Pediatric Surgery International

, Volume 24, Issue 8, pp 873–883 | Cite as

Down syndrome and the enteric nervous system

  • S. W. MooreEmail author
Review Article


Down syndrome (DS) is the most common chromosomal abnormality occurring in humans. Up to 77% of DS children have associated gastrointestinal (GI) abnormalities, which may be structural or functional in nature. Functional disturbances may, in turn, affect the outcome of corrective surgical procedures, prompting to caution. It is becoming clear that the processes affecting the enteric nervous system (ENS) in DS not only affect the micro-anatomy but also nerve function, and there is some histological evidence of ENS variations in both human and DS animal models. This suggests that developmental disorders of the ENS are probably fundamental to the functional GI disturbances encountered in patients with DS. The anomalous brain development, function and resulting intellectual impairment associated with DS appears to result from the genetic imbalance created by the trisomy of chromosome 21. The possible links between the brain, GI and ENS involvement are not as yet entirely clear. Neurotropic factors affecting brain development during embryogenesis are probably interlinked with ENS development, but the precise mechanism of how this occurs has yet to be established. This study explores what is known about the ENS dysfunction in DS and reviews the possible importance of chromosome 21 located and other genes in its etiology. Functional motor disturbances of the esophagus and colon are not uncommon and may be congenital or acquired in nature. The most prominent of these include esophageal dysmotility syndromes (e.g. achalasia, gastroesophageal reflux, dysphagia) as well as a higher incidence of chronic constipation and Hirschsprung’s disease (HSCR) (2–15%) occurring in association with DS. Chromosome 21 itself is thought to be the site of a modifier gene for HSCR. Recently identified candidate genetic mechanisms provide unique insights into the genetic background of the neurological and cognitive disorders associated with DS. Although the role of the triplicated chromosome 21 and genetic dosage remain important, the additional role of other chromosome 21 genes in the etiology of ENS developmental anomalies remains undetermined and requires ongoing research.


Chromosome 21 Down syndrome Trisomy 21 Enteric nervous system Genetic Children 


  1. 1.
    Altmann AE, Halliday JL, Giles GG (1998) Associations between congenital malformations and childhood cancer—a register-based case–control study. Br J Cancer 78:1244–1249PubMedGoogle Scholar
  2. 2.
    Argellati F, Massone S, d’Abramo C, Marinari UM, Pronzato MA, Domenicotti C, Ricciarelli R (2006) Evidence against the overexpression of APP in Down syndrome 2. IUBMB Life 58(2):103–106PubMedCrossRefGoogle Scholar
  3. 3.
    Arron JR, Winslow MM, Polleri A, Chang CP, Wu H, Gao X, Neilson JR et al (2006) NFAT dysregulation by increased dosage of DSCR1 and DYRK1A on chromosome 21. Nature 441(7093):595–600PubMedCrossRefGoogle Scholar
  4. 4.
    Badner JA, Sieber WK, Garver KL, Chakravarti A (1990) A genetic study of Hirschsprung disease. Am J Hum Genet 46:568–580PubMedGoogle Scholar
  5. 5.
    Barlow GM, Lyons GE, Richardson JA, Sarnat HB, Korenberg JR (2002) DSCAM: an endogenous promoter drives expression in the developing CNS and neural crest. Biochem Biophys Res Commun 299 (1):1–6Google Scholar
  6. 6.
    Baumann J (2007) Down syndrome cell adhesion molecule—a common determinant of brain and heart wiring. Pediatr Res 62(1):1PubMedCrossRefGoogle Scholar
  7. 7.
    Behar TN, Colton CA (2003) Redox regulation of neuronal migration in a Down syndrome model 1. Free Radic Biol Med 35(6):566–575Google Scholar
  8. 8.
    Benavides-Piccione R, Ballesteros-Yanez I, de Lagran MM, Elston G, Estivill X, Fillat C, Defelipe J, Dierssen M (2004) On dendrites in Down syndrome and DS murine models: a spiny way to learn. Prog Neurobiol 74(2):111–126PubMedCrossRefGoogle Scholar
  9. 9.
    Berto G, Camera P, Fusco C, Imarisio S, Ambrogio C, Chiarle R, Silengo L, Di Cunto F. (6-1-2007) The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase. J Cell Sci 120(Pt. 11):1859–1867Google Scholar
  10. 10.
    Besson WT, Kirby ML, Van Mierop LHS, Teabeaut JR (1986) Effects of the size of lesions of the cardiac neural crest at various embryonic ages on incidence and type of cardiac defects. Circulation 73:360–364PubMedGoogle Scholar
  11. 11.
    Bolk-Gabriel S, Salomon R, Pelet A et al (2002) Segregation at three loci explains familial and population risk in Hirschsprung disease. Nat Genet 1:89–93CrossRefGoogle Scholar
  12. 12.
    Bozinovski J, Poenaru D, Paterson W, Kamal I (2006) Esophageal aperistalsis following fundoplication in a patient with trisomy 21. Pediatr Surg Int 15(7):510–511CrossRefGoogle Scholar
  13. 13.
    Buchin PJ, Levy JS, Schullinger JN (1986) Down’s syndrome and the gastrointestinal tract. J Clin Gastroenterol 8(2):111–114PubMedCrossRefGoogle Scholar
  14. 14.
    Caniano DA, Teitelbaum DH, Qualman SJ (1990) Management of Hirschsprungs disease in children with Trisomy 21. Am J Surg 159:402–404PubMedCrossRefGoogle Scholar
  15. 15.
    Carrascosa-Romero MC, Fernández-Córdoba MS, Gonzálvez-Piñera J, Gutiérrez-Junquera C, Pardal-Fernández JM (2007) Neurocristopathies: a high incidence of cerebral dysgenesis in patients with Hirschsprung’s disease. Rev Neurol 45(12):707–712Google Scholar
  16. 16.
    Catto-Smith AG, Trajanovska M, Taylor RG (2006) Long-term continence in patients with Hirschsprung’s disease and Down syndrome. J Gastroenterol Hepatol 21(4):748–753PubMedCrossRefGoogle Scholar
  17. 17.
    Caviedes P, Caviedes R, Rapoport SI (2006) Altered calcium currents in cultured sensory neurons of normal and trisomy 16 mouse fetuses, an animal model for human trisomy 21 (Down syndrome). Biol Res 39(3):471–481PubMedGoogle Scholar
  18. 18.
    Cheon MS, Bajo M, Kim SH, Claudio JO, Stewart AK, Patterson D, Kruger WD, Kondoh H, Lubec G (2003) Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: challenging the gene dosage effect hypothesis (Part II). Amino Acids 24(1–2):119–125PubMedGoogle Scholar
  19. 19.
    Clarke SA, Van der Avoirt A (1999) Imperforate anus, Hirschsprung’s disease, and trisomy 21: a rare combination. J Pediatr Surg 34(12):1874PubMedCrossRefGoogle Scholar
  20. 20.
    Clegg DO, Wingerd KL, Hikita ST, Tolhurst EC (2003) Integrins in the development, function and dysfunction of the nervous system. Front Biosci 8:d723–d750PubMedCrossRefGoogle Scholar
  21. 21.
    Cleves MA, Hobbs CA, Cleves PA, Tilford JM, Bird TM, Robbins JM (2007) Congenital defects among liveborn infants with Down syndrome. Birth Defects Res A Clin Mol Teratol 79(9):657–663PubMedCrossRefGoogle Scholar
  22. 22.
    Conti A, Fabbrini F, D’Agostino P, Negri R, Greco D, Genesio R, D’Armiento M, Olla C, Paladini D, Zannini M, Nitsch L (2007) Altered expression of mitochondrial and extracellular matrix genes in the heart of human fetuses with chromosome 21 trisomy. BMC Genomics 8:268PubMedCrossRefGoogle Scholar
  23. 23.
    Crapo JD, Oury T, Rabouille C, Slot JW, Chang LY (1992) Copper, zinc superoxide dismutase is primarily a cytosolic protein in human cells. Proc Natl Acad Sci USA 89(21):10405–10409PubMedCrossRefGoogle Scholar
  24. 24.
    Deutsch S, Lyle R, Dermitzakis ET, Attar H, Subrahmanyan L, Gehrig C, Parand L, Gagnebin M, Rougemont J, Jongeneel CV, Antonarakis SE (2005) Gene expression variation and expression quantitative trait mapping of human chromosome 21 genes. Hum Mol Genet 14(23):3741–3749Google Scholar
  25. 25.
    Donnelly RJ, Friedhoff AJ, Beer B, Blume AJ, Vitek MP (1990) Interleukin-1 stimulates the beta-amyloid precursor protein promoter. Cell Mol Neurobiol 10(4):485–495PubMedCrossRefGoogle Scholar
  26. 26.
    Dowjat WK, Adayev T, Kuchna I, Nowicki K, Palminiello S, Hwang YW, Wegiel J (2007) Trisomy-driven overexpression of DYRK1A kinase in the brain of subjects with Down syndrome. Neurosci Lett 413(1):77–81Google Scholar
  27. 27.
    Engidawork E, Baiic N, Fountoulakis M, Dierssen M, Greber-Platzer S, Lubec G (2001) Beta-amyloid precursor protein, ETS-2 and collagen alpha 1 (VI) chain precursor, encoded on chromosome 21, are not overexpressed in fetal Down syndrome: further evidence against gene dosage effect. J Neural Transm Suppl 2001(61):335–346Google Scholar
  28. 28.
    Epstein CJ (2006) Down’s syndrome: critical genes in a critical region. Nature 44(7093):582–583CrossRefGoogle Scholar
  29. 29.
    Flageole H, Fecteau A, Laberge JM, Guttman FM (1996) Hirschsprung’s disease, imperforate anus, and Down’s syndrome: a case report. J Pediatr Surg 31(6):759–760PubMedCrossRefGoogle Scholar
  30. 30.
    Garver K, Law J, Garver B (1985) Hirschsprung disease: a genetic study. Clin Genet 28:503–508PubMedGoogle Scholar
  31. 31.
    Gershon MD (1999) Endothelin and the development of the enteric nervous system. Clin Exp Pharmacol Physiol 26(12):985–988PubMedCrossRefGoogle Scholar
  32. 32.
    Gershon MD, Chalazonitis A, Rothman TP (1993) From neural crest to bowel: development of the enteric nervous system. J Neurobiol. 24(2):199–214PubMedCrossRefGoogle Scholar
  33. 33.
    Goldberg EL (1984) An epidemiological study of Hirschsprung’s disease. Int J Epidemiol 13(4):479–485PubMedCrossRefGoogle Scholar
  34. 34.
    Goyal RK, Hirano I (1996) The enteric nervous system. N Engl J Med 334(17):1106–1115Google Scholar
  35. 35.
    Graivier L, Sieber WK (1966) Hirschsprungs disease and mongolism. Surgery 60:458–461PubMedGoogle Scholar
  36. 36.
    Gregory-Evans CY, Vieira H, Dalton R, Adams GG, Salt A, Gregory-Evans K (2004) Ocular coloboma and high myopia with Hirschsprung disease associated with a novel ZFHX1B missense mutation and trisomy 21. Am J Med Genet A 131(1):86–90PubMedCrossRefGoogle Scholar
  37. 37.
    Grosfeld J, Ballantine T, Csicsko J (1978) A critical evaluation of the Duhamel operation for HSCR. Arch Surg 113:454–459PubMedGoogle Scholar
  38. 38.
    Heber S, Herms J, Gajic V, Hainfellner J, Aguzzi A, Rülicke T, von Kretzschmar H, von Koch C, Sisodia S, Tremml P, Lipp HP, Wolfer DP, Müller U (2000) Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members. J Neurosci 20(21):7951–7963Google Scholar
  39. 39.
    Henderson A, Lynch SA, Wilkinson S, Hunter M (2007) Adults with Down’s syndrome: the prevalence of complications and health care in the community. Br J Gen Pract. 57(534):50–55PubMedGoogle Scholar
  40. 40.
    Hillemeier C, Buchin PJ, Gryboski J (1982) Esophageal dysfunction in Down’s syndrome. J Pediatr Gastroenterol Nutr 1(1):101–104PubMedCrossRefGoogle Scholar
  41. 41.
    Ikeda K, Goto S (1986) Additional anomalies in Hirschsprungs disease: an analysis based on a nationwide survey in Japan. Z Kinderchir 41:279–281PubMedGoogle Scholar
  42. 42.
    Aït Yahya-Graison E, Aubert J, Dauphinot L, Rivals I, Prieur M, Golfier G, Rossier J, Personnaz L, Creau N, Blehaut H, Robin S, Delabar JM, Potier MC (2007) Classification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes. Am J Hum Genet 81(3):475–491PubMedCrossRefGoogle Scholar
  43. 43.
    Jones SL, Sharief Y (2005) Asymmetrical protein kinase A activity establishes neutrophil cytoskeletal polarity and enables chemotaxis. J Leukoc Biol 78(1):248–245PubMedCrossRefGoogle Scholar
  44. 44.
    Julien JP, Kriz J (2006) Transgenic mouse models of amyotrophic lateral sclerosis. Biochim Biophys Acta 1762(11–12):1013–1024PubMedGoogle Scholar
  45. 45.
    Julies MG, Moore SW, Kotze MJ, du Plessis L (2001) Novel RET mutations in Hirschsprung’s disease patients from the diverse South African population. Eur J Hum Genet 9(6):419–423PubMedCrossRefGoogle Scholar
  46. 46.
    Kallen B, Mastroiacovo P, Robert E (1996) Major congenital malformations in Down syndrome. Am J Med Genet 65(2):160–166Google Scholar
  47. 47.
    Korenberg JR, Chen X, Schipper R, Sun Z, Gonsky R, Gerwehr S et al (1994) Down syndrome phenotypes: the consequence of chromosomal imbalance. Proc Natl Acad Sci 91:4997–5001PubMedCrossRefGoogle Scholar
  48. 48.
    Korenberg JR, Kawashima H, Pulst SM, Ikeuchi T, Ogasawara N, Yamamoto K, Schonberg SA, West R, Allen L, Magenis E (1990) Molecular definition of a region of chromosome 21 that causes features of the Down syndrome phenotype. Am J Hum Genet 47(2):236–246PubMedGoogle Scholar
  49. 49.
    Leffler A, Wedel T, Busch LC (1999) Congenital colonic hypoganglionosis in murine trisomy 16—an animal model for Down’s syndrome. Eur J Pediatr Surg 9(6):381–388PubMedGoogle Scholar
  50. 50.
    Levy J (1991) The gastrointestinal tract in Down syndrome. Prog Clin Biol Res 373:245–256PubMedGoogle Scholar
  51. 51.
    Li J, Busch LC, Kuhnel W (2000) PGP 9.5 immunohistochemical study on the development of the enteric nervous system of trisomy 16 mouse embryos and their normal littermates. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 22(2):159–164PubMedGoogle Scholar
  52. 52.
    Lott IT, Head E, Doran E, Busciglio J (2006) Beta-amyloid, oxidative stress and down syndrome. Curr Alzheimer Res 3(5):521–528PubMedCrossRefGoogle Scholar
  53. 53.
    Manabe Y, Nagano I, Gazi MS, Murakami T, Shiote M, Shoji M, Kitagawa H, Abe K (2003) Glial cell line-derived neurotrophic factor protein prevents motor neuron loss of transgenic model mice for amyotrophic lateral sclerosis. Neurol Res 25(2):195–200PubMedCrossRefGoogle Scholar
  54. 54.
    Mao R, Wang X, Spitznagel EL Jr, Frelin LP, Ting JC, Ding H, Kim JW, Ruczinski I, Downey TJ, Pevsner J (2005) Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart. Genome Biol 6(13):R107PubMedCrossRefGoogle Scholar
  55. 55.
    Marlin SD, Morton CC, Anderson DC, Springer TA (1986) LFA-1 Immunodeficiency disease. J Exp Med 164:855–867PubMedCrossRefGoogle Scholar
  56. 56.
    Matsuda H, Hirato J, Kuroiwa M, Nakazato Y (2006) Histopathological and immunohistochemical study of the enteric innervations among various types of aganglionoses including isolated and syndromic Hirschsprung disease. Neuropathology 26(1):8–23PubMedCrossRefGoogle Scholar
  57. 57.
    Meguid NA, Kholoussi NM, Afifi HH (2001) Evaluation of superoxide dismutase and glutathione peroxidase enzymes and their cofactors in Egyptian children with Down’s syndrome. Biol Trace Elem Res 81(1):21–28PubMedCrossRefGoogle Scholar
  58. 58.
    Meijers C, Mulder M (1995) Anteroposterior differences within caudal hindbrain neural crest cell populations and the development of the enteric nervous system. Presented at the Second International Meeting: Hirschsprung disease and related neurocristopathies. Cleveland, OH, October 1995Google Scholar
  59. 59.
    Mercer ES, Broecker B, Smith EA, Kirsch AJ, Scherz HC A, Massad C (2004) Urological manifestations of Down syndrome. J Urol 171(3):1250–1253PubMedCrossRefGoogle Scholar
  60. 60.
    Moore SW (2006) Down syndrome and Hirschsprungs disease: a significant relationship? Int J Disabil Hum Dev 5(4):369–375Google Scholar
  61. 61.
    Moore SW (2006) The contribution of associated congenital anomalies in understanding Hirschsprung’s disease. Pediatr Surg Int 22(4):305–315PubMedCrossRefGoogle Scholar
  62. 62.
    Moore SW (2008) Congenital anomalies and genetic associations in Hirschsprungs Disease. In: Holschneider AM, Puri P (eds) Hirschsprungs disease and Allied disorders, 3rd edn. Springer, Berlin, pp 115–131Google Scholar
  63. 63.
    Moore SW, Johnson GA (1998) Hirschsprung’s disease: Genetic and functional associations of Down and Waardenburghs Syndromes. Semin Pediatr Surg 7(3):156–161PubMedGoogle Scholar
  64. 64.
    Moore SW, Rode H, Millar AJ, Albertyn R, Cywes S (1991) Familial Aspects of Hirschsprungs Disease. Eur J Pediat Surg 1:97–107Google Scholar
  65. 65.
    Moore SW and Zaahl MG (2008) The ITGB2 immunomodulatory gene (CD18), enterocolitis and Hirschsprung’s disease (HSCR). J Pediatr Surg (in press)Google Scholar
  66. 66.
    Moore SW, Zaahl MG (2007) Association of endothelin-beta receptor (EDNRB) gene variants in anorectal malformations. J Pediatr Surg 42(7):1266–1270PubMedCrossRefGoogle Scholar
  67. 67.
    Morabito A, Lall A, Gull S, Mohee A, Bianchi A (2006) The impact of Down’s syndrome on the immediate and long-term outcomes of children with Hirschsprung’s disease. Pediatr Surg Int 22(2):179–181PubMedCrossRefGoogle Scholar
  68. 68.
    Mrak RE, Griffin WS (2004) Trisomy 21 and the brain. J Neuropathol Exp Neurol 63(7):679–685PubMedGoogle Scholar
  69. 69.
    Murtomaki S, Risteli J, Risteli L, Koivisto UM, Johansson S, Liesi P (1992) Laminin and its neurite outgrowth-promoting domain in the brain in Alzheimer’s disease and Down’s syndrome patients. J Neurosci Res 32(2):261–273PubMedCrossRefGoogle Scholar
  70. 70.
    Nakazato Y, Landing BH (1986) Reduced number of neurons in esophageal plexus ganglia in Down syndrome: additional evidence for reduced cell number as a basic feature of the disorder. Pediatr Pathol 5(1):55–63PubMedCrossRefGoogle Scholar
  71. 71.
    Netto CB, Portela LV, Ferreira CT, Kieling C, Matte U, Felix T, da Silveira TR, Souza DO, Goncalves CA, Giugliani R (2005) Ontogenetic changes in serum S100B in Down syndrome patients. Clin Biochem 38(5):433–435PubMedCrossRefGoogle Scholar
  72. 72.
    Netto CB, Siqueira IR, Fochesatto C, Portela LV, da Purificacao Tavares M, Souza DO, Giugliani R, Goncalves CA (2004) S100B content and SOD activity in amniotic fluid of pregnancies with Down syndrome. Clin Biochem 37(2):134–137PubMedCrossRefGoogle Scholar
  73. 73.
    Okawada M, Okazaki T, Yamataka A, Lane GJ, Miyano T (2005) Down’s syndrome and esophageal achalasia: a rare but important clinical entity. Pediatr Surg Int 21(12):997–1000PubMedCrossRefGoogle Scholar
  74. 74.
    Omenn GS, McKusick VA (1979) The association of Waardenburgh syndrome and Hirschsprungs megacolon. Am J Med Genet 3:217–223PubMedCrossRefGoogle Scholar
  75. 75.
    Ordonez FJ, Rosety-Rodriguez M (2007) Correlation between glutathione peroxidase activity and anthropometrical parameters in adolescents with Down syndrome. Res Dev Disabil 28(1):105–108PubMedCrossRefGoogle Scholar
  76. 76.
    Passarge E (1967) The genetics of Hirschsprungs Disease. N Engl J Med 276:138–143PubMedGoogle Scholar
  77. 77.
    Pearce R, Galdzicki Z, Rapoport SI (1995) Decreased sensitivity to nerve growth factor of dorsal root ganglion neurons cultured from mouse trisomy 16, a model of Down’s syndrome. Brain Res 680(1–2):108–116PubMedCrossRefGoogle Scholar
  78. 78.
    Petersen MB, Slaugenhaupt SA, Lewis JG, Warren AC, Chakravarti A, Antonarakis SE (1991) A genetic linkage map of 27 markers on human chromosome 21. Genomics 9:407–419PubMedCrossRefGoogle Scholar
  79. 79.
    Preiksaitis HG, Miller L, Pearson FG, Diamant NE (1994) Achalasia in Down’s syndrome. J Clin Gastroenterol 19(2):105–107PubMedCrossRefGoogle Scholar
  80. 80.
    Puffenberger E, Kauffman E, Bolk S et al (1994) Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum Mol Genet 3:1217–1225PubMedCrossRefGoogle Scholar
  81. 81.
    Quinn FM, Surana R, Puri P (1994) The influence of trisomy 21 on outcome in children with Hirschsprung’s disease. J Pediatr Surg 29:781–783PubMedCrossRefGoogle Scholar
  82. 82.
    Rachidi M, Lopes C (2007) Mental retardation in Down syndrome: from gene dosage imbalance to molecular and cellular mechanisms. Neurosci Res. 59(4):349–369PubMedCrossRefGoogle Scholar
  83. 83.
    Reeves RH, Yao J, Crowley MR, Buck S, Zhang X, Yarowsky P, Gearhart JD, Hilt DC (1994) Astrocytosis and axonal proliferation in the hippocampus of S100b transgenic mice. Proc Natl Acad Sci USA 91(12):5359–5363Google Scholar
  84. 84.
    Rivera-Matos I, Rakita R, Mariscalco M, Elder F, Dreyer S, Cleary T (1995) Leukocyte adhesion deficiency mimicking Hirschsprung disease. J Pediatr 127(5):755–757PubMedCrossRefGoogle Scholar
  85. 85.
    Ross GD (2000) Regulation of the adhesion versus cytotoxic functions of the Mac-1/CR3/alphaMbeta2-integrin glycoprotein. Crit Rev Immunol 20(3):197–222PubMedGoogle Scholar
  86. 86.
    Rothman TP, Chen J, Howard MJ, Costantini F, Schuchardt A, Pachnis V, Gershon MD (1996) Increased expression of laminin-1 and collagen (IV) subunits in the aganglionic bowel of ls/ls, but not c-ret −/− mice. Dev Biol 178(2):498–513PubMedCrossRefGoogle Scholar
  87. 87.
    Rothman TP, Goldowitz D, Gershon MD (1993) Inhibition of migration of neural crest-derived cells by the abnormal mesenchyme of the presumptive aganglionic bowel of ls/ls mice: analysis with aggregation and interspecies chimeras. Dev Biol 159(2):559–573PubMedCrossRefGoogle Scholar
  88. 88.
    Sakai T, Wakizaka A, Nirasawa Y, Ito Y (1999) Point nucleotidic changes in both the RET proto-oncogene and the endothelin-B receptor gene in a Hirschsprung disease patient associated with Down syndrome. Tohoku J Exp Med 187(1):43–47PubMedCrossRefGoogle Scholar
  89. 89.
    Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K et al (2006) Increased App expression in a mouse model of Down’s syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron 51(1):29–42PubMedCrossRefGoogle Scholar
  90. 90.
    Satge D, Sasco AJ, Carlsen NL, Stiller CA, Rubie H et al (1998) A lack of neuroblastoma in Down syndrome: a study from 11 European countries. Cancer Res 58(3):448–452PubMedGoogle Scholar
  91. 91.
    Saud K, Arriagada C, Cardenas AM, Shimahara T, Allen DD, Caviedes R, Caviedes P (2006) Neuronal dysfunction in Down syndrome: contribution of neuronal models in cell culture. J Physiol Paris 99(2–3):201–210PubMedCrossRefGoogle Scholar
  92. 92.
    Siddique T, Figlewicz DA, Pericak-Vance MA, Haines JL, Rouleau G, Jeffers AJ, Sapp P, Hung WY, Bebout J, McKenna-Yasek D et al (1991) Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N Engl J Med 24(20):1381–1384Google Scholar
  93. 93.
    Solomon E, Palmer RW, Hing S, Law SK (1988) Regional localization of CD18, the beta-subunit of the cell surface adhesion molecule LFA-1, on human chromosome 21 by in situ hybridization. Ann Hum Genet. 52(Pt 2):123–128PubMedCrossRefGoogle Scholar
  94. 94.
    Spahis JK, Wilson GN (1999) Down syndrome: perinatal complications and counseling experiences in 216 patients. Am J Med Genet 89(2):96–99PubMedCrossRefGoogle Scholar
  95. 95.
    Spouge D, Baird PA (1985) Hirschsprungs Disease in a large birth cohort. Teratology 32:171–177PubMedCrossRefGoogle Scholar
  96. 96.
    Stanchina L, Baral V, Robert F, Pingault V, Lemort N, Pachnis V, Goossens M, Bondurand N (2006) Interactions between Sox10, Edn3 and Ednrb during enteric nervous system and melanocyte development. Dev Biol 295(1):232–249PubMedCrossRefGoogle Scholar
  97. 97.
    Takahashi T, Nowakowski RS, Caviness VS Jr (1995) The cell cycle of the pseudostratified ventricular epithelium of the embryonic murine cerebral wall. J Neurosci 15(9):6046–6057PubMedGoogle Scholar
  98. 98.
    Tamamaki N, Nakamura K, Okamoto K, Kaneko T (2001) Radial glia is a progenitor of neocortical neurons in the developing cerebral cortex. Neurosci Res 41(1):51–60PubMedCrossRefGoogle Scholar
  99. 99.
    Tanyel FC, Muftuoglu SF, Dagdeviren A, Unsal I, Buyukpamukcu N, Hicsonmez A (1997) Expression of beta-1 integrins in ganglionic and aganglionic segments of patients with Hirschsprung’s disease. Eur J Pediatr Surg 7(1):16–20PubMedCrossRefGoogle Scholar
  100. 100.
    Taylor GM, Haigh H, Williams A, D’Souza SW, Harris R (1988) Down’s syndrome lymphoid cell lines exhibit increased adhesion due to the over-expression of lymphocyte function-associated antigen (LFA-1). Immunology 64(3):451–456PubMedGoogle Scholar
  101. 101.
    Teitelbaum DH, Qualman SJ, Caniano DA (1988) Hirschsprungs disease: identification of risk factors for enterocolitis. Ann Surg 207:240–244PubMedCrossRefGoogle Scholar
  102. 102.
    Thomas RM, Fang S, Leichus LS, Oberley LW, Christensen J, Murray JA, Ledlow A, Conklin JL (1996) Antioxidant enzymes in intramural nerves of the opossum esophagus. Am J Physiol 270(1 Pt 1):G136–G142PubMedGoogle Scholar
  103. 103.
    van Trotsenburg AS, Heymans HS, Tijssen JG, de Vijlder JJ, Vulsma T (2006) Comorbidity, hospitalization, and medication use and their influence on mental and motor development of young infants with Down syndrome. Pediatrics 118(4):1633–1639PubMedCrossRefGoogle Scholar
  104. 104.
    Vlug AS, Teuling E, Haasdijk ED, French P, Hoogenraad CC, Jaarsma D (2006) ATF3 expression precedes death of spinal motoneurons in amyotrophic lateral sclerosis-SOD1 transgenic mice and correlates with c-Jun phosphorylation, CHOP expression, somato-dendritic ubiquitination and Golgi fragmentation. Eur J Neurosci 22(8):1881–1894CrossRefGoogle Scholar
  105. 105.
    Wallace RA (2007) Clinical audit of gastrointestinal conditions occurring among adults with Down syndrome attending a specialist clinic. J Intellect Dev Disabil 32(1):45–50PubMedCrossRefGoogle Scholar
  106. 106.
    Weir K, McMahon S, Barry L, Ware R, Masters IB, Chang AB (2007) Oropharyngeal aspiration and pneumonia in children. Pediatr Pulmonol. 42(11):1024–1031PubMedCrossRefGoogle Scholar
  107. 107.
    Wilson-Storey WD, Scobie WG, Raeburn JA (1988) Defective white blood cell function in Hirschsprungs disease: a possible predisposing factor for enterocolitis. J Roy Coll Surg Edin 33(4):185–188Google Scholar
  108. 108.
    Wright TC, Orkin RW, Destrempes M, Kurnit D (1984) Increased adhesiveness of Down syndrome fetal fibroblasts in vitro. Proc Natl Acad Sci USA 81:2426–2430PubMedCrossRefGoogle Scholar
  109. 109.
    Young-Pearse TL, Bai J, Chang R, Zheng JB, LoTurco JJ, Selkoe DJ (2007) A critical function for beta-amyloid precursor protein in neuronal migration revealed by in utero RNA interference. J Neurosci 27(52):14459–14469Google Scholar
  110. 110.
    Zaahl MG, du Plessis L, Warnich L, Kotze MJ, Moore SW (2003) Significance of novel endothelin-B receptor gene polymorphisms in Hirschsprung’s disease: Predominance of a novel variant (561C/T) in patients with co-existing Down’s syndrome. Mol Cell Probes 17(1):49–54PubMedCrossRefGoogle Scholar
  111. 111.
    Zaahl MG, van Huyssteen B, Strickland N, Panton NA, and Moore SW (2006) Hirschsprung’s disease (HSCR) and Chromosome 21: Investigating two possible modifier loci, superoxide dismutase (SOD1) and integrin-â2 gene (ITGB2) (in press)Google Scholar
  112. 112.
    Zarate N, Mearin F, Hidalgo A, Malagelada JR (2001) Prospective evaluation of esophageal motor dysfunction in Down’s syndrome. Am J Gastroenterol 96(6):1718–1724PubMedGoogle Scholar
  113. 113.
    Zarate N, Mearin F, Gil-Vernet JM, Camarasa F, Malagelada JR (1999) Achalasia and Down’s syndrome: coincidental association or something else? Am J Gastroenterol 94(6):1674–1677PubMedGoogle Scholar
  114. 114.
    Zhang J, Huang EJ (2006) Dynamic expression of neurotrophic factor receptors in postnatal spinal motoneurons and in mouse model of ALS. J Neurobiol 66(8):882–895PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  1. 1.Division of Paediatric Surgery, Department of Surgical Sciences, Faculty of Health SciencesUniversity of StellenboschTygerbergSouth Africa

Personalised recommendations