Accessible Requires Authentication Published by De Gruyter June 3, 2015

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

Lucia Ciccoli, Claudio De Felice, Silvia Leoncini, Cinzia Signorini, Alessio Cortelazzo, Gloria Zollo, Alessandra Pecorelli, Marcello Rossi and Joussef Hayek
From the journal Biological Chemistry


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.

Corresponding authors: Lucia Ciccoli, Department of Molecular and Developmental Medicine, University of Siena, Via A. Moro 2, I-53100 Siena, Italy, e-mail: ; and Claudio De Felice, Neonatal Intensive Care Unit, University Hospital Azienda Ospedaliera Universitaria Senese (AOUS), Viale M. Bracci 16, I-53100 Siena, Italy, e-mail:


American Psychiatric Association (2014). Highlights of Changes from DSM-IV-TR to DSM-5. (Arlington, VA: American Psychiatric Publishing), pp. 1–19. Search in Google Scholar

Amir, R.E., Van den Veyver, I.B., Wan, M., Tran, C.Q., Francke, U., and Zoghbi, H.Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188. Search in Google Scholar

Ariani, F., Hayek, J., Rondinella, D., Artuso, R., Mencarelli, M.A., Spanhol-Rosseto, A., Pollazzon, M., Buoni, S., Spiga, O., Ricciardi, S., et al. (2008) FOXG1 is responsible for the congenital variant of Rett syndrome. Am. J. Hum. Genet. 83, 89–93. Search in Google Scholar

Baio, J. (2012). Prevalence of autism spectrum disorders, autism and developmental disabilities monitoring network, 14 sites, United States, 2008. MMWR Surveill. Summ. 61, 1–19. Search in Google Scholar

Bobrowska-Hagerstrand, M., Hagerstrand, H., and Iglic, A. (1998). Membrane skeleton and red blood cell vesciculation at low pH, Biochem. Biophys. Acta 1371, 123–128. Search in Google Scholar

Calder, P.C. (2015). Marine omega-3 fatty acids and inflammatory processes, Effects, mechanisms and clinical relevance. Biochim. Biophys. Acta 1851, 469–484. Search in Google Scholar

Calder, P.C. and Yaqoob, P. (2009). Understanding omega-3 polyunsaturated fatty acids. Postgrad. Med. 121, 148–157. Search in Google Scholar

Chao, H.T., Zoghbi, H.Y., and Rosenmund, C. (2007). MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65. Search in Google Scholar

Ciccoli, L., Signorini, C., Alessandrini, C., Ferrali, M., and Comporti M. (1994). Iron release, lipid peroxidation, and morphological alterations of erythrocytes exposed to acrolein and phenylhydrazine. Exp. Mol. Pathol. 60, 108–118. Search in Google Scholar

Ciccoli, L., Rossi, V., Leoncini, S., Signorini, C., Blanco-Garcia, J., Aldinucci, C., Buonocore, G., and Comporti, M. (2004). Iron release, superoxide production and binding of autologous IgG to band 3 dimers in newborn and adult erythrocytes exposed to hypoxia and hypoxia-reoxygenation. Biochim. Biophys. Acta 1672, 203–213. Search in Google Scholar

Ciccoli, L., De Felice, C., Paccagnini, E., Leoncini, S., Pecorelli, A., Signorini, C., Belmonte, G., Valacchi, G., Rossi, M., and Hayek, J. (2012). Morphological changes and oxidative damage in Rett syndrome erythrocytes. Biochim. Biophys. Acta 1820, 511–520. Search in Google Scholar

Ciccoli, L., De Felice, C., Paccagnini, E., Leoncini, S., Pecorelli, A., Signorini, C., Belmonte, G., Guerranti, R., Cortelazzo, A., Gentile, M. et al. (2013). Erythrocyte shape abnormalities, membrane oxidative damage, and β-actin alterations: an unrecognized triad in classical autism. Mediators Inflamm. 2013, 432616. Search in Google Scholar

Comporti, M., Signorini, C., Buonocore, G., and Ciccoli, L. (2002). Iron release, oxidative stress and erythrocyte ageing, Free Radic. Biol. Med. 32, 568–576. Search in Google Scholar

Cortelazzo, A., De Felice, C., Pecorelli, A., Belmonte, G., Signorini, C., Leoncini, S., Zollo, G., Capone, A., Della Giovampaola, C., Sticozzi, C. et al. (2014a). Beta-actin deficiency with oxidative posttranslational modifications in Rett syndrome erythrocytes, insights into an altered cytoskeletal organization. PLoS One 9, e93181. Search in Google Scholar

Cortelazzo, A., De Felice, C., Guerranti, R., Signorini, C., Leoncini, S., Pecorelli, A., Zollo, G., Landi, C., Valacchi, G., Ciccoli, L. et al. (2014b). Subclinical inflammatory status in Rett syndrome. Mediators Inflamm. 2014, Article ID 480980. Doi:10.1155/2014/480980. Search in Google Scholar

De Felice, C., Ciccoli, L., Leoncini, S., Signorini, C., Rossi, M., Vannuccini, L., Guazzi, G., Latini, G., Comporti, M., Valacchi, G. et al. (2009). Systemic oxidative stress in classic Rett syndrome. Free Radic. Biol. Med. 47, 440–448. Search in Google Scholar

De Felice, C., Guazzi, G., Rossi, M., Ciccoli, L., Signorini, C., Leoncini, S., Tonni, G., Latini, G., Valacchi, G., and Hayek J. (2010). Unrecognized lung disease in classic Rett syndrome, a physiologic and high-resolution CT imaging study. Chest 138, 386–392. Search in Google Scholar

De Felice, C., Signorini, C., Leoncini, S., Pecorelli, A., Durand, T., Valacchi, G., Ciccoli, L., and Hayek, J. (2012). The role of oxidative stress in Rett syndrome, an overview. Ann. N. Y. Acad. Sci. 1259:121–135. Search in Google Scholar

De Felice, C., Signorini, C., Leoncini, S., Pecorelli, A., Durand, T., Galano, J-M., Bultel-Poncé, V., Guy, A., Oger, C., Zollo, G. et al. (2013). Fatty acids and autism spectrum disorders, the Rett syndrome conundrum. Food Nutr. Sci. 4, 71–75. Search in Google Scholar

Delépine, C., Nectoux, J., Bahi-Buisson, N., Chelly, J., and Bienvenu, T. (2013). MeCP2 deficiency is associated with impaired microtubule stability. FEBS Lett. 587, 245–253. Search in Google Scholar

De Felice, C., Rossi, M., Leoncini, S., Chisci, G., Signorini, C., Lonetti, G., Vannuccini, L., Spina, D., Ginori, A., Iacona, I., et al. (2014a). Inflammatory lung disease in Rett syndrome. Mediators Inflamm. 2014, Article ID 560120. Doi:10.1155/2014/560120. Search in Google Scholar

De Felice, C., Della, Ragione, F., Signorini, C., Leoncini, S., Pecorelli, A., Ciccoli, L., Scalabrì, F., Marracino, F., Madonna, M., Belmonte, G., et al. (2014b) Oxidative brain damage in Mecp2-mutant murine models of Rett syndrome. Neurobiol. Dis. 68, 66–77. Search in Google Scholar

Dominguez, R. and Holmes, K.C. (2011). Actin structure and function. Annu. Rev. Biophys. 40, 169–186. Search in Google Scholar

D’Orsi, G., Demaio, V., Scarpelli, F., Calvario, T., and Minervini, M.G. (2009). Central sleep apnoea in Rett syndrome. Neurol. Sci. 30, 389–391. Search in Google Scholar

Farah, M.E., Sirotkin, V., Haarer, B., Kakhniashvili, D., and Amberg, D.C. (2011) Diverse protective roles of the actin cytoskeleton during oxidative stress. Cytoskeleton 68, 340–354. Search in Google Scholar

Ferreri,C. and Chatgilialoglu, C. (2012). Role of fatty acid-based functional lipidomics in the development of molecular diagnostic tools. Exp. Rev. Mol. Diagn.12, 767–780. Search in Google Scholar

Fowler, V.M. (2013). The human erythrocyte plasma membrane, a Rosetta Stone for decoding membrane–cytoskeleton structure. Curr. Top. Membr. 72, 39–88. Search in Google Scholar

Ghezzo, A., Visconti, P., Abruzzo, P.M., Bolotta, A., Ferreri, C., Gobbi, G., Malisardi, G., Manfredini, S., Marini, M., Nanetti, L., et al. (2013). Oxidative stress and erythrocyte membrane alterations in children with autism, correlation with clinical features. PLoS One 8, e66418. Search in Google Scholar

Gold, W.A., Williamson, S.L., Kaur, S., Hargreaves, I.P., Land, J.M., Pelka, G.J., Tam, P.P., and Christodoulou, J. (2014). Mitochondrial dysfunction in the skeletal muscle of a mouse model of Rett syndrome (RTT), implications for the disease phenotype. Mitochondrion 15, 10–7. Search in Google Scholar

Goldani, A.A., Downs, S.R., Widjaja, F., Lawton, B., and Hendren, R.L. (2014). Biomarkers in autism. Front. Psychiatry 5, 100. Search in Google Scholar

Guy, J., Cheval, H., Selfridge, J., and Bird, A. (2011). The role of MeCP2 in the brain. Ann. Rev. Cell Dev. Biol. 27, 631–652. Search in Google Scholar

Haast, R.A. and Kiliaan, A.J. (2015). Impact of fatty acids on brain circulation, structure and function. Prostaglandins Leukot. Essent. Fatty Acids 92C, 3–14. Search in Google Scholar

Hagberg, B. (2002). Clinical manifestations and stages of Rett syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 8, 61–65. Search in Google Scholar

Hagebeuk, E.E., Bijlmer, R.P., Koelman, J.H., and Poll-The, B.T. (2012). Respiratory disturbances in Rett syndrome, don’t forget to evaluate upper airway obstruction. J. Child Neurol. 27, 888–892. Search in Google Scholar

Halliwell, B. (2007). Free Radicals in Biology and Medicine (Oxford, UK: OUP). Search in Google Scholar

Julu, P.O., Engerström, I.W., Hansen, S., Apartopoulos, F., Engerström, B., Pini, G., Delamont, R.S., and Smeets, E.E. (2008). Cardiorespiratory challenges in Rett’s syndrome. Lancet 371, 1981–1983. Search in Google Scholar

Kerr, A.M., Nomura, Y., Armstrong, D., Anvret, M., Belichenko, P.V., Budden, S., Cass, H., Christodoulou, J., Clarke, A., Ellaway, C., et al. (2001). Guidelines for reporting clinical features in cases with MECP2 mutations. Brain Dev. 23, 208–211. Search in Google Scholar

Laurvick, C.L., de Klerk, N., Bower, C., Christodoulou, J., Ravine, D., Ellaway, C., Williamson, S., and Leonard, H. (2006). Rett syndrome in Australia, a review of the epidemiology. J. Paediatr. 148, 347–352. Search in Google Scholar

Lim, G.H.W., Wortis, M., and Mukhopadhyay, R. (2002). Stomatocyte- discocyte echinocyte sequence of the human red blood cell, evidence for the bilayer-couple hypotesis from membrane mechanics, Proc. Natl. Acad. Sci. USA 99, 16766–16769. Search in Google Scholar

Liyanage, V.R. and Rastegar, M. (2014). Rett syndrome and MeCP2. Neuromol. Med. 16, 231–264. Search in Google Scholar

Mari, F., Azimonti, S., Bertani, I., Bolognese, F., Colombo, E., Caselli, R., Scala, E., Longo, I., Grosso, S., Pescucci, C., et al. (2005). CDKL5 belongs to the same molecular pathway of MeCP2 and it is responsible for the early-onset seizure variant of Rett syndrome. Hum. Mol. Genet. 14, 1935–1946. Search in Google Scholar

McNamara, R.K. (2010). DHA deficiency and prefrontal cortex neuropathology in recurrent affective disorders. J. Nutr. 140, 864–868. Search in Google Scholar

Minotti, G. (1993). Sources and role of iron in lipid peroxidation. Chem. Res. Toxicol. 6, 134–146. Search in Google Scholar

Nans, A., Mohandas, N., and Stokes, D.L. (2011). Native ultrastructure of the red cell cytoskeleton by cryo-electron tomography. Biophys. J. 101, 2341–2350. Search in Google Scholar

Percy, A.K. (2011). Rett syndrome, exploring the autism link. Arch. Neurol. 68, 985–989. Search in Google Scholar

Ramirez, J.M., Ward, C.S., and Neul, J.L. (2013). Breathing challenges in Rett syndrome, lessons learned from humans and animal models. Respir. Physiol. Neurobiol. 189, 280–287. Search in Google Scholar

Rosti, R.O., Sadek, A.A., Vaux, K.K., and Gleeson, J.G. (2014). The genetic landscape of autism spectrum disorders. Dev. Med. Child Neurol. 56, 12–18. Search in Google Scholar

Roux, J.C. and Villard, L. (2010). Biogenic amines in Rett syndrome, the usual suspects. Behav. Genet. 40, 59–75. Search in Google Scholar

Sastry, P.S. (1985). Lipids of nervous tissue, composition and metabolism. Progr. Lipid Res. 24, 69–176. Search in Google Scholar

Schmidt, S., Stahl. F., Mutz, K.O., Scheper, T., Hahn, A., and Schuchardt, J.P. (2012). Transcriptome-based identification of antioxidative gene expression after fish oil supplementation in normo- and dyslipidemic men. Nutr. Metab. 9, 45. Search in Google Scholar

Sierra, C., Vilaseca, M.A., Brandi, N., Artuch, R., Mira, A., Nieto, M., and Pineda, M. (2001). Oxidative stress in Rett syndrome. Brain Dev. 23, 236–239. Search in Google Scholar

Signorini, C., De Felice, C., Durand, T., Oger, C., Galano, J-M., Leoncini, S., Pecorelli, A., Valacchi, G., Ciccoli, L., and Hayek, J. (2013). Isoprostanes and 4-hydroxy-2-nonenal, markers or mediators of disease? Focus on Rett syndrome as a model of autism spectrum disorder. Oxid. Med. Cell. Longev. 2013, Article ID 343824. Doi:10.1155/2013/343824. Search in Google Scholar

Signorini, C., Leoncini, S., De Felice, C., Pecorelli, A., Meloni, I., Ariani, F., Mari, F., Amabile, S., Paccagnini, E., Gentile, M. et al. (2014a). Redox imbalance and morphological changes in skin fibroblasts in typical Rett syndrome. Oxid. Med. Cell. Longev. 2014, Article ID 195935. Doi:10.1155/2014/195935. Search in Google Scholar

Signorini, C., De Felice, C., Leoncini, S., Durand, T., Galano, J-M., Cortelazzo, A., Zollo, G., Guerranti, R., Gonnelli, S., Caffarelli, C., et al. (2014b). Altered erythrocyte membrane fatty acid profile in typical Rett syndrome, effects of omega-3 polyunsaturated fatty acid supplementation. Prostaglandins Leukot. Essent. Fatty Acids 91, 183–193. Search in Google Scholar

Simmonds, M.J., Meiselman, H.J., and Baskurt, O.K. (2013) Blood rheology and aging. J. Geriatr. Cardiol. 10, 291–301. Search in Google Scholar

Srour, T., Bilto, Y.Y., Juma, M., and Irhimeh, M.R. (2000). Exposure of human erythrocytes to oxygen radicals causes loss of deformability, increased osmotic fragility, lipid peroxidation and protein degradation. Clin. Hemorheol. Microcirc. 23:13–21. Search in Google Scholar

Tan, Z.S., Harris, W.S., Beiser, A.S., Au, R., Himali, J.J., Debette, S., Pikula, A., Decarli, C., Wolf, P.A., Vasan, R.S. et al. (2012). Red blood cell ω3 fatty acid levels and markers of accelerated brain aging. Neurology 78, 658–664. Search in Google Scholar

Uchida, K. (2003). 4-hydroxy-2-nonenal, a product and mediator of oxidative stress. Prog. Lipid Res. 42, 318–343. Search in Google Scholar

Weese-Mayer, D.E., Lieske, S.P., Boothby, C.M., Kenny, A.S., Bennett, H.L., Silvestri, J.M., and Ramirez, J.M. (2006). Autonomic nervous system dysregulation, breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome. Pediatric Res. 60, 443–449. Search in Google Scholar

Received: 2015-1-30
Accepted: 2015-5-7
Published Online: 2015-6-3
Published in Print: 2015-11-1

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