Trisomy 21 or Down syndrome (DS) is a complex syndrome, of genetic origin with multiple and variable neurobiological and neuropsychological manifestations. DS patients have consistent signs of brain damage along their lives, but understanding the biology of DS is complicated due to the extraordinary heterogeneity of the phenotypic signs. Thus, treatment of DS mental retardation poses significant challenges for clinicians and scientists. The review addresses the classical pharmacological and environmental treatments and also critically reviews the new possibilities that are emerging from the exciting advances in gene or cell therapy. We describe some of the most recent developments in the field and give a sense of the prospects for future prevention and therapy.
Similar content being viewed by others
References
Abdelgany A., Wood M., and Beeson D. (2003). Allele-specific silencing of a pathogenic mutant acetylcholine receptor subunit by RNA interference. Human mol. genet. 12:2637–2644
Anneren G., and Edman B. (1993). Down syndrome-a gene dosage disease caused by trisomy of genes within a small segment of the long arm of chromosome 21, exemplified by the study of the effects from the superoxide type-1 (SOD-1) gene. AMPIS Suppl. 40:71–79
Antila, E., Norberg, U. R., Syvaoja, E. L., and Wetermarck, T. (eds.), (1990). Selenium therapy in down syndrome: a theory and clinical trial Antioxidants in therapy and preventative medicine. New York: Plenum Press, pp. 183–186.
Becker L. E., Armstrong D. L., and Chan F. (1986). Dendritic atrophy in children with Down’s syndrome. Annals neurol. 20:520–526
Becker L., Mito T., Takashima S., and Onodera K. (1991). Growth and development of the brain in Down syndrome. Progress Clin. Biol. Res. 373:133–152
Behl, C., Moosman, B., Manthey, D., and Heck, S. (2000). The female sex hormone estrogen as neuroprotectant: activities at various levels. In: Neuronal and cognitive effects of estrogen. Chichester, Wiley (Novartis Foundation Symposium, 230), pp. 21–38
Benavides-Piccione R., Ballesteros-Yanez I., Martínez de Lagran M., Elston G., Estivill X., Fillat C., Defelipe J., and Dierssen M. (2004). On dendrites in Down syndrome and DS murine models: a spiny way to learn. Progress Neurobiol. 74:111–126
Bimonte-Nelson H. A., Hunter C. L., Nelson M. E., and Granholm A. C. (2003). Frontal cortex BDNF levels correlate with working memory in an animal model of Down syndrome. Behav. Brain Res. 139:47–57
Bucci I., Napolitano G., Giuliani C., Lio S., Minnucci A., Di Giacomo F., Calabrese G., Sabatino G., Palka G., and Monaco F. (1999). Zinc sulfate supplementation improves thyroid function in hypozincemic Down children. Biol. Trace Element Res. 67:257–268
Caplen N. J., Parrish S., Imani F., Fire A., and Morgan R. A. (2001). Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems. Proc. Nat. Acad. Sci. USA 98:9742–9747
Capone G. T. (2001). Down Syndrome: Advances in Molecular Biology and the Neurosciences. J. Develop. Behav. Pediatrics: JDBP 22:40–59
Chez M., Tremb R., Nowinski C., and Field-Chez M. (2001). Double-blinded placebo-controlled aricept study in children with autistic spectrum disorder. Annals Neurol. 49:95–96
Chez M., Aimonovitch M., Buchanan T., Mrazek S., and Tremb R. (2004). Treating autistic spectrum disorders in children: Utility of the cholinesterase inhibitor rivastigmine tartrate. J. Child Neurol. 19:165–169
Ciaccio M., Piccione M., Giuffre M., Macaione V., Vocca L., Bono A., and Corsello G. (2003). Aminoacid profile and oxidative status in children affected by Down syndrome before and after supplementary nutritional treatment. The Ital. J. Biochem 52:72–79
Connolly, B. H., Morgan, S. B., Russell, F. F., and Fulliton, W. L. (1993).A longitudinal study of children with Down Syndrome who experienced early intervention programming Phys. Ther.73:170–181.
Davidson B. L., and Breakefield X. O. (2003). Viral vectors for gene delivery to the nervous system. Nature Rev.: Neurosci. 4:353–364
Deglon N., and Hantraye P. (2005). Viral vectors as tools to model and treat neurodegenerative disorders. The J. Gene Med. 5:123–128
Delenda C. (2004). Lentiviral vectors: optimization of packaging, transduction and gene expression. The J. Gene Med. 6:S125–138
Dierssen M. (2003a). Special interest section–Down’s syndrome: postgenomic approaches to neurobiological problems. Genes, Brain, Behavior 2:152–155
Dierssen M., Benavides-Piccione R., Martinez-Cue C., Estivill X., Florez J., Elston G. N., and DeFelipe J. (2003b). Alterations of neocortical pyramidal cell phenotype in the Ts65Dn mouse model of Down syndrome: effects of environmental enrichment. Cerebral Cortex 13:758–764
Dierssen, M., and Ramakers, G. Dendritic pathology in mental retardation: from molecular genetics to neurobiology. Genes, Brain, Behavior. in press
Dorn G., Patel S., Wotherspoon G., Hemmings-Mieszczak M., Barclay J., and Natt F. J. (2004). siRNA relieves chronic neuropathic pain. Nucleic Acids Res. 32:e49
Elbashir S. M., Lendeckel W., and Tuschl T. (2001). RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Develop. 15:188–200
Fillon-Emery N., Chango A., Mircher C., Barbé F., Bléhaut H., Herbeth B., Rosenblatt D. S., Réthoré M. O., Lambert D., and Nicolas J. P. (2004). Homocysteine concentrations in adults with trisomy 21: effect of B vitamins and genetic polymorphisms1–4. The Am. J. Clin. Nutrition 80:1551–1557
Fire A., Xu S., Montgomery M. K., Kostas S. A., Driver S. E., and Mello C. C. (1998). Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811
Flórez, J. (1992). Neurologic abnormalities. In: Pueschel S. M. and Pueschel J. K. (eds). Biomedical Concerns in Persons with Down Syndrome. Baltimore, Paul H. Brookes Pub., pp. 159–173
Geldmacher D. S., Lerner A. J., Voci J. M., Noelker E. A., Somple L. C., and Whitehouse P. J. (1997). Treatment of functional decline in adults with Down syndrome using selective serotonin-reuptake inhibitor drugs. J. Geriatric Psychiatry Neurol. 10:99–104
Gedye A. (1990). Dietary increase in serotonin reduces self-injurious behaviour in a Down’s syndrome adult. J. Mental Deficiency Res. 34:195–203
Gedye A. (1991). Serotonergic treatment for aggression in a Down’s syndrome adult showing signs of Alzheimer’s disease. J. Mental Deficiency Res. 35:247–258
Genc S., Koroglu T. F., and Genc K. (2004). RNA interference in neuroscience. Brain Res. Mol Brain Res. 132:260–270
Giacobini E. (2004). Cholinesterase inhibitors: new roles and therapeutic alternatives. Pharmacol. Res. 50:433–440
Gibson D. and Harris A. (1988). Aggregated early intervention effects for Down’s syndrome persons: patterning and longevity of benefits. J. Mental Deficiency Res. 32:1–17
Gonzalez-Alegre P., Millar V. M., Davidson B. L., and Paulson H. L. (2003). Toward therapy for DYT1 dystonia: allele-specific silencing of mutant TorsinA. Annals Neurol. 53:781–787
Granholm A. C. (2000). Oestrogen and nerve growth factor-neuroprotection and repair in Alzheimer’s disease. Expert Opinion Invest. Drugs 9:685–694
Griffin W. S., Stanley L. C., Ling C., White L., Machead V., Perrot L. J., White C. L., and Araoz C. (1989). Brain interleukin I and S-100 immunoreactivity are elevated in Down syndrome and Alzheimer disease. Proc. Nat. Acad. Sci. USA 86:7611–7615
Gulesserian T., Engidawork E., Cairns N., and Lubec G. (2000). Increased protein levels of serotonin transporter in frontal cortex of patients with Down syndrome. Neurosci. Lett. 296:53–57
Guralnick M. J. (1998). Effectiveness of early intervention for vulnerable children: A developmental perspective. Am. J. Mental Retard. 102:319–345
Harrell R. F., Capp R. H., Davis D. R., Peerless J., and Ravitz L. R. (1981). Can nutritional supplements help mentally retarded children?. Proc. Nat. Acad. Sci. USA 78:574–578
Heller J. H., Spiridigliozzi G. A., Sullivan J. A., Doraiswamy P. M., Krishnan R. R., and Kishnani P. S. (2003). Donepezil for the treatment of language deficits in adults with Down syndrome: A preliminary 24-week open trial. Am. J. Med. Genet. 116A:111–116
Heller J. H., Spiridigliozzi G. A., Doraiswamy P. M., Sullivan J. A., Crissman B. G., and Kishnani P. S. (2004). Donepezil effects on language in children with Down syndrome: results of the first 22-week pilot clinical trial. Am. J. Med. Genet. 130:325–326
Hesser B. A., Liang X. H., Camenisch G., Yang S., Lewin D. A., Scheller R., Ferrara N., and Gerber H. P. (2004). Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Blood 104:149–158
Holtzman D. M., Bayney R. M., Li Y., Khosrovi H., Berger C. N., Epstein C. J., and Mobley W. C. (1992). Dysregulation of gene expression in mouse trisomy 16, an animal model of Down syndrome. The EMBO J. 11:619–627
Hommel J. D., Sears R. M., Georgescu D., Simmons D. L., and DiLeone R. J. (2003). Local gene knockdown in the brain using viral-mediated RNA interference. Nat. Med. 9:1539–1544
Hunter C. L., Bachman D., and Granholm A. C. (2004a). Minocycline Prevents Cholinergic Loss in a Mouse Model of Down’s Syndrome. Annals Neurol. 56:675–688
Hunter C. L., Bimonte-Nelson H. A., Nelson M., Eckmanb C. B., and Granholm A. C. (2004b). Behavioral and neurobiological markers of Alzheimer’s disease in Ts65Dn mice: effects of estrogen. Neurobiol. Aging 25:873–888
Kishnani P. S., Sullivan J. A., Walter B. K., Spiridigliozzi G. A., Doraiswamy P. M., and Krishnan R. R. (1999). Cholinergic therapy for Down’s syndrome. Lancet 353:1064–1065
Kondoh T., Amamoto N., Doi T., Hamada H., Ogawa Y., Nakashima M., Sasaki H., Aikawa K., Tanaka T., Aoki M., Harada J., and Moriuchi H. (2005). Dramatic Improvement in Down Syndrome–Associated Cognitive Impairment with Donepezil. The Annals Pharmacotherapy 39:563–566
Kugler S., Kilic E., and Bahr M. (2003). Human synapsin 1 gene promoter confers highly neuron-specific long-term transgene expression from an adenoviral vector in the adult rat brain depending on the transduced area. Gene Therapy 10:337–347
Makimura H., Mizuno T. M., Mastaitis J. W., Agami R., and Mobbs C. V. (2002). Reducing hypothalamic AGRP by RNA interference increases metabolic rate and decreases body weight without influencing food intake. BMC Neurosci. 7:3–18
Mann D. M. (1988). Alzheimer’s disease and Down’s syndrome. Histol. Histopathol. 13:125–137
Marin-Padilla M. (1972). Structural abnormalities of the cerebral cortex in human chromosomal aberrations: a Golgi study. Brain Res. 44:625–629
Marin-Padilla M. (1976). Pyramidal cell abnormalities in the motor cortex of a child with Down’s syndrome. A Golgi study. The J. Comp. Neurol. 167:63–81
Martinez-Cue C., Baamonde C., Lumbreras M., Paz J., Davisson M. T., Schmidt C., Dierssen M., and Florez J. (2002). Differential effects of environmental enrichment on behavior and learning of male and female Ts65Dn mice, a model for Down syndrome. Behav. Brain Res. 134:185–200
McGeer P. L., and McGeer E. G. (1995). The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Behav. Brain Res. 21:195–218
McGeer E. G., and McGeer P. L. (2001). Innate immunity in Alzheimer’s disease: a model for local inflammatory reactions. Mol. Interventions 1:22–29
McKee J. R., Sunder T. R., FineSmith R., Vuong A., Varner J. A., Hammer A. E., and Barrett P. S. (2003). Lamotrigine as adjunctive therapy in patients with refractory epilepsy and mental retardation. Epilepsy Behavior 4:386–394
McManus M. T., and Sharp P. A. (2002). Gene silencing in mammals by small interfering RNAs. Nature reviews. Genetics 3:737–747
Miller, J. F. (1995). Individual differences in vocabulary acquisition in children with Down syndrome. In L. Nadel and D. Rosenthal (eds.). Baltimore: Paul H Brookes Pub
Miller V. M., Gouvion C. M., Davidson B. L., and Paulson H. L. (2004). Targeting Alzheimer’s disease genes with RNA interference: an efficient strategy for silencing mutant alleles. Nucleic Acids Res. 32:661–668
Miller V. M., Xia H., Marrs G. L., Gouvion C. M., Lee G., Davidson B. L., and Paulson H. L. (2003). Allele-specific silencing of dominant disease genes. Proc. Nat. Acad. Sci. USA 100:7195–7200
Muller N., Riedel M., Schwarz M. J., and Engel R. R. (2005). Clinical effects of COX-2 inhibitors on cognition in schizophrenia. Eur. Arch. Psychiat. Clin. Neurosci. 255:149–151
Mufson E. J., Cochran E., Benzing W., and Kordower J. H. (1993). Galaninergic innervation of the cholinergic vertical limb of the diagonal band (Ch2) and bed nucleus of the stria terminalis in aging, Alzheimer’s disease and Down’s syndrome. Dementia 4:237–250
Nadel L. (2003). Down’s syndrome: a genetic disorder in biobehavioral perspective. Genes, Brain, Behavior 2:156–166
Napolitano G., Palka G., Lio S., Bucci I., De Remigis P., Stuppia L., and Monaco F. (1990). Is zinc deficiency a cause of subclinical hypothyroidism in Down syndrome?. Annales de genetique 33:9–15
Netto C. B., Siquiera I. A., Fochesatto C., Portela L. V., Tavares M. P., Souza D. O., Giugliani R., and Goncalves C. A. (2004). S100B content and SOD activity in amniotic fluid of pregnancies with Down syndrome. Clinical Biochem. 37:134–137
Okada T., Nomoto T., Shimazaki K., Lijun W., Lu Y., Matsushita T., Mizukami H., Urabe M., Hanazono Y., Kume A., Muramatsu S., Nakano I., and Ozawa K. (2002). Adeno-associated virus vectors for gene transfer to the brain. Methods 28:237–247
Paddison P. J., Caudy A. A., Bernstein E., Hannon G. J., and Conklin D. S. (2002). Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Develop. 16:948–958
Patel B. N., Seltzer G. B., Wu H. S., and Schupf N. (2001). Effect of menopause on cognitive performance in women with Down syndrome. Neuroreport 12:2659–2662
Pennington B. F., Moon J., Edgin J., Stedron J., and Nadel L. (2003). The neuropsychology of Down syndrome: evidence for hippocampal dysfunction. Child Develop. 74:75–93
Perry E. K., Perry R. H., Blessed G., and Tomlinson B. E. (1978). Changes in brain cholinesterases in senile dementia of Alzheimer type. Neuropathol. Appl. Neurobiol. 4:273–277
Pruess J. B., Fewell R. R., and Bennett F. C. (1989). Vitamin therapy and children with Down syndrome: a review of the research. Exceptional Children 55:336–341
Romano C., Tine A., Fazior G., Rizzo R., Colognola R. M., and Sorge G. (1990). Seizures in patients with trisomy 21. Am. J. Med. Genet. Suppl. 7:298–300
Ralph G. S., Radcliffe P. A., Day D. M., Carthy J. M., Leroux M. A., Lee D. C., Wong L. F., Bilsland L. G., Greensmith L., Kingsman S. M., Mitrophanous K. A., Mazarakis N. D., and Azzouz M. (2005). Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model. Nat. Med. 11:429–433
Raoul C., Abbas-Terki T., Bensadoun J. C., Guillot S., Haase G., Szulc J., Henderson C. E., and Aebischer P. (2005). Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nat. Med. 11:423–428
Roizen N. J., and Patterson D. (2003). Down’s syndrome. Lancet 361:1281–1289
Salman M. S. (2002). Systematic review of the effect of therapeutic dietary supplements and drugs on cognitive function in subjects with Down syndrome. Eur. J. Paediat. Neurol.: EJPN 6:213–219
Shishkina G. T., Kalinina T. S., and Dygalo N. N. (2004). Attenuation of alpha2A-adrenergic receptor expression in neonatal rat brain by RNA interference or antisense oligonucleotide reduced anxiety in adulthood. Neuroscience 129:521–528
Schubert P., Ogata T., Marchini C., and Ferroni S. (2001). Glia-related pathomechanisms in Alzheimer’s disease: a therapeutic target?. Mech. Ageing Develop. 123:47–57
Scheuer K., Maras A., Gattaz W. F., Cairns N., Forstl H., and Muller W. C. (1996). Cortical NMDA receptor properties and membrane fluidity are altered in Alzheimer’s disease. Dementia 7:210–214
Schupf N., Zigman W., Kapell D., Lee J. H., Kline J., and Levin B. (1997). Early menopause in women with Down’s syndrome. J. Intellect. Disability Res.: JIDR 41:264–267
Sebastià J., Cristófol R., Pertusa M., Vílchez D., Torà N., Barambio S., Rodríguez-Farré E., and Sanfeliu C. (2004). Down’s syndrome astrocytes have greater antioxidant capacity than euploid astrocytes. Eur. J. Neurosci. 20:2355–2366
Seidl R., Kaehler S. T., Prast H., Singewald N., Cairns N., Gratzer M., and Lubec G. (1999). Serotonin (5-HT) in brains of adult patients with Down syndrome. J. Neural Transmission. Supplementum 57:221–232
Siarey R. J., Coan E. J., Rapoport S. I., and Galdzicki Z. (1997). Responses to NMDA in cultured hippocampal neurons from trisomy 16 embryonic mice. Neurosci. Lett. 232:131–134
Sinet P. M. (1982). Metabolism of oxygen derivatives in Down’s syndrome. Annals N.Y. Acad. Sci. 185:83–94
Singh B. K., and White-Scott S. (2002). Role of topiramate in adults with intractable epilepsy, mental retardation, and developmental disabilities. Seizure 11:47–50
Sodhi M. S., and Sanders-Bush E. (2004). Serotonin and brain development. Int. Rev. Neurobiol. 59:111–174
Spiker D., and Hopmann M. R. (1997). The effectiveness of early intervention for children with Down syndrome. In: Guralnick M. J. (eds). The Effectiveness of Early Intervention. Baltimore, Paul H. Brookes., pp. 271–305
Stafstrom C. E. (1993). Epilepsy in Down syndrome: clinical aspects and possible mechanisms. Am. J. Mental Retard.: AJMR 98:12–26
Stafstrom C. E., Gilmore H. E., and Ehrenberg B. L. (1988). Seizures in persons with Down syndrome: cause and prognosis. Annals Neurol. 24:308–309
Takashima, S., Becker, L. E., Armstrong, D. L., and Chan, F. (1981). Abnormal neuronal development in the visual cortex of the human fetus and infant with down's syndrome. A quantitative and qualitative Golgi study. J. Neuro pathol. Exp. Neurol. 39:487–501
Takashima S., Iida K., Mito T., and Arima M. (1994). Dendritic and histochemical development and ageing in patients with Down’s syndrome. J. Intellect. Disability Res.: JIDR 38:265–273
Thakker D. R., Natt F., Husken D., Maier R., Muller M., van der Putten H., Hoyer D., and Cryan J. F. (2004). Neurochemical and behavioral consequences of widespread gene knockdown in the adult mouse brain by using nonviral RNA interference. Proc. Nat. Acad. Sci. USA 101:17270–17275
Thiel R., and Fowkes S. W. (2005). Can cognitive deterioration associated with Down syndrome be reduced?. Medical hypotheses 64:524–532
Torchilin V. P. (2005). Recent advances with liposomes as pharmaceutical carriers. Nature Reviews. Drug Discovery 4:145–160
Turrens J. F. (2001). Increased superoxide dismutase and Down’s syndrome. Medical Hypotheses 56:617–619
Van Trotsenburg, A. S. P., Vulsma, T., van Rozenburg-Marres, S. L. R., van Baar, A. L., Ridder, J. C. D., Heymans, H. S. A., Tijssen, J. G. P., and de Vijlde, J. J. M. (2005). The effect of thyroxine treatment started in the neonatal period on development and growth of two years old Down syndrome children: a randomized clinical trial. The J. Clin. Endocrinol. Metabol. Epub.
Vernon M. W., and Sorkin E. M. (1991). Piracetam. An overview of its pharmacological properties and a review of its therapeutic use in senile cognitive disorders. Drugs Aging 1:17–35
Vuksic M., Petanjek Z., Rasin M., and Kostovic I. (2002). Perinatal growth of prefrontal layer III pyramids in Down syndrome. Pediatric Neurol. 27:36–38
Wishart J. G. (1995). Cognitive abilities in children with Down syndrome: developmental instability and motivational deficits. Progr. Clin. Biol. Res. 393:57–91
Wisniewski K. E., Wisniewski H. M., and Wen G. Y. (1985). Occurrence of neuropathological changes and dementia of Alzheimer’s disease in Down’s syndrome. Annals Neurol. 17:278–282
Wright C. I., Geula C., and Mesulam M. M. (1993). Neuroglial cholinesterases in the normal brain and in Alzheimer’s disease: relationship to plaques, tangles and patterns of selective vulnerability. Annals Neurol. 34:373–384
Xia H., Mao Q., Eliason S. L., Harper S. Q., Martins I. H., Orr H. T., Paulson H. L., Yang L., Kotin R. M., and Davidson B. L. (2004). RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat. Med. 10:816–820
Xia H., Mao Q., Paulson H. L., and Davidson B. L. (2002). siRNA-mediated gene silencing in vitro and in vivo. Nat. Biotechnol. 20:1006–1010
Zamore P. D., Tuschl T., Sharp P. A., and Bartel D. P. (2000). RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101:25–33
Zhang Y., Boado R. J., and Pardridge W. M. (2003a). In vivo knockdown of gene expression in brain cancer with intravenous RNAi in adult rats. The J. Gene Med. 5:1039–1045
Zhang Y. F., Boado R. J., and Pardridge W. M. (2003b). Absence of toxicity of chronic weekly intravenous gene therapy with pegylated immunoliposomes. Pharmaceutical Res. 20:1779–1785
Zigman W. B., Schupf N., and Sersen E. (1995). Prevalence of dementia in adults with and without Down syndrome. Am. J. Mental Retard.: AJMR 100:403–412
Acknowledgments
C.F. and M.D. have funded projects from Jerôme Lejeune Foundation (JLF). G.A. is supported by JLF. Other funding supporting the investigation are FIS PI041559, CIEN Foundation, MCYT (SAF2002–00799), EU QLGI-CT-2002–00816
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dierssen, M., Ortiz-Abalia, J., Arqué, G. et al. Pitfalls And Hopes in Down Syndrome Therapeutic Approaches: In the Search for Evidence-Based Treatments. Behav Genet 36, 454–468 (2006). https://doi.org/10.1007/s10519-006-9050-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10519-006-9050-2