Cerebral palsy: causes, pathways, and the role of genetic variants
Alastair H. MacLennan, MD, FRANZCOG; Suzanna C. Thompson, MBBS, FRACP; Jozef Gecz, PhD
Cerebral palsy (CP) is heterogeneous with different clinical types, comorbidities, brain imaging patterns, causes, and now also heterogeneous underlying genetic variants. Few are solely due to severe hypoxia or ischemia at birth. This common myth has held back research in causation. The cost of litigation has devastating effects on maternity services with unnecessarily high cesarean delivery rates and subsequent maternal morbidity and mortality.
CP rates have remained the same for 50 years despite a 6-fold increase in Cesarean birth.
Epidemiological studies have shown that the origins of most CP are prior to labor.
Increased risk is associated with preterm delivery, congenital malformations, intrauterine infection, fetal growth restriction, multiple pregnancy, and placental abnormalities. Hypoxia at birth may be primary or secondary to preexisting pathology and international criteria help to separate the few cases of CP due to acute intrapartum hypoxia. Until recently, 1-2% of CP (mostly familial) had been linked to causative mutations. Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are
Hypoxia at birth may be primary or secondary to preexisting pathology and international criteria help to separate the few cases of CP due to acute intrapartum hypoxia. Until recently, 1-2% of CP (mostly familial) had been linked to causative mutations. Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are
Hypoxia at birth may be primary or secondary to preexisting pathology and international criteria help to separate the few cases of CP due to acute intrapartum hypoxia. Until recently, 1-2% of CP (mostly familial) had been linked to causative mutations. Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are
Recent genetic studies of sporadic CP cases using new-generation exome sequencing show that 14% of cases have likely causative single-gene mutations and up to 31% have clinically relevant copy number variations. The genetic variants are het- erogeneous and require function investigations to prove causation. Whole genome sequencing, fine-scale copy number variant investigations, and gene expression studies may extend the percentage of cases with a genetic pathway. Clinical risk factors could act as triggers for CP where there is genetic susceptibility. These new findings should refocus research about the causes of these complex and varied neurodevelopmental disorders.
Epidemiologic and genetic risk factors for cerebral palsy
Preterm delivery
Coexisting congenital anomaly (maldevelopment)
Probable genetic causes
Bacterial and viral intrauterine infection
Altered fetal inflammatory or thrombophilic response (perinatal stroke)
Fetal growth restriction
Higher-order pregnancy, risk greater with monozygosity and in vitro fertilization
Tight nuchal umbilical cord
Prolonged shoulder dystocia
Placental pathology, eg, chorioamnionitis, funisitis, villitis
Inborn errors of metabolism
Male:female ratio 1.3:1
Conclusion
The long-held belief that most or many cases of CP are due to trauma or asphyxia around the time of birth and that earlier intervention can prevent the neuropathology is not evidence-based, has held back research into other pathways, and has fuelled unwarranted litigation that has had an untoward effect on modern maternity care and maternal outcomes.
While it is possible that a severe acute de novo metabolic acidosis could be a rare primary cause of CP, or that intrapartum hypoxia could be a continuing or secondary cause of CP, the great likelihood is that, with the exception of uncommon causes in infancy, the pathways to the neuropathology of CP usually begin well before labor and often in earlier pregnancy.
It is now important to consider possible genetic causes that may directly, or through genetic susceptibility, trigger different pathways to different neuropathologies that share the common clinical trait of a nonprogressive movement disorder diagnosed as CP (Video).
In the near future, it will be possible to test for many of the putative or validated genes that have been associated with CP to date. This panel of different pathogenic genetic variations contributing to the CP spectrum is very likely to grow over the next decade and should open a new direction into the causes of CP and challenge previous medicolegal assumptions about the culpability of the accoucheur.
REFERENCES
1. MacLennan AH. A template for defining a causal relation between acute events and cerebral palsy: international consensus statement. BMJ 1999;319:1054-9.
2. Hankins GDV, Speer M. Defining the pathogenesis and pathophysiology of neonatal encephalopathy and cerebral palsy. Obstet Gynecol 2003;102:628-36.
3. American College of Obstetricians and Gynecologists and American Academy of Pediatrics. Neonatal encephalopathy and neurologic outcome. Washington, DC: American College of Obstetricians and Gynecologists; 2014.
4. Watson L, Blair E, Stanley F. Report of the Western Australian Cerebral Palsy Register to birth year 1999. Perth (Australia): Telethon Institute for Child Health Research; 2006.
5. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy, I: univariate analysis of risks. Am J Dis Child 1985;139:1031-8.
6. Nelson KB, Ellenberg JH. Antecedents of cerebral palsy: multivariate analysis of risk. N Engl J Med 1986;315:81-6.
7. Blair E, Stanley F. Intrapartum asphyxia: a rare cause of cerebral palsy. J Pediatr 1988;112: 515-9.
8. Strijbis EM, Oudman I, van Essen P, MacLennan AH. Cerebral palsy and the appli- cation of the international criteria for acute intrapartum hypoxia. Obstet Gynecol 2006;107: 1357-65.
9. Badawi NK, Kurinczuk JJ, Keogh JM, et al. Intrapartum risk factors for newborn encepha- lopathy: the Western Australian case-control study. BMJ 1998;317:1554-8.
10. Badawi N, Felix JE, Kurinczuk JJ, et al. Cerebral palsy following term newborn en- cephalopathy: a population-based study. Dev Med Child Neurol 2005;47:293-8.
11. Moreno-De-Luca A, Ledbetter DH, Martin CL. Genetic insights into the causes and classification of the cerebral palsies. Lancet Neurol 2012;11:283-92.
12. McMichael G, Bainbridge MN, Haan E, et al. Whole-exome sequencing points to consider- able genetic heterogeneity of cerebral palsy. Mol Psychiatr 2015;20:176-82.
13. Wong L, MacLennan AH. Gathering the evidence: cord gases and placental histology for births with low Apgar scores. Aust N Z J Obstet Gynaecol 2011;51:17-21.
14. Page FO, Martin JN, Palmer SM, et al. Correlation of neonatal acid-base status with Apgar scores and fetal heart rate tracings. Am J Obstet Gynecol 1986;154:1306-11.
15. Phelan PP, Korst LM, Martin GI. Application of criteria developed by the task force on neonatal encephalopathy and cerebral palsy to acutely asphyxiated neonates. Obstet Gynecol 2011;118:824-30.
16. Alfirevic Z, Devane D, Gyte GML. Contin- uous cardiotocography (CTG) as a form of electronic fetal monitoring (EFM) for fetal assessment during labor. Cochrane Database Syst Rev 2006;3:CD006066. 786 American Journal of Obstetrics & Gynecology DECEMBER 2015 culpability of the accoucheur.
17. Maternity Services in England. Report by the Comptroller and Auditor General, National Audit Office, Department of Health, United Kingdom. 2013 Summary 1.17. Available at: http://www. nao.org.uk/wp-content/uploads/2013/11/10259- 001-Maternity-Services-Book-1.pdf. Accessed June 24, 2015.
18. Sartwelle TP, Johnston JC. Cerebral palsy litigation: change course or abandon ship. J Child Neurol 2015;30:828-41.
19. Daubert v Merrell Dow Pharmaceuticals Inc. Bloomberg Law. 509 US 579, 113 S Ct 2786, 125 L Ed 2d 469, 1993 US.
20. Stanley F, Blair E, Alberman E. Cerebral palsies: epidemiology and causal pathways, Vol 151. London (United Kingdom): MacKeith Press; 2000.
21. Murphy DJ, Johnson AM, Sellers S, MacKenzie IZ. Case-control study of antenatal and intrapartum risk factors for cerebral palsy in very preterm singleton babies. Lancet 1995; 346:1449-54.
22. Oskoui M, Coutinho F, Dykeman J, Jette E, Pringsheim T. An update on the prevalence of cerebral palsy: a systematic review and meta- analysis. Dev Med Child Neurol 2013;55: 509-19.
23. Garne E, Dolk H, Krageloh-Mann I, Holst Ravn S, Cans C. Cerebral palsy and congenital malformations. Eur J Paediatr Neurol 2008;12: 82-8.
24. Blair E, Asedy F, Badawi N, Bower C. Is cerebral palsy associated with other defects other than cerebral defects? Dev Med Child Neurol 2007;49:252-8.
25. McIntyre S, Blair E, Badawi N, Keogh J, Nelson K. Antecedents of cerebral palsy and perinatal death in term and late preterm single- tons. Obstet Gynecol 2013;122:869-77.
26. Grether JK, Nelson KB. Maternal infection and cerebral palsy in infants of normal birth weight. JAMA 1997;278:207-11.
27. O’Callaghan ME, MacLennan AH, Gibson CS, et al. Epidemiologic associations with cerebral palsy. Obstet Gynecol 2011;118: 576-82.
28. Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TB. Chorioamnionitis and cerebral palsy in term and near-term infants. JAMA 2003;290:2677-84.
29. Yoon BH, Romero R, Park JS, Kim SH, Choi J, Han TR. Fetal exposure to an intra- amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 2000;182:675-81.
30. Bashiri A, Burstein E, Mazor M. Cerebral palsy and fetal inflammatory response syndrome: a review. J Perinat Med 2006;34: 5-12.
31. Gibson CS, MacLennan AH, Hague WM, et al. for the South Australian Cerebral Palsy Research Group. Associations between inheri- ted thrombophilias, gestational age, and cere- bral palsy. Am J Obstet Gynecol 2005;193: 1437-43.
32. Gibson CS, MacLennan AH, Goldwater PN, et al. The association between inherited
cytokine polymorphisms and cerebral palsy. Obstet Gynecol 2006;194:674.e1-11.
33. Blair EM, Nelson KB. Fetal growth restriction and risk of cerebral palsy in singletons born at least 35 weeks gestation. Am J Obstet Gynecol 2015;212:520.e1-7.
34. Williams MC, O’Brien WF. Cerebral palsy in infants with asymmetric growth restriction. Am J Perinatol 1997;14:211-5.
35. Gardosi J. Customized growth curves. Clin Obstet Gynecol 1997;40:715-22.
36. Davies MJ, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med 2012;366:1803-13.
37. Nelson KB, Grether KB. Potentially asphyxiating conditions and spastic cerebral palsy in infants of normal birth weight. Am J Obstet Gynecol 1998;179:507-13.
38. Craver RD, Baldwin VJ. Necrotizing funisitis. Obstet Gynecol 1992;79:64-70.
39. Redline RW. Severe fetal placental vascular lesions in term infants with neuro- logical impairment. Am J Obstet Gynecol 2005;192:452-7.
40. McMichael G, MacLennan AH, Gibson G, et al. Cytomegalovirus and Epstein-Barr virus may be associated with some cases of cerebral palsy. J Matern Fetal Neonatal Med 2012;25: 2078-81.
41. Polivka BJ, Nickel JT, Wilkins JR. Urinary tract infection during pregnancy: a risk factor for cerebral palsy? J Obstet Gynecol Neonatal Nurs 1996;26:405-13.
42. Leach EL, Shevell M, Bowden K, Stockler- Ipsiroglu S, van Karnebeek C. Treatable inborn errors of metabolism presenting as cerebral palsy mimics: systematic literature review. Orphanet J Rare Dis 2014;9:197.
43. Schaefer GB. Genetics considerations in cerebral palsy. Pediatr Neurol 2008;15:21-6. 44. O’Callaghan ME, MacLennan AH, Gibson CS, et al. for the Australian Collaborative Cerebral Palsy Research Group. Fetal and maternal candidate SNP associations with ce- rebral palsy: a case-control study. Pediatrics 2012;129:414-23.
45. Stoknes M, Lien E, Andersen GL, et al. Child apolipoprotein E gene variants and risk of cere- bral palsy: estimation from case-parent triads. Eur J Paediatr Neurol 2015;19:286-91.
46. Rajab A, Yoo SY, Abdulgalil A, et al. An autosomal recessive form of spastic cerebral palsy (CP) with microcephaly and mental retar- dation. Am J Med Genet 2006;140:1504-10. 47. Lerer I, Sagi M, Meiner V, Cohen T, Zlotogora J, Abeliovich D. Deletion of the ANKRD15 gene at 9p24.3 causes parent- of-origin-dependent inheritance of familial cerebral palsy. Hum Mol Genet 2005;14: 3911-20.
48. Verkerk AJ, Schot R, Dumee B, et al. Mu- tation in the AP4M1 gene provides a model for neuroaxonal injury in cerebral palsy. Am J Hum Genet 2009;85:40-52.
49. Lynex CN, Carr IM, Leek JP, et al. Homo- zygosity for a missense mutation in the 67 kDa isoform of glutamate decarboxylase in a family
with autosomal recessive spastic cerebral palsy: parallels with stiff-person syndrome and other movement disorders. BMC Neurol 2004;4:20.
50. Hemminki K, Li X, Sundquist K, Sundquist J. High familial risks for cerebral palsy implicate partial heritable etiology. Paediatr Perinat Epi- demiol 2007;21:235-41.
51. McHale DP, Mitchell S, Bundey S, et al. A gene for autosomal recessive symmetrical spastic cerebral palsy maps to chromosome 2q24-25. Am J Hum Genet 1999;64:526-32. 52. Hirata H, Nanda I, van Riesen A, et al. Mu- tations of ZC4H2 are associated with intellectual disability and arthrogryposis multiplex congenita through impairment of central and peripheral synaptic plasticity. Am J Hum Genet 2013;93: 681-95.
53. McMichael G, Haan E, Gardner A, et al. NKX2e1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy. Eur J Med Genet 2013;56:506-9.
54. Petrovski S, Wang Q, Heinzen EL, Allen AS, Goldstein DB. Genic intolerance to functional variation and the interpretation of personal ge- nomes. PLoS Genet 2013;9:e1003709.
55. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of hu- man genetic variants. Nat Genet 2014;46: 310-5.
56. McMichael G, Girirajan S, Moreno-De- Luca A, et al. Rare copy number variation in cerebral palsy. Eur J Hum Genet 2013;22: 40-5.
57. Segel R, Ben-Pazi H, Zeligson S, et al. Copy number variations in cryptogenic cerebral palsy. Neurology 2015;84:1660-8.
58. Lawlor KT, O’Keefe LV, Samaraweera SE, et al. Double-stranded RNA is pathogenic in Drosophila models of expanded repeat neuro- degenerative diseases. Hum Mol Genet 2011;20:3757-68.
59. Manzini CM, Tambunan DE, Hill RS, et al. Exome sequencing and functional validation in zebrafish identify GTDC2 mutations as a cause of Walker-Warburg syndrome. Am J Hum Genet 2012;91:541-7.
60. Jacquemont S, Coe BP, Hersch M, et al. A higher mutational burden in females supports a “female protective model” in neurodevelop- mental disorders. Am J Hum Genet 2014;94: 415-25.
61. Shah PS, Ohlsson A, Perlman M. Hypo- thermia to treat neonatal hypoxic ischemic en- cephalopathy. Arch Pediatr Adolesc Med 2007;161:951-8.
62. O’Callaghan M, MacLennan AH. Cesarean delivery and cerebral palsy: a systematic review and meta-analysis. Obstet Gynecol 2013;122: 1169-75.
63. Phelan JP, Ahn MO, Jàuregui I, Phelan SL, Kim C. A timely cesarean decisioneincision time does not prevent fetal brain injury. Am J Obstet Gynecol 1999;180:S112.
64. Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D. Magnesium sulfate for
DECEMBER 2015 American Journal of Obstetrics & Gynecology 787
Expert Reviews Obstetrics
ajog.org
women at risk of preterm birth for neuro- protection of the fetus. Cochrane Database Syst Rev 2009;1:CD004661.
65. The definition and classification of cerebral palsy. Dev Med Child Neurol 2007;49:1-44. 66. Mirzaa GM, Millen KJ, Barkovich AJ, Dobyns WB, Paciorkowski AR. The
developmental brain disorders database (DBDB): a curated neurogenetics knowl- edge base with clinical and research ap- plications. Am J Med Genet A 2014;164A: 1503-11.
67. Maclennan AH. A “no-fault” cerebral palsy pension scheme would benefit all
Australians. Aust N Z J Obstet Gynaecol 2011;51:479-84.
68. Cerebral Palsy Alliance Research Institute. Australian Cerebral Palsy Register. Report 2013. Available at: https://www.cpregister.com/pubs/ pdf/ACPR-Report_Web_2013.pdf. Accessed June24,2015.
