Human Genetics

, Volume 126, Issue 1, pp 149–172 | Cite as

The genomic basis of cerebral palsy: a HuGE systematic literature review

  • M. E. O’CallaghanEmail author
  • A. H. MacLennan
  • E. A. Haan
  • G. Dekker
  • The South Australian Cerebral Palsy Research Group
Review Article


Cerebral palsy has been associated with a number of candidate genes. To date, no systematic review has been conducted to synthesise genetic polymorphism associations with cerebral palsy. We apply the HuGE NET guidelines to search PubMed and EMBASE databases for publications investigating single nucleotide polymorphisms (SNPs) and cerebral palsy outcome. 22 papers were identified and are discussed in this review. Candidate genes were grouped as (1) thrombophilic, (2) cytokine, (3) apolipoprotein E or (4) other SNPs, largely related to cardiovascular physiology/pathophysiology and the functioning of the immune system. Of the studies identified, cohorts were usually small, without adequate control and ethnically diverse, making direct comparison between studies difficult. The most promising candidate genes include factor V Leiden, methylenetetrahydrofolate reductase, lymphotoxin-α, tumour necrosis factor-α, eNOS and mannose binding lectin. Large case–control studies are needed to confirm these candidates with attention given to cohort ethnicity, cerebral palsy subtype analysis and possible multiple gene and gene–environment interactions.


Cerebral Palsy Mannose Binding Lectin Factor Versus Leiden Spastic Cerebral Palsy Prothrombin G20210A 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Arbour NC, Lorenz E, Schutte BC, Zabner J, Kline JN, Jones M, Frees K, Watt JL, Schwartz DA (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25(2):187–191PubMedCrossRefGoogle Scholar
  2. Ates O, Musellim B, Ongen G, Topal-Sarikaya A (2008) Interleukin-10 and tumor necrosis factor-alpha gene polymorphisms in tuberculosis. J Clin Immunol 28(3):232–236PubMedCrossRefGoogle Scholar
  3. Atochin DN, Demchenko IT, Astern J, Boso AE, Piantadosi CA, Huang PL (2003) Contributions of endothelial and neuronal nitric oxide synthases to cerebrovascular responses to hyperoxia. J Cereb Blood Flow Metab 23(10):1219–1226PubMedCrossRefGoogle Scholar
  4. Bashiri A, Burstein E, Mazor M (2006) Cerebral palsy and fetal inflammatory response syndrome: a review. J Perinat Med 34(1):5–12PubMedCrossRefGoogle Scholar
  5. Braun JS, Hoffmann O, Schickhaus M, Freyer D, Dagand E, Bermpohl D, Mitchell TJ, Bechmann I, Weber JR (2007) Pneumolysin causes neuronal cell death through mitochondrial damage. Infect Immun 75(9):4245–4254PubMedCrossRefGoogle Scholar
  6. Chauhan M, McGuire W (2008) Interleukin-6 (-174C) polymorphism and the risk of sepsis in very-low-birth-weight infants: meta-analysis. Arch Dis Child Fetal Neonatal EdGoogle Scholar
  7. Christen WG, Ajani UA, Glynn RJ, Hennekens CH (2000) Blood levels of homocysteine and increased risks of cardiovascular disease: causal or casual? Arch Intern Med 160(4):422–434PubMedCrossRefGoogle Scholar
  8. Chudakova DA, Minushkina LO, Zateishchikov DA, Nosik VV (2004) Association of polymorphic marker G(-455)A of gene FGB with coronary artery disease. Genetika 40(10):1406–1409PubMedGoogle Scholar
  9. Cipollone F, Toniato E, Martinotti S, Fazia M, Iezzi A, Cuccurullo C, Pini B, Ursi S, Vitullo G, Averna M et al (2004) A polymorphism in the cyclooxygenase 2 gene as an inherited protective factor against myocardial infarction and stroke. JAMA 291(18):2221–2228PubMedCrossRefGoogle Scholar
  10. Curry CJ, Bhullar S, Holmes J, Delozier CD, Roeder ER, Hutchison HT (2007) Risk factors for perinatal arterial stroke: a study of 60 mother-child pairs. Pediatr Neurol 37(2):99–107PubMedCrossRefGoogle Scholar
  11. Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM (1993) The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 268(15):10739–10745PubMedGoogle Scholar
  12. Dekker G, de Vries J, Doelitzsch P, Huijgens P, von Blomberg B, Jakobs C, van Geijn H (1995) Underlying disorders associated with severe early-onset preeclampsia. Am J Obstet Gynecol 173:1042–1048PubMedCrossRefGoogle Scholar
  13. Dickinson J (1994) Viral teratology. In: Gonik B (ed) Viral diseases in pregnancy. Springer, HeidelbergGoogle Scholar
  14. Dordelmann M, Kerk J, Dressler F, Brinkhaus MJ, Bartels DB, Dammann CE, Dork T, Dammann O (2006) Interleukin-10 high producer allele and ultrasound-defined periventricular white matter abnormalities in preterm infants: a preliminary study. Neuropediatrics 37(3):130–136PubMedCrossRefGoogle Scholar
  15. Fattal-Valevski A, Kenet G, Kupferminc MJ, Mesterman R, Leitner Y, Rimon E, Harel S, Hassner A (2005) Role of thrombophilic risk factors in children with non-stroke cerebral palsy. Thromb Res 116(2):133–137PubMedCrossRefGoogle Scholar
  16. Gibson CS, MacLennan AH, Hague WM, Haan EA, Priest K, Chan A, Dekker GA (2005a) Associations between inherited thrombophilia, gestational age, and cerebral palsy. Am J Obstet Gynecol 193(4):1437PubMedCrossRefGoogle Scholar
  17. Gibson CS, MacLennan AH, Hague WM, Haan EA, Priest K, Chan A, Dekker GA (2005b) Associations between inherited thrombophilias, gestational age, and cerebral palsy. Am J Obstet Gynecol 193(4)Google Scholar
  18. Gibson CS, MacLennan AH, Goldwater PN, Haan EA, Priest K, Dekker GA (2006a) The association between inherited cytokine polymorphisms and cerebral palsy. Am J Obstet Gynecol 194(3):674 e1–674 e11CrossRefGoogle Scholar
  19. Gibson CS, MacLennan AH, Goldwater PN, Haan EA, Priest K, Dekker GA (2006b) The association between inherited cytokine polymorphisms and cerebral palsy. Am J Obstet Gynecol 194(3)Google Scholar
  20. Gibson CS, Maclennan AH, Dekker GA, Goldwater PN, Sullivan TR, Munroe DJ, Tsang S, Stewart C, Nelson KB (2008a) Candidate genes and cerebral palsy: a population-based study. Pediatrics 122(5):1079–1085PubMedCrossRefGoogle Scholar
  21. Gibson CS, MacLennan AH, Goldwater PN, Haan EA, Priest K, Dekker GA (2008b) Mannose-binding lectin haplotypes may be associated with cerebral palsy only after perinatal viral exposure. Am J Obstet Gynecol 198(5):509 e1–509 e8CrossRefGoogle Scholar
  22. Gotsch F, Romero R, Kusanovic JP, Mazaki-Tovi S, Pineles BL, Erez O, Espinoza J, Hassan SS (2007) The fetal inflammatory response syndrome. Clin Obstet Gynecol 50(3):652–683PubMedCrossRefGoogle Scholar
  23. Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7(2):195–200PubMedCrossRefGoogle Scholar
  24. Grether JK, Nelson KB (1997) Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 278(3):207–211PubMedCrossRefGoogle Scholar
  25. Halliday JL, Reddihough D, Byron K, Ekert H, Ditchfield M (2000) Hemiplegic cerebral palsy and the factor V Leiden mutation. J Med Genet 37(10):787–789PubMedCrossRefGoogle Scholar
  26. Harding DR, Dhamrait S, Whitelaw A, Humphries SE, Marlow N, Montgomery HE (2004) Does interleukin-6 genotype influence cerebral injury or developmental progress after preterm birth? Pediatrics 114(4):941–947PubMedCrossRefGoogle Scholar
  27. Harding DR, Humphries SE, Whitelaw A, Marlow N, Montgomery HE (2007) Cognitive outcome and cyclo-oxygenase-2 gene (-765 G/C) variation in the preterm infant. Arch Dis Child Fetal Neonatal Ed 92(2):F108–F112PubMedCrossRefGoogle Scholar
  28. Harum KH, Hoon AH Jr, Kato GJ, Casella JF, Breiter SN, Johnston MV (1999) Homozygous factor-V mutation as a genetic cause of perinatal thrombosis and cerebral palsy. Dev Med Child Neurol 41(11):777–780CrossRefGoogle Scholar
  29. Heinzmann A, Ahlert I, Kurz T, Berner R, Deichmann KA (2004) Association study suggests opposite effects of polymorphisms within IL8 on bronchial asthma and respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol 114(3):671–676PubMedCrossRefGoogle Scholar
  30. Hemminki K, Li X, Sundquist K, Sundquist J (2007) High familial risks for cerebral palsy implicate partial heritable aetiology. Paediatr Perinat Epidemiol 21(3):235–241PubMedCrossRefGoogle Scholar
  31. Henry M, Chomiki N, Scarabin PY, Alessi MC, Peiretti F, Arveiler D, Ferrieres J, Evans A, Amouyel P, Poirier O et al (1997) Five frequent polymorphisms of the PAI-1 gene: lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population. Arterioscler Thromb Vasc Biol 17(5):851–858PubMedGoogle Scholar
  32. Hoffman M, Cooper ST (1995) Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms. Blood Cells Mol Dis 21(2):156–167PubMedCrossRefGoogle Scholar
  33. Holm PI, Hustad S, Ueland PM, Vollset SE, Grotmol T, Schneede J (2007) Modulation of the homocysteine-betaine relationship by methylenetetrahydrofolate reductase 677 C->t genotypes and B-vitamin status in a large-scale epidemiological study. J Clin Endocrinol Metab 92(4):1535–1541PubMedCrossRefGoogle Scholar
  34. Hunault M, Arbini AA, Lopaciuk S, Carew JA, Bauer KA (1997) The Arg353Gln polymorphism reduces the level of coagulation factor VII. In vivo and in vitro studies. Arterioscler Thromb Vasc Biol 17(11):2825–2829PubMedGoogle Scholar
  35. Jacobsson B, Hagberg G, Hagberg B, Ladfors L, Niklasson A, Hagberg H (2002) Cerebral palsy in preterm infants: a population-based case–control study of antenatal and intrapartal risk factors. Acta Paediatr 91(8):946–951PubMedCrossRefGoogle Scholar
  36. Jacobsson B, Ahlin K, Francis A, Hagberg G, Hagberg H, Gardosi J (2008) Cerebral palsy and restricted growth status at birth: population-based case–control study. BJOG 115(10):1250–1255PubMedCrossRefGoogle Scholar
  37. Kalafatis M, Bertina RM, Rand MD, Mann KG (1995) Characterization of the molecular defect in factor VR506Q. J Biol Chem 270(8):4053–4057PubMedCrossRefGoogle Scholar
  38. Kilpinen S, Hulkkonen J, Wang XY, Hurme M (2001) The promoter polymorphism of the interleukin-6 gene regulates interleukin-6 production in neonates but not in adults. Eur Cytokine Netw 12(1):62–68PubMedGoogle Scholar
  39. Kist WJ, Janssen NG, Kalk JJ, Hague WM, Dekker GA, de Vries JI (2008) Thrombophilias and adverse pregnancy outcome––a confounded problem. Thromb Haemost 99(1):77–85PubMedGoogle Scholar
  40. Kroeger KM, Carville KS, Abraham LJ (1997) The -308 tumor necrosis factor-alpha promoter polymorphism effects transcription. Mol Immunol 34(5):391–399PubMedCrossRefGoogle Scholar
  41. Kuroda MM, Weck ME, Sarwark JF, Hamidullah A, Wainwright MS (2007) Association of apolipoprotein E genotype and cerebral palsy in children. Pediatrics 119(2):306–313PubMedCrossRefGoogle Scholar
  42. Lazarus M, Hajeer AH, Turner D, Sinnott P, Worthington J, Ollier WE, Hutchinson IV (1997) Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol 24(12):2314–2317PubMedGoogle Scholar
  43. Lynch JK, Nelson KB, Curry CJ, Grether JK (2001) Cerebrovascular disorders in children with the factor V Leiden mutation. J Child Neurol 16(10):735–744PubMedCrossRefGoogle Scholar
  44. McCarron MO, Delong D, Alberts MJ (1999) APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis. Neurology 53(6):1308–1311PubMedGoogle Scholar
  45. McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D (1994) Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature 371(6497):508–510PubMedCrossRefGoogle Scholar
  46. McMichael GL, Gibson CS, Goldwater PN, Haan EA, Priest K, Dekker GA, MacLennan AH (2008) Association between apolipoprotein E genotype and cerebral palsy is not confirmed in a Caucasian population. Hum Genet 124(4):411–416PubMedCrossRefGoogle Scholar
  47. Medina P, Navarro S, Estelles A, Vaya A, Woodhams B, Mira Y, Villa P, Migaud-Fressart M, Ferrando F, Aznar J et al (2004) Contribution of polymorphisms in the endothelial protein C receptor gene to soluble endothelial protein C receptor and circulating activated protein C levels, and thrombotic risk. Thromb Haemost 91(5):905–911PubMedGoogle Scholar
  48. Meirelles Kalil Pessoa de B, Rodrigues CJ, de Barros TE, Bevilacqua RG (2000) Presence of apolipoprotein E epsilon 4 allele in cerebral palsy. J Pediatr Orthop 20(6):786–789Google Scholar
  49. Moore KW, O’Garra A, l Malefyt R, Vieira P, Mosmann TR (1993) Interleukin-10. Annu Rev Immunol 11:165–190PubMedCrossRefGoogle Scholar
  50. Nelson KB (2002) The epidemiology of cerebral palsy in term infants. Ment Retard Dev Disabil Res Rev 8(3):146–150PubMedCrossRefGoogle Scholar
  51. Nelson KB (2007) Perinatal ischemic stroke. Stroke 38(2 Suppl):742–745PubMedCrossRefGoogle Scholar
  52. Nelson KB, Grether JK (1999) Causes of cerebral palsy. Curr Opin Pediatr 11(6):487–491PubMedCrossRefGoogle Scholar
  53. Nelson KB, Lynch JK (2004) Stroke in newborn infants. Lancet Neurol 3(3):150–158PubMedCrossRefGoogle Scholar
  54. Nelson KB, Dambrosia JM, Iovannisci DM, Cheng S, Grether JK, Lammer E (2005) Genetic polymorphisms and cerebral palsy in very preterm infants. Pediatr Res 57(4):494–499PubMedCrossRefGoogle Scholar
  55. Ozaki K, Ohnishi Y, Iida A, Sekine A, Yamada R, Tsunoda T, Sato H, Hori M, Nakamura Y, Tanaka T (2002) Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nat Genet 32(4):650–654PubMedCrossRefGoogle Scholar
  56. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE, Laurent GJ (2002) Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc Biol 22(10):1631–1636PubMedCrossRefGoogle Scholar
  57. Pociot F, Molvig J, Wogensen L, Worsaae H, Nerup J (1992) A TaqI polymorphism in the human interleukin-1 beta (IL-1 beta) gene correlates with IL-1 beta secretion in vitro. Eur J Clin Invest 22(6):396–402PubMedCrossRefGoogle Scholar
  58. Quek SC, Low PS, Saha N, Heng CK (2006) The effects of three factor VII polymorphisms on factor VII coagulant levels in healthy Singaporean Chinese, Malay and Indian newborns. Ann Hum Genet 70(Pt 6):951–957PubMedCrossRefGoogle Scholar
  59. Reid S, Halliday J, Ditchfield M, Ekert H, Byron K, Glynn A, Petrou V, Reddihough D (2006) Factor V Leiden mutation: a contributory factor for cerebral palsy? Dev Med Child Neurol 48(1):14–19PubMedCrossRefGoogle Scholar
  60. Robertson L, Wu O, Langhorne P, Twaddle S, Clark P, Lowe GD, Walker ID, Greaves M, Brenkel I, Regan L et al (2006) Thrombophilia in pregnancy: a systematic review. Br J Haematol 132(2):171–196PubMedCrossRefGoogle Scholar
  61. Rodgers GM, Kane WH (1986) Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 77(6):1909–1916PubMedCrossRefGoogle Scholar
  62. Rosenbaum P, Paneth N, Leviton A, Goldstein M, Bax M, Damiano D, Dan B, Jacobsson B (2007) A report: the definition and classification of cerebral palsy April 2006. Dev Med Child Neurol Suppl 109:8–14PubMedGoogle Scholar
  63. Sabroe I, Dower SK, Whyte MK (2005) The role of Toll-like receptors in the regulation of neutrophil migration, activation, and apoptosis. Clin Infect Dis 41(Suppl 7):S421–S426PubMedCrossRefGoogle Scholar
  64. Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, Rosi BL, Gusella JF, Crapper-MacLachlan DR, Alberts MJ et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. Neurology 43(8):1467–1472PubMedGoogle Scholar
  65. Scantlebury MH, David M, Carmant L (2002) Association between factor V Leiden mutation and the hemiconvulsion, hemiplegia, and epilepsy syndrome: report of two cases. J Child Neurol 17(9):713–717PubMedCrossRefGoogle Scholar
  66. Senbil N, Yuksel D, Yilmaz D, Gurer YKY (2007) Prothrombotic risk factors in children with hemiplegic cerebral palsy. Pediatr Int 49(5):600–602PubMedCrossRefGoogle Scholar
  67. Smith RA, Skelton M, Howard M, Levene M (2001) Is thrombophilia a factor in the development of hemiplegic cerebral palsy? Dev Med Child Neurol 43(11):724–730PubMedCrossRefGoogle Scholar
  68. Srinivasan SR, Ehnholm C, Elkasabany A, Berenson G (1999) Influence of apolipoprotein E polymorphism on serum lipids and lipoprotein changes from childhood to adulthood: the Bogalusa heart study. Atherosclerosis 143(2):435–443PubMedCrossRefGoogle Scholar
  69. Steiner M, Hodes MZ, Shreve M, Sundberg S, Edson JR (2000) Postoperative stroke in a child with cerebral palsy heterozygous for factor V Leiden. J Pediatr Hematol Oncol 22(3):262–264PubMedCrossRefGoogle Scholar
  70. Takahashi M, Mori S, Shigeta S, Fujita T (2007) Role of MBL-associated serine protease (MASP) on activation of the lectin complement pathway. Adv Exp Med Biol 598:93–104PubMedCrossRefGoogle Scholar
  71. Thompson SG, Kienast J, Pyke SD, Haverkate F, van de Loo JC (1995) Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European concerted action on thrombosis and disabilities Angina Pectoris study group. N Engl J Med 332(10):635–641PubMedCrossRefGoogle Scholar
  72. Thorarensen O, Ryan S, Hunter J, Younkin DP (1997) Factor V Leiden mutation: an unrecognized cause of hemiplegic cerebral palsy, neonatal stroke, and placental thrombosis. Ann Neurol 42(3):372–375CrossRefGoogle Scholar
  73. Thorngren-Jerneck K, Herbst A (2006) Perinatal factors associated with cerebral palsy in children born in Sweden. Obstet Gynecol 108(6):1499–1505PubMedGoogle Scholar
  74. Vagiakou EA, Voudris KA, Dimitriou Y, Skardoutsou A, Mastroyianni S (2006) Different additional risk factors for cerebral infarctions associated with the factor V Leiden mutation in a family. J Child Neurol 21(10):903–907PubMedCrossRefGoogle Scholar
  75. Vigneswaran R, Aitchison SJ, McDonald HM, Khong TY, Hiller JE (2004) Cerebral palsy and placental infection: a case–cohort study. BMC Pregnancy Childbirth 4(1):1PubMedCrossRefGoogle Scholar
  76. Walker I (2000) Thrombophilia in pregnancy. J Clin Pathol 53:573–580PubMedCrossRefGoogle Scholar
  77. Wang G, Woo CW, Sung FL, Siow YL, O K (2002) Increased monocyte adhesion to aortic endothelium in rats with hyperhomocysteinemia: role of chemokine and adhesion molecules. Arterioscler Thromb Vasc Biol 22(11):1777–1783Google Scholar
  78. Welch G, Loscalzo J (1998) Homocysteine and atherothrombosis. N Engl J Med 338:1042–1051PubMedCrossRefGoogle Scholar
  79. Yehezkely-Schildkraut V, Kutai M, Hugeirat Y, Levin C, Shalev SA, Mazor G, Koren A (2005) Thrombophilia: a risk factor for cerebral palsy? Israel Med Assoc J 7(12):808–811Google Scholar
  80. Yoon BH, Romero R, Kim CJ, Koo JN, Choe G, Syn HC, Chi JG (1997) High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 177(2):406–411PubMedCrossRefGoogle Scholar
  81. Zaretsky MV, Alexander JM, Byrd W, Bawdon RE (2004) Transfer of inflammatory cytokines across the placenta. Obstet Gynecol 103(3):546–550PubMedGoogle Scholar
  82. Zetterberg H, Regland B, Palmer M, Ricksten A, Palmqvist L, Rymo L, Arvanitis DA, Spandidos DA, Blennow K (2002) Increased frequency of combined methylenetetrahydrofolate reductase C677T and A1298C mutated alleles in spontaneously aborted embryos. Eur J Hum Genet 10(2):113–118PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • M. E. O’Callaghan
    • 1
    Email author
  • A. H. MacLennan
    • 1
  • E. A. Haan
    • 2
  • G. Dekker
    • 1
  • The South Australian Cerebral Palsy Research Group
  1. 1.Discipline of Obstetrics and GynaecologyThe University of AdelaideAdelaideAustralia
  2. 2.Department of Genetic Medicine, SA Pathology, Women’s and Children’s Hospital and Discipline of PaediatricsThe University of AdelaideAdelaideAustralia

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