Genetic Abnormalities May Cause Cerebral Palsy
For years it was thought that a difficult birth and other perinatal factors were the leading causes of cerebral palsy (CP), a group of disorders that can involve brain and nervous system functions such as movement, learning, hearing, seeing and thinking. Now, researchers at Geisinger Health System find that the majority of cerebral palsy causes may in fact be caused by genetic abnormalities.
Published in the The Lancet Neurology, Geisinger researchers find that CP - the most common physical disability of childhood - is probably caused by multiple genetic factors, similar to other neurodevelopmental disorders such as autism and intellectual disability. The paper suggests physicians should consider performing genetic testing when children present with CP and CP-like conditions.
“There is a widespread misconception that most cases of CP are caused by difficult delivery leading to birth asphyxia,” said Andres Moreno De Luca, M.D., research scientist at the Genomic Medicine Institute, Geisinger Health System, and lead author of the paper. “What we’re finding is a growing body of evidence that suggests mutations in multiple genes are responsible for CP. In fact, we suspect these genetic abnormalities may also be the cause of some difficult births to begin with.”
Despite substantial improvements in obstetric and neonatal care, the paper finds the worldwide prevalence of cerebral palsy has remained stable at 2 to 3 per 1,000 livebirths for more than 40 years. Inadequate oxygen supply to fetuses, known as birth asphyxia, remains the most studied factor associated with CP, though electronic fetal monitoring and other technologies have been developed to detect fetal distress.
“What we’re finding is even though more preventative efforts have been put in place, like fetal monitoring, the incidence of CP has not decreased,” said David Ledbetter, Ph.D., chief scientific officer, Geisinger Health System. “We’ve seen a five-fold increase in the rate of caesarean sections, which are done in part to avoid potentially difficult delivery, and again, the CP rates remain steady. These findings lead us to believe genetics play a much bigger role than previously thought.”
Genetic factors play a part in cerebral palsy both as part of a multi causal pathway and as a sole source of damage. In cultures where consanquinous marriage is common or in smaller isolated areas, genetic origins of cerebral palsy can surface.
“…the pathological effect of later factors can be dependent on the presence of earlier factors while not being a direct result of them. For example, Morton et al., (1991) reported a series of cases of cerebral palsy among the Amish of North America. These were neurologically damaged during an infection in infancy, but the pathological effect of the infection was dependent on their genetically inherited metabolic defect.” (Stanley et al., p 6-7)
Studies report that in families where cerebral palsy has occurred, the chances of it happening again are higher when compared with controls. When twins are involved, if one of the twins dies in utero or after birth, the chances that the second twin will contract CP increases whether they identical twins or not. Yet it has been estimated that if the twins are same sex, monochorionicity is a factor increasing the chance that both twins will suffer CP.
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Stanley, Fiona, Blair, Eve, Alberman, Eva. (2000) Cerebral Palsies: Epidemiology & Causal Pathways. Mac Keith Press
The paper also reports that even though most cases of CP are not caused by birth asphyxia and those that are can rarely be prevented by obstetric intervention, between 1999 and 2003 an estimated 76 percent of obstetricians in the U.S. faced medical malpractice litigation, most often for alleged birth mismanagement resulting in CP.
“We now know of six genes that can cause CP when disrupted, and we estimate that many other developmental brain genes probably contribute to the genetic heterogeneity of this disorder,” said Dr. Moreno De Luca. “Many capable obstetricians face legal action even though research is telling us genetics is the likely cause of most cases of CP.”
As the paradigm shift continues and more researchers, clinicians, and the general population start to consider the cerebral palsies as a group of neurogenetic disorders, the paper states we will probably witness an increase in research efforts, a change in the diagnostic approach, and eventually novel therapies for treating CP.
What are the causes of cerebral palsy?
Cerebral palsy usually is caused by factors that disrupt normal development of the brain before birth. In some cases, genetic defects may contribute to brain malformations and “miswiring” of nerve cell connections in the brain, resulting in cerebral palsy (2). Other cases are caused by injuries to the developing brain, such as a fetal stroke. Contrary to common belief, few cases of cerebral palsy are caused by a lack of oxygen reaching the fetus during labor and delivery (2).
A small number of babies develop brain injuries in the first months or years of life that can result in cerebral palsy (2). These injuries may be caused by brain infection (such as meningitis) and head injuries. In many cases, the cause of cerebral palsy in a child is not known.
Certain risk factors make it more likely that a baby will develop cerebral palsy. However, most babies with one of these risk factors do not develop cerebral palsy.
Risk factors for cerebral palsy include:
Prematurity: Premature babies (those born before 37 completed weeks of pregnancy) who weigh less than 3 1/3 pounds are between 20 and 80 times more likely to develop cerebral palsy than full-term babies (3). Many of these tiny babies suffer from bleeding in the brain, which can damage delicate brain tissue, or develop periventricular leukomalacia, destruction of nerves around the fluid-filled cavities (ventricles) in the brain.
Infections during pregnancy: Certain infections in the mother can cause brain damage and result in cerebral palsy. Examples of these infections include rubella, cytomegalovirus (usually mild viral infection), herpes (viral infections that can cause genital sores), and toxoplasmosis (a usually mild parasitic infection). Maternal infections involving the placental membranes (chorioamnionitis) may contribute to cerebral palsy in full-term as well as premature babies (2). A 2003 study at the University of California at San Francisco found that full-term babies were 4 times more likely to develop cerebral palsy if they were exposed to chorioamnionitis in the womb (4).
Insufficient oxygen reaching the fetus: This may occur when the placenta is not functioning properly or it tears away from the wall of the uterus before delivery.
Asphyxia during labor and delivery: Until recently, it was widely believed that asphyxia (lack of oxygen) during a difficult delivery was the cause of most cases of cerebral palsy. Studies now show that birth complications, including asphyxia, contribute to only 5 to 10 percent of cases of cerebral palsy (2).
Severe jaundice: Jaundice, a yellowing of the skin and whites of the eyes, is caused by the build-up of a pigment called bilirubin in the blood. Mild cases of jaundice usually clear up without treatment and do not harm the baby. However, jaundice can occasionally become severe. Affected babies have high levels of bilirubin in the blood. Without treatment, high bilirubin levels can pose a risk of permanent brain damage, resulting in athetoid cerebral palsy. Certain blood diseases, such as Rh disease, can cause severe jaundice and brain damage, resulting in cerebral palsy. Rh disease is an incompatibility between the blood of the mother and her fetus. It usually can be prevented by giving an Rh-negative woman an injection of a blood product called Rh immune globulin around the 28th week of pregnancy and again after the birth of an Rh-positive baby.
Blood clotting disorders (thrombophilias): These disorders in either mother or baby may increase the risk of cerebral palsy.
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March of Dimes Foundation
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References
Centers for Disease Control and Prevention (CDC). Cerebral Palsy. October 4, 2004, accessed September 14, 2007.
National Institute of Neurological Disorders and Stroke. Cerebral Palsy: Hope Through Research. NIH Publication Number 06-159, updated 7/13/07.
Platt, M., et al. Trends in Cerebral Palsy Among Infants of Very Low Birthweight (<1500 g) or Born Prematurely (<32 Weeks) in 16 European Centres: A Database Study. Lancet, volume 369, January 6, 2006, pages 43-50.
Wu, Y.W., et al. Chorioamnionitis and Cerebral Palsy in Term and Near-Term Infants. Journal of the American Medical Association, volume 290, number 20, November 26, 2003, pages 2677-2684.
About Geisinger Health System
Geisinger is an integrated health services organization widely recognized for its innovative use of the electronic health record, and the development and implementation of innovative care models including ProvenHealth Navigator, an advanced medical home model, and ProvenCare program. The system serves more than 2.6 million residents throughout 44 counties in central and northeastern Pennsylvania.
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Source: Geisinger Health System