive clinical entities, but their pathogenesis is still unclear and a definitive cure does not yet exist. Rett syndrome (RTT) is a rare genetically determined cause of autism linked to mutations in the X-linked MeCP2 gene or, more rarely, in CDKL5 or FOXG1. A wide phenotypical heterogeneity is a known feature of the disease. Although several studies have focused on the molecular genetics and possible protein changes at different levels, to date very little attention has been paid to fatty acids in this disease, which could be con- sidered as a natural paradigm for the ASDs. To this regard, a quite enigmatic feature of the disease is the evidence in the affected patients of an extensive peroxidation of polyunsaturated fatty acids (arachidonic acid, AA, docosaexahenoic acid, DHA, adrenic acid, AdA and, to a lesser extent, eicosapentaenoic acid, EPA), in contrast with amelioration of the redox changes and phenotypical severity following the supplementation of some of those same fatty acids (DHA + EPA). Therefore, fatty acids may represent a kind of Janus Bifrons in the particular context of RTT. Here, we propose a rational explanation for this apparent "fatty acid paradox" in RTT. A better understanding of this paradox could also be of help to get a better insight into the complex mechanism of action for polyunsaturated fatty acids in health and dis- ease

Erythrocyte Shape Abnormalities, Membrane Oxidative Damage, and β-Actin Alterations: An Unrecognized Triad in Classical Autism

Autism spectrum disorders (ASDs) are a complex group of neurodevelopment disorders steadily rising in frequency and treatment refractory, where the search for biological markers is of paramount importance. Although red blood cells (RBCs) membrane lipidomics and rheological variables have been reported to be altered, with some suggestions indicating an increased lipid peroxidation in the erythrocyte membrane, to date no information exists on how the oxidative membrane damage may affect cytoskeletal membrane proteins and, ultimately, RBCs shape in autism. Here, we investigated RBC morphology by scanning electron microscopy in patients with classical autism, that is, the predominant ASDs phenotype (age range: 6–26 years), nonautistic neurodevelopmental disorders (i.e., “positive controls”), and healthy controls (i.e., “negative controls”). A high percentage of altered RBCs shapes, predominantly elliptocytes, was observed in autistic patients, but not in both control groups. The RBCs altered morphology in autistic subjects was related to increased erythrocyte membrane F2-isoprostanes and 4-hydroxynonenal protein adducts. In addition, an oxidative damage of the erythrocyte membrane β-actin protein was evidenced. Therefore, the combination of erythrocyte shape abnormalities, erythrocyte membrane oxidative damage, and β-actin alterations constitutes a previously unrecognized triad in classical autism and provides new biological markers in the diagnostic workup of ASDs

Altered erythrocyte membrane fatty acid profile in typical Rett syndrome: Effects of omega-3 polyunsaturated fatty acid supplementation

International audienceThis study mainly aims at examining the erythrocyte membrane fatty acid (FAs) profile in Rett syndrome (RTT), a genetically determined neurodevelopmental disease. Early reports suggest a beneficial effects of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) on disease severity in RTT. A total of 24 RTT patients were assigned to ω-3 PUFAs-containing fish oil for 12 months in a randomized controlled study (average DHA and EPA doses of 72.9, and 117.1mg/kgb.w./day, respectively). A distinctly altered FAs profile was detectable in RTT, with deficient ω-6 PUFAs, increased saturated FAs and reduced trans 20:4 FAs. FAs changes were found to be related to redox imbalance, subclinical inflammation, and decreased bone density. Supplementation with ω-3 PUFAs led to improved ω-6/ω-3 ratio and serum plasma lipid profile, decreased PUFAs peroxidation end-products, normalization of biochemical markers of inflammation, and reduction of bone hypodensity as compared to the untreated RTT group. Our data indicate that a significant FAs abnormality is detectable in the RTT erythrocyte membranes and is partially rescued by ω-3 PUFAs