Abstract
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.
References
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, 185–188.10.1038/13810Search 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, 123–128.10.1016/S0005-2736(98)00011-XSearch in Google Scholar
Calder, P.C. (2015). Marine omega-3 fatty acids and inflammatory processes, Effects, mechanisms and clinical relevance. Biochim. Biophys. Acta 1851, 469–484.10.1016/j.bbalip.2014.08.010Search in Google Scholar PubMed
Calder, P.C. and Yaqoob, P. (2009). Understanding omega-3 polyunsaturated fatty acids. Postgrad. Med. 121, 148–157.10.3810/pgm.2009.11.2083Search in Google Scholar PubMed
Chao, H.T., Zoghbi, H.Y., and Rosenmund, C. (2007). MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number. Neuron 56, 58–65.10.1016/j.neuron.2007.08.018Search in Google Scholar PubMed PubMed Central
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, 108–118.10.1006/exmp.1994.1010Search in Google Scholar PubMed
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, 203–213.10.1016/j.bbagen.2004.04.003Search in Google Scholar PubMed
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, 511–520.10.1016/j.bbagen.2011.12.002Search in Google Scholar PubMed
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, 432616.10.1155/2013/432616Search in Google Scholar PubMed PubMed Central
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, e93181.10.1371/journal.pone.0093181Search in Google Scholar PubMed PubMed Central
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:10.1155/2014/480980.10.1155/2014/480980Search in Google Scholar PubMed PubMed Central
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, 440–448.10.1016/j.freeradbiomed.2009.05.016Search in Google Scholar PubMed
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, 386–392.10.1378/chest.09-3021Search in Google Scholar PubMed
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, 71–75.10.4236/fns.2013.49A1012Search 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, 245–253.10.1016/j.febslet.2012.11.033Search in Google Scholar PubMed
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:10.1155/2014/560120.10.1155/2014/560120Search in Google Scholar PubMed PubMed Central
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, 66–77.10.1016/j.nbd.2014.04.006Search in Google Scholar PubMed PubMed Central
Dominguez, R. and Holmes, K.C. (2011). Actin structure and function. Annu. Rev. Biophys. 40, 169–186.10.1146/annurev-biophys-042910-155359Search in Google Scholar PubMed PubMed Central
D’Orsi, G., Demaio, V., Scarpelli, F., Calvario, T., and Minervini, M.G. (2009). Central sleep apnoea in Rett syndrome. Neurol. Sci. 30, 389–391.10.1007/s10072-009-0108-9Search in Google Scholar PubMed
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, 340–354.10.1002/cm.20516Search in Google Scholar PubMed PubMed Central
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, 767–780.10.1586/erm.12.73Search in Google Scholar
Fowler, V.M. (2013). The human erythrocyte plasma membrane, a Rosetta Stone for decoding membrane–cytoskeleton structure. Curr. Top. Membr. 72, 39–88.10.1016/B978-0-12-417027-8.00002-7Search 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, e66418.10.1371/journal.pone.0066418Search 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, 10–7.10.1016/j.mito.2014.02.012Search in Google Scholar
Goldani, A.A., Downs, S.R., Widjaja, F., Lawton, B., and Hendren, R.L. (2014). Biomarkers in autism. Front. Psychiatry 5, 100.10.3389/fpsyt.2014.00100Search 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, 631–652.10.1146/annurev-cellbio-092910-154121Search 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, 3–14.10.1016/j.plefa.2014.01.002Search 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, 888–892.10.1177/0883073811429859Search in Google Scholar
Halliwell, B. (2007). Free Radicals in Biology and Medicine (Oxford, UK: OUP).10.1002/3527600906.mcb.200300036Search 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, 1981–1983.10.1016/S0140-6736(08)60849-1Search 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, 208–211.10.1016/S0387-7604(01)00193-0Search 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, 347–352.10.1016/j.jpeds.2005.10.037Search in Google Scholar PubMed
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, 16766–16769.10.1073/pnas.202617299Search in Google Scholar PubMed PubMed Central
Liyanage, V.R. and Rastegar, M. (2014). Rett syndrome and MeCP2. Neuromol. Med. 16, 231–264.10.1007/s12017-014-8295-9Search in Google Scholar PubMed PubMed Central
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, 1935–1946.10.1093/hmg/ddi198Search in Google Scholar PubMed
McNamara, R.K. (2010). DHA deficiency and prefrontal cortex neuropathology in recurrent affective disorders. J. Nutr. 140, 864–868.10.3945/jn.109.113233Search in Google Scholar PubMed PubMed Central
Minotti, G. (1993). Sources and role of iron in lipid peroxidation. Chem. Res. Toxicol. 6, 134–146.10.1021/tx00032a001Search in Google Scholar PubMed
Nans, A., Mohandas, N., and Stokes, D.L. (2011). Native ultrastructure of the red cell cytoskeleton by cryo-electron tomography. Biophys. J. 101, 2341–2350.10.1016/j.bpj.2011.09.050Search in Google Scholar PubMed PubMed Central
Percy, A.K. (2011). Rett syndrome, exploring the autism link. Arch. Neurol. 68, 985–989.10.1001/archneurol.2011.149Search in Google Scholar PubMed PubMed Central
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, 280–287.10.1016/j.resp.2013.06.022Search in Google Scholar PubMed PubMed Central
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, 12–18.10.1111/dmcn.12278Search in Google Scholar
Roux, J.C. and Villard, L. (2010). Biogenic amines in Rett syndrome, the usual suspects. Behav. Genet. 40, 59–75.10.1007/s10519-009-9303-ySearch in Google Scholar
Sastry, P.S. (1985). Lipids of nervous tissue, composition and metabolism. Progr. Lipid Res. 24, 69–176.10.1016/0163-7827(85)90011-6Search 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, 45.10.1186/1743-7075-9-45Search 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, 236–239.10.1016/S0387-7604(01)00369-2Search 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:10.1155/2013/343824.10.1155/2013/343824Search 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:10.1155/2014/195935.10.1155/2014/195935Search 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, 183–193.10.1016/j.plefa.2014.08.002Search 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, 658–664.10.1212/WNL.0b013e318249f6a9Search in Google Scholar
Uchida, K. (2003). 4-hydroxy-2-nonenal, a product and mediator of oxidative stress. Prog. Lipid Res. 42, 318–343.10.1016/S0163-7827(03)00014-6Search 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, 443–449.10.1203/01.pdr.0000238302.84552.d0Search in Google Scholar PubMed
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