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Cerebral palsy: causes, pathways, and the role of genetic variants

American Journal of Obstetrics and Gynecology, Volume 213, Issue 6, December 2015, Pages 779 - 788

Editor’s comment: Prof. YvesVille: Cerebral Palsy: the changing face of an old enemy
Cerebral palsy (CP) encompasses a heterogeneous group of early-onset, non-progressive, neuromotor disorders that affect the developing fetal or infant brain. CP has become our enemy but also our curse since Little linked this condition to birth asphyxia in the mid-19th century. Freud attributed the disorder to brain injury from various causes, including prenatal events, and emphasised that extended labour was not the exclusive or even principal cause, therefore increasing our responsibility not to say our feeling of guilt. Although our practice has been hugely influenced by this threat over the last 50 years, mainly through an increase in cesarean section rates. An update on the prevalence of cerebral palsy through a systematic review and meta-analysis gauging the prevalence of CP over time has shown that it has remained depressingly and frustratingly stable over the last 10 years at around 2 per 1,000 births. (Oskoui et al, 2013) The main illustration of this catch-22 situation in developed nations is largely explained by an increase in survival of very premature and low-birthweight babies together with higher numbers of multiple births, which often result in preterm births. This has therefore led to a new generation of people affected with CP, probably because of vulnerability of the immature brain, especially in babies with intraparenchymal or intraventricular bleeds or periventricular white-matter abnormalities. The increase in such high-risk situations may contribute to mask teh factors that may contribute to decrease the prevalence of CP, such as the use of antenatal corticosteroids, cooling for term-born asphyxiated infants, and the use of magnesium sulphate...

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 heterogeneous 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.

Key words: causes, cerebral palsy, DNA variants, epidemiological risk factors, genetic variants, genomics, heterogeneity, whole exome sequencing.

Footnotes

a Australian Collaborative Cerebral Palsy Research Group at the Robinson Research Institute, the University of Adelaide, Adelaide, Australia

b Department of Paediatric Neurology, Adelaide Women’s and Children’s Hospital, School of Pediatrics and Reproductive Health, the University of Adelaide, Adelaide, Australia

c Neurogenetics Research Program, School of Pediatrics and Reproductive Health, the University of Adelaide, Adelaide, Australia

Corresponding author: Alastair H. MacLennan, MD, FRANZCOG.

These studies have been supported by grants from the Australian National Health and Medical Research Council (1041920 and 1019928), Cerebral Palsy Foundation, Tenix Foundation, Women’s and Children’s Research Foundation, and Robinson Research Institute Foundation.

The authors report no conflict of interest.