Neurogenetic Analysis and Cognitive Functions in Trisomy 21

Trisomy 21 (TRS21) is also known as “Down’s syndrome” and for a long time was called “mongolism”. At the beginning of the third millennium, TRS21 remains the most frequent genetic cause of mental deficiency in Western society. According to estimates in recent studies by Roizen and Patterson (2003), TRS21 occurs once in every 800 or 1,000 births. TRS21 is a syndrome, defined by a complex set of cardiac, immune, bone, brain, and cognitive disorders, most being highly variable in expression. Not all persons with TRS21 have leukemia, although it is more prevalent in the TRS21 population compared to the general population. Cardiac disorders are responsible for approximately 60% of perinatal mortality in neonates with TRS21. Immune disorders are more common in TRS21 (30% of TRS21 persons have abnormal levels of T-lymphocytes – Ugazio, Maccario, Notarangelo, & Burgio, 1990); bone anomalies are also more common. The characteristic morphology is short and stocky with virtually no neck because of skeletal abnormalities. Facial features of persons with TRS21 typically include oblique eye fissures, epicanthic eye-folds, a flat nasal bridge, the mouth permanently open and the tongue protruding. The limbs are malformed, and hands are short and broad with a single transverse palmar crease and shortened, incurved fifth finger. Mental deficiency, while of variable severity, is the most constant feature of persons with TRS21 (Antonarakis, Lyle, Dermitzakis, Reymond, & Deutsch, 2004; Patterson & Costa, 2005).


Down Syndrome Morris Water Maze Williams Syndrome Radial Maze Partial Trisomy 


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  1. Altafaj, X., Dierssen, M., Baamonde, C., Marti, E., Visa, J., Guimera, J., et al. (2001). Neurodevelopmental delay, motor abnormalities and cognitive deficits in transgenic mice overexpressing Dyrk1A (minibrain), a murine model of Down’s syndrome. Human Molecular Genetics, 10, 1915–1923.PubMedCrossRefGoogle Scholar
  2. Antonarakis, S. E., Lyle, R., Dermitzakis, E. T., Reymond, A., & Deutsch, S. (2004). Chromosome 21 and Down syndrome: from genomics to pathophysiology. Nature Review Genetics, 5, 725–738.CrossRefGoogle Scholar
  3. Aula, P., Leisti, J., & von Koskull, H. (1973). Partial trisomy 21. Clinical Genetics, 4, 241–251.PubMedCrossRefGoogle Scholar
  4. Baxter, L. L., Moran, T. H., Richtsmeier, J. T., Troncoso, J., & Reeves, R. H. (2000). Discovery and genetic localization of down syndrome cerebellar phenotypes using the Ts65Dn mouse. Human Molecular Genetics, 9, 195–202.PubMedCrossRefGoogle Scholar
  5. Bayés, M., Magano, L. F., Rivera N., Flores R., & Pérez Jurado L. A. (2003). Mutational mechanisms of Williams-Beuren syndrome deletions. American Journal of Human Genetics, 73, 131–151.PubMedCrossRefGoogle Scholar
  6. Belichenko, P. V., Masliah, E., Kleschevnikov, A. M., Villar, A. J., Epstein, C. J., Salehi, A., et al. (2004). Synaptic structural abnormalities in the Ts65Dn mouse model of Down syndrome. Journal of Comparative Neurology, 480, 281–298.PubMedCrossRefGoogle Scholar
  7. Bellugi, U., Lichtenberger, L., Mills, D., Galaburda A., & Korenberg, J. R. (1999). Bridging cognition, the brain and molecular genetics: Evidence from Williams syndrome. Trends in Neuroscience, 22, 197–207.CrossRefGoogle Scholar
  8. Boddaert, N., Mochel, F., Meresse, I., Seidenwurm, D., Cachia, A., Brunelle, F., et al. (2005). Parieto-occipital grey matter abnormalities in children with Williams syndrome. Neuroimage, 30, 721–725.PubMedCrossRefGoogle Scholar
  9. Brown, J. H., Johnson, M. H., Paterson, S. J., Gilmore, R., Longhi, E., & Karmiloff-Smith, A. (2003). Spatial representation and attention in toddlers with Williams syndrome and Down syndrome. Neuropsychology, 41, 1037–1046.CrossRefGoogle Scholar
  10. Carlier, M., & Ayoun, C. (2007). Déficiences intellectuelles et intégration sociale. Wavre (Belgique): Mardaga.Google Scholar
  11. Carlier, M., Stefanini, S., Deruelle, C., Volterra, V., Doyen, A.-L., Lamard, C., et al. (2006). Laterality in Persons with Intellectual Disability. I. – Do Patients with Trisomy 21 and Williams-Beuren syndrome differ from typically developing persons? Behavior Genetics, 36, 365–376.PubMedCrossRefGoogle Scholar
  12. Carr, J. (2005). Stability and change in cognitive ability over the life span: A comparison of population with and without Down syndrome. Journal of Intellectual Disability Research, 49, 915–928.PubMedCrossRefGoogle Scholar
  13. Chabert, C., Jamon, M., Cherfouh, A., Duquenne, V., Smith, D. J., Rubin, E., et al. (2004). Functional analysis of genes implicated in Down syndrome: 1. Cognitive abilities in mice transpolygenic for Down syndrome chromosomal region-1 (DCR-1). Behavior Genetics, 34, 559–569.PubMedCrossRefGoogle Scholar
  14. Chapman, R. S., & Hesketh, L. J. (2000). Behavioral phenotype of individuals with Down syndrome. Mental Retardation and Developmental Disabilities Research Reviews, 6, 84–95.PubMedCrossRefGoogle Scholar
  15. Clark, D., & Wilson, G.N. (2003). Behavioral assessment of children with Down syndrome using the Reiss psychopathology scale. American Journal Medical Genetics, 118, 210–216.CrossRefGoogle Scholar
  16. Crnic, L. S., & Pennington, B. F. (2000). Down syndrome: Neuropsychology and animal models. Progress in Infancy Research, 1, 69–111.Google Scholar
  17. Davisson, M. T., Schmidt, C., & Akeson, E. C. (1990). Segmental trisomy of murine chromosome 16: A new model system for studying Down syndrome. Progress in Clinical and Biological Research, 360, 263–280.PubMedGoogle Scholar
  18. Davisson, M. T., Schmidt, C., Reeves, R. H., Irving, N. G., Akeson, E. C., Harris, B. S., & Bronson, R. T. (1993). Segmental trisomy as a mouse model for Down syndrome. Progress in Clinical and Biological Research, 384, 117–133.PubMedGoogle Scholar
  19. Delabar, J. M., Theophile, D., Rahmani, Z., Chettouh, Z., Blouin, J. L., Prieur, M., et al. (1993). Molecular mapping of twenty-four features of Down syndrome on chromosome 21. European Journal of Human Genetics, 1, 114–124.PubMedGoogle Scholar
  20. Down, J. L. H. (1862). Observations on an Ethnic Classification of Idiots. London Hospital Report, 3, 259–262.Google Scholar
  21. Down, J. L. H. (1867). Observations on an ethnic classification of idiots. Journal of Mental Science, 13, 121–123.Google Scholar
  22. Doyle, T. F., Bellugi, U., Korenberg, J. R., & Graham, J. (2004). “Everybody in the world is my friend” hypersociability in young children with Williams syndrome. American Journal of Medical Genetics, 124, 263–273.CrossRefGoogle Scholar
  23. Esquirol, J. E. D. (1838). Des maladies mentales considérées sous les rapports médical, hygiénique et médico-légal. Paris J.-B. Bailléres.Google Scholar
  24. Fotaki, V., Dierssen, M., Alcantara, S., Martinez, S., Marti, E., Casas, C., et al. (2002). Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Molecular and Cellular Biology, 22, 6636–6647.PubMedCrossRefGoogle Scholar
  25. Gérard-Desplanches, A., Deruelle, C., Stefanini, S., Ayoun, C., Volterra, V., Vicari, S., et al. (2006). Laterality in Persons with Intellectual Disability. II. Hand, foot, ear and eye laterality in persons with Trisomy 21 and Williams-Beuren syndrome. Developmental Psychobiology, 4, 482–497.CrossRefGoogle Scholar
  26. Gitton, Y., Dahmane, N., Baik, S., Ruiz i Altaba, A., Neidhardt, L., Scholze, M., et al. (2002). A gene expression map of human chromosome 21 orthologues in the mouse. Nature, 420, 586–590.PubMedCrossRefGoogle Scholar
  27. Gray, V., Karmiloff-Smith, A., Funnell, E., & Tassebehji, M. (2006). In-depth analysis of spatial cognition in Williams syndrome: A critical assessment of the role of the LIMK1 gene. Neuropsychologia, 44, 679–685.Google Scholar
  28. Gropp, A., Kolbus, U., & Giers, D. (1975). Systematic approach to the study of trisomy in the mouse II. Cytogenetics and Cell Genetics, 14, 42–62.PubMedCrossRefGoogle Scholar
  29. Harris-Cerruti, C., Kamsler, A., Kaplan, B., Lamb, B., Segal, M., & Groner, Y. (2004). Functional and morphological alterations in compound transgenic mice overexpressing Cu/Zn superoxide dismutase and amyloid precursor protein. European Journal of Neuroscience, 19, 1174–1190.PubMedCrossRefGoogle Scholar
  30. Hassold, T., & Sherman, S. (2000). Down syndrome: Genetic recombination and the origin of the extra chromosome 21. Clinical Genetics, 57, 95–100.PubMedCrossRefGoogle Scholar
  31. Hattori, M., Fujiyama, A., Taylor, T. D., Watanabe, H., Yada, T., Park, H. S., et al. (2000). The DNA sequence of human chromosome 21. Nature, 405, 311–319.PubMedCrossRefGoogle Scholar
  32. Hodapp, R. M., Ewans, D. E., & Gray, F. L. (1999). Intellectuel development in children with Down syndrome. In J.-A. Rondal, J. Perera, & L. Nadel (Eds.), Down Syndrome: A Review of Current Knowledge (pp. 124–132). Whurr Publisher: London, U.K.Google Scholar
  33. Jackson, J. F., North III, E. R., & Thomas, J. G. (1976). Clinical diagnosis of Down’s syndrome. Clinical Genetics, 9, 483–487.PubMedCrossRefGoogle Scholar
  34. Kahlem, P. (2006). Gene dosage effect on chromosome 21 transcriptome in trisomy 21: Implication in Down’s syndrome cognitive disorders. Behavior Genetics, 36, 416–428.PubMedCrossRefGoogle Scholar
  35. Kahlem, P., Sultan, M., Herwig, R., Steinfath, M., Balzereit, D., Eppens, B., et al. (2004). Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of Down syndrome. Genome Research, 14, 1258–1267.PubMedCrossRefGoogle Scholar
  36. Korenberg, J. R., Chen, X. N., Schipper, R., Sun, Z., Gonsky, R., Gerwehr, S., et al. (1994). Down syndrome phenotypes: The consequences of chromosomal imbalance. Proceedings of the National Academy of Sciences USA, 91, 4997–5001.CrossRefGoogle Scholar
  37. Krinsky-McHale, S. J., Devenny, D. A., & Silverman, W. P. (2002). Changes in explicit memory associated with early dementia in adults with Down’s syndrome. Journal of Intellectual Disability Research, 46, 198–208.PubMedCrossRefGoogle Scholar
  38. Laws, G. (2002). Working memory in children and adolescents with Down syndrome: evidence from a colour memory experiment. Journal of Child Psychology and Psychiatry, 43, 353–364.PubMedCrossRefGoogle Scholar
  39. Lejeune, J., Turpin, R., & Gautier, M. (1958/1959). Le mongolisme. Premier exemple d’aberration autosomique humaine. Annales de génétique, Paris, 1, 41–49.Google Scholar
  40. Lejeune, J., Gauthier, M., & Turpin, R. (1959). Etude des chromosomes somatiques de neuf enfants mongoliens. Comptes Rendus de l’Académie des Sciences Paris, 248, 1721–1722.Google Scholar
  41. Liu, H., Abecasis, G. R., Heath, S. C., Knowles, A., Demars, S., Chen, Y. J., et al. (2002). Genetic variation in the 22q11 locus and susceptibility to schizophrenia. Proceedings of the National Academy of Sciences USA, 99, 16859–16864.CrossRefGoogle Scholar
  42. Lyle, R., Gehrig, C., Neergaard-Henrichsen, C., Deutsch, S., & Antonarakis, S. E. (2004). Gene expression from the aneuploid chromosome in a trisomy mouse model of Down syndrome. Genome Research, 14, 1268–1274.PubMedCrossRefGoogle Scholar
  43. Mervis, C. B. (2003). Williams syndrome: 15 years of psychological research. Develomental Neuropsychology, 23, 1–12.CrossRefGoogle Scholar
  44. Meyer-Lindenberg, A., Kohn, P., Mervis, C. B., Kippenhan, J. S., Olsen, R. K., Morris, C. A., et al. (2004). Neural basis of genetically determined visuospatial construction deficit in Williams syndrome. Neuron, 43, 623–631.PubMedCrossRefGoogle Scholar
  45. Meyer-Lindenberg, A., Mervis, C. B., Sarpal, D., Koch, P., Steele, S., Kohn, P., et al. (2005). Functional, structural, and metabolic abnormalities of the hippocampal formation in Williams syndrome. Journal of Clinical Investigation, 115, 1888–1895.PubMedCrossRefGoogle Scholar
  46. Milner, B, Squire, L. R., & Kandel, E. R. (1998). Cognitive neuroscience and the study of memory. Neuron, 20, 445–468.PubMedCrossRefGoogle Scholar
  47. Morris C. A., & Mervis, C. B. (2000). Williams syndrome and related disorders. Annual Review of Genomics and Human Genetics, 1, 461–484.PubMedCrossRefGoogle Scholar
  48. Nadel, L. (1995). Neural and cognitive development in Down syndrome. In L. Nadel & D. Rosenthal (Eds.), Down syndrome Living and learning in the community (pp. 107–114). New-York: J. Wiley.Google Scholar
  49. Nadel, L. (1999). Learning and memory in Down syndrome. In J. Rondal, J. Perera, & L. Nadel (Eds.), Down syndrome A review of current knowledge (pp.133–142). London: Whurr Publishers.Google Scholar
  50. O’Doherty, A., Ruf, S., Mulligan, C., Hildreth, V., Errington, M. L., Cooke, S., et al. (2005). An aneuploid mouse strain carrying human chromosome 21 with Down syndrome phenotypes. Science, 309, 2033–2037.PubMedCrossRefGoogle Scholar
  51. Olson, L. E., Richtsmeier J. T., Leszl, J., & Reeves R. H. (2004). A chromosome 21 critical region does not cause specific Down syndrome phenotypes. Science, 306, 687–690.PubMedCrossRefGoogle Scholar
  52. Patterson, D., & Costa, A. C. (2005). Down syndrome and genetics – a case of linked histories. Nature Review Genetics, 6, 137–147.CrossRefGoogle Scholar
  53. Pennington, B. F., Moon, J., Edgin, J., Stedron, J., & Nadel, L. (2003). The neuropsychology of Down syndrome: Evidence for hippocampal dysfunction. Child Development, 74, 75–93.PubMedCrossRefGoogle Scholar
  54. Raz, N., Torres, I. J., Briggs, S. D., Spencer, W. D., Thornton, A. E., Loken, W. J., et al. (1995). Selective neuroanatomic abnormalities in Down’s syndrome and their cognitive correlates: evidence from MRI morphometry. Neurology, 45, 356–366.PubMedGoogle Scholar
  55. Reymond, A., Marigo, V., Yaylaoglu, M. B., Leoni, A., Ucla, C., Scamuffa, N., et al. (2002). Human chromosome 21 gene expression atlas in the mouse. Nature, 420, 582–586.PubMedCrossRefGoogle Scholar
  56. Roizen, N. J., & Patterson, D. (2003). Down’s syndrome. Lancet, 361, 1281–1289.PubMedCrossRefGoogle Scholar
  57. Rondal, J. A. (1999) Language in Down syndrome: Current perspectives. In J. Rondal, J. Perera, & L. Nadel (Eds.), Down syndrome A review of current knowledge (pp. 143–149). London: Whurr Publishers.Google Scholar
  58. Roubertoux, P. L., Bichler, Z., Pinoteau, W., Sérégaza, Z., Fortes, S., Jamon, M., et al. (2005). Functional analysis of genes implicated in Down syndrome: 2. Laterality and corpus callosum size in mice transpolygenic for Down syndrome chromosomal region-1 (DCR-1). Behavior Genetics, 35, 333–341.PubMedCrossRefGoogle Scholar
  59. Roubertoux, P. L., Bichler, Z., Pinoteau, W., Jamon, M., Sérégaza, Z., Smith, D. J., et al. (2006). Pre-weaning Sensorial and Motor Development in Mice Transpolygenic for the Critical Region of Trisomy 21. Behavior Genetics, 36, 377–386.PubMedCrossRefGoogle Scholar
  60. Roubertoux, M., & Carlier M. (2007). From DNA to the mind. EMBO Reports, 8, Science & Society, Special Issue, S7–S11.PubMedCrossRefGoogle Scholar
  61. Roubertoux, P. L., & Kerdelhué, B. (2006). Trisomy 21: From chromosomes to mental retardation. Behavior Genetics, 36, 434–345.Google Scholar
  62. Sago, H., Carlson, E. J., Smith, D. J., Kilbridge, J., Rubin, E. M., Mobley, W. C., et al. (1998). Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities. Proceedings of the National Academy of Sciences USA, 95, 6256–6261.CrossRefGoogle Scholar
  63. Sago, H., Carlson, E. J., Smith, D. J., Rubin, E. M., Crnic, L. S., Huang, T. T., et al. (2000). Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatric Research, 48, 606–613.PubMedCrossRefGoogle Scholar
  64. Séguin, E. (1846). Traitement moral, hygiéne et éducation des idiots et autres enfants arriérés ou retardés dans leurs mouvements, agités de mouvements volontaires. Paris: J.-B. Balliéres.Google Scholar
  65. Séguin, E. (1856). Origin of the treatment and training of idiots. American Journal of Education, 2, 145–152.Google Scholar
  66. Séguin, E. (1866) Idiocy and its treatment by the physiological method. New York: William Wood & Co.Google Scholar
  67. Sérégaza, Z., Roubertoux, P. L., Jamon, M., & Soumireu-Mourat, B. (2006). Mouse Models of Cognitive Disorders in Trisomy 21: A Review. Behavior Genetics, 36, 387–404.PubMedCrossRefGoogle Scholar
  68. Shinohara, T., Tomizuka, K., Miyabara, S., Takehara, S., Kazuki, Y., Inoue, J., et al. (2001). Mice containing a human chromosome 21 model behavioral impairment and cardiac anomalies of Down’s syndrome. Human Molecular Genetics, 10, 1163–1175.PubMedCrossRefGoogle Scholar
  69. Smith, D. J., Zhu, Y., Zhang, J., Cheng, J. F., & Rubin, E. M. (1995). Construction of a panel of transgenic mice containing a contiguous 2-Mb set of YAC/P1 clones from human chromosome 21q22.2. Genomics, 27, 425–434.PubMedCrossRefGoogle Scholar
  70. Smith, D. J., Stevens, M. E., Sudanagunta, S. P., Bronson, R. T., Makhinson, M., Watabe, A. M., et al. (1997). Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nature Genetics, 16, 28–36.PubMedCrossRefGoogle Scholar
  71. Teipel, S. J., & Hampel, H. (2006). Neuroanatomy of Down syndrome in vivo: A model of preclinical Alzheimer’s disease. Behavior Genetics, 36, 405–415.Google Scholar
  72. Thompson, P. M., Lee, A. D., Dutton, R. A., Geaga, J. A., Hayashi, K. M., Eckert, M. A., et al. (2005). Abnormal cortical complexity and thickness profiles mapped in Williams syndrome. Journal of Neuroscience, 25, 4146–4158.PubMedCrossRefGoogle Scholar
  73. Tijo, H., & Levan, A. (1956). The chromosomes of man. Hereditas, 42, 1–6.CrossRefGoogle Scholar
  74. Tomaiuolo, F., Di Paola, M., Caravale, B., Vicari, S., Petrides, M., & Caltagirone, C. (2002). Morphology and morphometry of the corpus callosum in Williams Syndrome: A magnetic resonance imaging analysis. NeuroReport, 13, 1–5CrossRefGoogle Scholar
  75. Ugazio, A. G, Maccario, R., Notarangelo, L. D., & Burgio, G. R. (1990). Immunology of Down syndrome: A review. American Journal of Medical Genetics, (Suppl.) 7, 204–212.CrossRefGoogle Scholar
  76. Vicari, S. (2006). Motor development and neuropsychological patterns in persons with Down syndrome. Behavior Genetics, 36, 355–364.PubMedCrossRefGoogle Scholar
  77. Vicari, S., Belluci, S., & Carlesimo G. A. (2005). Visual and spatial long-term memory: Differential pattern of impairments in Williams and Down syndromes. Developmental Medicine & Child Neurology, 47, 305–311.CrossRefGoogle Scholar
  78. Watanabe, H., Fujiyama, A., Hattori, M., Taylor, T. D., Toyoda, A., Kuroki, Y., et al. (2004). DNA sequence and comparative analysis of chimpanzee chromosome 22, Nature, 429, 382–388.PubMedCrossRefGoogle Scholar
  79. Winocur, G., Roder, J., & Lobaugh, N. (2001). Learning and memory in S100-beta transgenic mice: an analysis of impaired and preserved function. Neurobiology of Learning and Memory, 75, 230–243.PubMedCrossRefGoogle Scholar
  80. Wishart, J. G. (1993). The development of learning difficulties in children with Down’s syndrome. Journal of Intellectual Disability Research, 37, 389–403.PubMedCrossRefGoogle Scholar
  81. Yu, Y., & Bradley, A. (2001). Engineering chromosomal rearrangements in mice. Nature Review Genetics, 10, 780–790.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.INSERM UMR910 Génétique Médicale et Génomique FonctionnelleUniversité d’Aix-Marseille 2, Faculté de Médecine13385 Marseille Cedex 05France
  2. 2.Institut Universitaire de France and Laboratoire Psychologie Cognitive, UMR 6146Marseille Cedex 20France

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