Apolipoprotein E genotype and cerebral palsy

Cerebral palsy (CP) includes a group of nonprogressive disorders of movement and posture thought to result from adverse events during fetal or infant brain development, such as preterm birth, placental abruption, infection, or physical abuse. However, there has been increasing interest in the genetic aspects of CP, focusing not only on genes that are associated with hereditary spastic syndromes but also on those that might affect the intrauterine milieu, predispose to stroke, or alter the brain’s response to injury. One of the prominent candidates undergoing increasing study is Apolipoprotein E (ApoE), a gene with three alleles ( 2, 3, 4) that codes for lipid transport proteins that participate in neuronal maintenance and repair. Interest in the relationship between ApoE and CP was sparked by Kuroda et al.’s finding that the frequency of ApoE 4 was higher in children with CP (12 ⁄ 100) than in an age-sexrace-matched comparison group of unaffected children (4 ⁄ 100). They concluded that ApoE 4 is a risk factor for CP. One significant problem with this study, conducted in Chicago, USA, is that the frequency of ApoE 4 in the comparison group was far lower than that of other reports of ApoE in healthy children (12 ⁄ 100 to 32 ⁄ 100). Since ApoE allele frequencies are more dependent on specific geographic origins than on selfidentified racial group membership, matching based on race or ethnicity alone could result in misleading data, especially in a cosmopolitan city like Chicago whose citizens typically have very diverse family roots, regardless of what racial group they claim to belong to. It is possible, perhaps likely, that the comparison group, despite racial matching, had ancestors from world regions with low ApoE 4 frequencies rather than a lower risk of CP. In their study, Braga et al. report an increased prevalence of the 2 but not 4 among individuals with CP in Brazil. Similarly, McMichael et al. found no association between ApoE 4 and cerebral risk in a large population-based sample in southern Australia. Each of these studies lessened the risk of spurious results due to ethnic diversity by utilizing more homogenous samples, especially in Australia, and refuted the implication that ApoE 4 is a risk factor for CP. It seems more likely that ApoE is involved in modifying the brain’s response to injury, rather than affecting risk of injury itself. In contrast to adults, among whom ApoE is a risk factor for Alzheimer disease and worse outcome after traumatic brain injury and other neurological disorders, there is growing evidence that ApoE 4 may be protective in the developing brain. ApoE 4 has been shown to favor embryonic development and fetal survival, preserve brain development after chronic diarrhea and malnutrition, and lessen the severity of perinatal brain injury. Conversely, the 2 allele, protective against Alzheimer disease, appears detrimental to fetal well-being and to developmental outcomes for infants undergoing surgery for congenital heart disease. Is ApoE simply the CP gene of interest du jour? Does it hold promise beyond a theoretical understanding of factors that explain differences in outcome as a possible therapy? While much of the attention regarding the therapeutic potential of a modified ApoE molecule is focused on Alzheimer and cardiovascular disease, the possibility exists for its use in prevention or amelioration of CP. The relationship between the various polymorphisms of ApoE and CP should be explored further, with the expectation that the role of its various alleles in children, particularly during rapid brain development, may be opposite from that in adults. If an ApoE treatment proves successful in adults, it could be tragic to assume the same form of treatment would be beneficial for newborn infants.