Published online February 1, 2007
PEDIATRICS Vol. 119 No. 2 February 2007, pp. 306-313 (doi:10.1542/peds.2006-1083)
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ARTICLE

Association of Apolipoprotein E Genotype and Cerebral Palsy in Children

Maxine M. Kuroda, PhD, MPHa, Mary E. Weck, PTb, John F. Sarwark, MDc, Aaliyah Hamidullah, BSca and Mark S. Wainwright, MD, PhDa,d,e

a Department of Pediatrics, Division of Neurology
b Department of Physical Therapy, Division of Rehabilitative Services
c Department of Orthopedic Surgery
d Department of Molecular Pharmacology and Biological Chemistry
e Center for Drug Discovery and Chemical Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVES. We tested the hypotheses that apolipoprotein E genotype, in particular carriage of the {varepsilon}4 allele, is more likely to be associated with cerebral palsy and that children with more severe neurologic impairment are more likely to carry this allele.

METHODS. In this cross-sectional study, 209 children with cerebral palsy were matched with healthy control subjects according to gender and race. Diagnosis of cerebral palsy was confirmed through physician consultation, medical chart review, and parent interview. Apolipoprotein E genotyping was performed with DNA obtained with buccal swabs. Severity of motor impairment was rated by physical therapists, and occipitofrontal circumference was measured.

RESULTS. Compared with gender- and race-matched control subjects, overall risk for cerebral palsy was elevated 3.4-fold among children carrying an {varepsilon}4 allele and was particularly elevated for children with quadriplegia/triplegia. This finding was independent of birth weight. Carriage of the {varepsilon}4 allele was also associated with increased severity of cerebral palsy and with a trend toward increased likelihood for microcephaly. Moreover, children carrying an {varepsilon}2 allele were at greater risk for cerebral palsy.

CONCLUSIONS. These data implicate the apolipoprotein E {varepsilon}4 and {varepsilon}2 genotypes as susceptibility factors in determining neurologic outcomes after perinatal brain injury. Additional studies are warranted to establish the role of apolipoprotein E in specific pathogenetic pathways leading to cerebral palsy or poor neurologic outcomes after perinatal brain injury.

Key Words: cerebral palsy • apolipoprotein E • genotype

Abbreviations: CP—cerebral palsy • apoE—apolipoprotein E • AD—Alzheimer disease • OFC—occipitofrontal circumference • OR—odds ratio • CI—confidence interval

Cerebral palsy (CP) affects 2 of every 1000 school-aged children in the United States,1,2 has an annual economic toll on society estimated at $5 billion, and is the most costly of the clinically significant birth defects in the United States.3 The diagnosis of CP encompasses a heterogeneous group of disorders characterized by nonprogressive impairment of motor function resulting from injury to the developing brain.4 CP is often associated with impaired intellectual function, sensory deficits, behavioral disorders, and seizures. In the majority of cases, a specific cause is not identified; the diagnosis does not imply a particular prognosis.5 The mechanisms leading to CP are not known, but a number of lines of evidence implicate intrauterine infection or central nervous system inflammation.6 The combination of delays in diagnosis and diversity of pathophysiologic features limits our ability to identify infants at risk for developing CP and thus to improve strategies for treatment.7

Genetic factors may determine the severity of injury, capacity for recovery, and outcome after neurologic injury.8 Since the initial report identifying apolipoprotein E (apoE) as a susceptibility factor for the development of Alzheimer disease (AD),9 APOE genotype is now recognized as a major determinant of neurologic outcomes in acute and chronic brain injuries in adults.10 ApoE is a lipid transport protein that is expressed widely in the central nervous system. The protein has 3 isoforms, E2, E3, and E4, encoded by the alleles {varepsilon}2, {varepsilon}3, and {varepsilon}4, respectively, on the long arm of chromosome 19. Individuals with ≥1 copy of the {varepsilon}4 allele are at increased risk for developing late-onset familial AD, as well as sporadic nonfamilial AD.11 The {varepsilon}4 allele is the best-validated gene in other neurologic disorders, related to genetic susceptibility to ischemic stroke,12 risk of neurologic impairment associated with traumatic brain injury,13 and aging.14 However, the role of apoE in the pathogenesis of CP is unknown.

We conducted a cross-sectional study of pediatric patients to determine whether APOE genotypes are associated with CP. We tested the hypotheses that APOE genotype, in particular carriage of the {varepsilon}4 allele, is more likely to be associated with CP and that children with CP with more-severe neurologic impairment are more likely to carry this allele. To our knowledge, this is the first study of these associations in a US pediatric population.


   METHODS
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 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patient Selection
Consecutive patients who were diagnosed by their referring physicians as having congenital spastic CP and were monitored by the orthopedic clinic or the department of physical therapy at Children's Memorial Hospital were eligible for inclusion. CP was defined as a history of chronic motor spasticity with nonprogressive injury after insult to the fetal or neonatal brain.4 The diagnosis was confirmed by physician consultation, interview with the parents, and review of the medical charts. Purely choreoathetotic and ataxic forms of CP without spasticity were excluded because of the rarity of these subtypes, to maintain a rigorously defined phenotype. Patients with postneonatally (>28 days of life) acquired static motor impairment were excluded. Control patients were recruited from continuity clinics, where most were seen for well-child checkups and immunizations. Control patients seen for any neurologic condition (central nervous system infection, developmental delay, seizure disorder, attention-deficit/hyperactivity disorder, or migraine headache) or predefined medical conditions (juvenile diabetes mellitus or growth retardation) were not eligible for the study. Subjects were recruited between November 2003 and July 2005. The study was approved by the local institutional review board, and all subjects and parents gave written assent or consent, respectively.

Four children with CP and 5 eligible control subjects or their parents refused to participate. Among the 239 patients referred with a diagnosis of CP, 30 (13%) subsequently were found to be ineligible. Four had acquired CP postneonatally (eg, fall down stairs or automobile accident) and 26 had motor deficits attributable to genetic syndromes with spastic features, including DiGeorge syndrome 22q deletion and Osler-Weber-Rendu syndrome (n = 6); gait and bone abnormalities not classifiable as CP, including cavovarus foot deformity and equines deformity (n = 8); other brain abnormalities, including Dandy-Walker cyst and tumor (n = 10); and congenital cytomegalovirus infection (n = 2). Fifty-three control subjects (25%) were seen for conditions other than well-child visits, including acute infections (n = 28), asthma/allergies (n = 15), injuries (n = 5), nonspecific pain (n = 4), and obesity (n = 1).

Demographic Data
Gender, race, date of birth, birth weight, and gestational age were recorded. The variable of race was obtained through parental interview, by asking, "With which group does your child most closely identify?" Categories included white, black, Hispanic, American Indian, Asian, East Indian, other (including mixed races), and unknown (eg, father unknown or adoptive parent not certain of child's birth parents' race).

Assignment of CP Severity
Attending physicians and physical therapists indicated the subtype of CP (quadriplegia/triplegia, diplegia, or hemiplegia). Ratings of severity were described separately according to subtype of CP. To assess the severity of impairment, a rating form that describes levels of severity for the 3 major spastic subtypes of CP was developed by the physical therapists (Table 1). Before initiation of the study, 19 patients with CP (7 with quadriplegia/triplegia, 8 with diplegia, and 4 with hemiplegia) were selected randomly. For each patient, the 2 physical therapists who worked most closely with the patient independently rated the subtype and severity of CP. The pairs agreed for all except one patient. For that individual, severity was rated as mild but was questioned by one of the therapists. Therefore, {kappa} was not calculable, but there was agreement on 95% of the forms.


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  		TABLE 1 Levels of Severity of CP According to Subtype

 
Occipitofrontal circumference (OFC), an effective marker of brain growth, development, and intelligence,15 was measured by one of the investigators (Dr Kuroda). The investigator and therapists were blinded with respect to the severity scores and OFC measurements, respectively. OFC measurements were plotted by using the charts for male and female subjects published by Nellhaus.16 These charts cover the entire pediatric age range (through 18 years of age). Therefore, OFC measurements normalized with respect to gender and age were available for data analysis. To determine the nature and frequency of coexisting conditions in the CP cohort, the charts of these patients were reviewed and the clinical data were summarized according to impairment related to the central nervous system (epilepsy, cognition, vision, speech, or hearing) or not related to the central nervous system.

Determination of APOE Genotype
DNA was obtained with buccal swabs (Swube swab; Becton Dickinson, Franklin Lakes, NJ) and extracted with commercially available reagents (Puregene DNA purification kit; Puregene, Minneapolis, MN). Genomic DNA was amplified through polymerase chain reaction with published primers (5'-ACAGAATTCGCCCCGGCCTGGTAC-3' and 5'-TAAGCTTGGCACGGCTGTCCAAGGA-3'), following the amplification protocol for APOE genotyping.17 Each autoradiograph was then analyzed by 2 blinded observers. In cases of discrepancy between observers, genotyping was repeated. Results of the APOE genotyping were not available to the investigators until all demographic, clinical, and parent-reported data were obtained and entered into a secured computer spreadsheet.

Statistical Analyses
Control subjects were matched to the case subjects with respect to gender and race. For descriptive purposes, continuous variables are reported as mean ± SD and discrete variables as number and percentage. The principal ethnic groups studied were white, black, and Hispanic. Because there were too few subjects in the remaining categories, they were considered as a combined group.

Differences between case and control subjects in continuous variables (birth weight and gestational age) were tested with paired t tests because of the matched design of this study. Differences between case and control subjects in carriage of the {varepsilon}4 and {varepsilon}2 alleles were tested with McNemar's {chi}2 test, with Yates' continuity correction.18 Inferential analyses for carriage of the {varepsilon}4 allele did not include subjects carrying the {varepsilon}2 allele, because the latter might have some neuroprotective effects that could offset the effects of the {varepsilon}4 allele.19,20 Specifically, a case-control pair was excluded if either the case subject or the control subject carried an {varepsilon}2 allele. Similarly, subjects carrying the {varepsilon}4 allele were excluded from inferential analyses of the {varepsilon}2 allele. Risks (odds ratios [ORs]) for the matched data and 95% confidence intervals (CIs) were determined with the methods detailed by Fleiss.18

For children with CP, associations of the {varepsilon}4 allele with severity of motor impairment were tested with the {chi}2 test for trend, with Yates' continuity correction. The test was conducted if the subtype of CP had sufficient numbers in the 3 levels of severity. For children with CP, an OFC measurement 2 SDs below the mean for gender and age was considered microcephalic.16 Association of the {varepsilon}4 allele with OFC (dichotomized as microcephalic or normocephalic) was tested with the {chi}2 test or Fisher's exact test, as appropriate.

Sampling of children with CP was based on attendance in the division of rehabilitative services, with an initial goal of enrolling ~225 to ~250 children with CP and matched control subjects. This allowed for exclusion of subjects as described above and would result in a minimal sample size of 200 case and control subjects. A power analysis used a stringent type I error probability (P = .001), to permit additional comparisons according to severity of CP and OFC measurements, and a 25% probability of carriage of the {varepsilon}4 allele among control subjects (in the middle of the range of population distributions reported for this allele).21 This study had a power of 90% to detect a twofold risk for CP with carriage of the {varepsilon}4 allele.

Statistical analyses were performed with SPSS 11.0.1 (SPSS Inc, Chicago, IL). Differences were considered statistically significant at P < .05.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
The final study sample consisted of 209 children with CP and 209 matched control subjects (Table 2). As found in most studies of CP, the majority (62%) of case subjects were male. The racial distribution among case subjects (white, 46%; black, 20%; Hispanic, 28%; other races, 6%) was similar to that of the general population of the Chicago area for Hispanic (26%) and other races (7%). However, there were more white subjects than black subjects in the current study sample than in the general Chicago-area population, in which 31% are white and 36% are black.22 Most children (96%) diagnosed as having CP were >3 years of age. Birth weight was significantly lower among children with CP (2.0 ± 1.1 kg) than among control subjects (3.4 ± 0.6 kg; P < .001), as was gestational age (32.8 ± 6.3 weeks and 39.7 ± 1.6 weeks, respectively; P < .001).


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  		TABLE 2 Demographic and Clinical Characteristics of Children With CP and Gender- and Race-Matched Control Subjects

 
A significant percentage (49%) of the children with CP also had, or were evaluated for, another condition (Table 3). The most common neurologic conditions were seizures (27%) and vision problems (23%). In the CP group, only 10% had a gastrostomy tube placed.


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  		TABLE 3 Coconditions Among Children With CP

 
Twenty-five children with CP (12%) had ≥1 {varepsilon}4 allele, compared with 9 children (4%) in the control group (Table 4). The majority of case subjects (82%) and control subjects (95%) carried the {varepsilon}3{varepsilon}3 genotype. There was variation among the 4 racial groups. Carriage of the {varepsilon}3{varepsilon}3 genotype was lower among white case subjects than control subjects (79% and 98%, respectively) and lower among black case subjects than control subjects (74% and 91%, respectively). Carriage of the {varepsilon}3{varepsilon}3 genotype was similar among Hispanic children (90% and 93%) and children of other races (92% and 100%). None of the subjects in this study (either case or control subjects) had the APOE {varepsilon}2{varepsilon}2 or {varepsilon}2{varepsilon}4 genotype.


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  		TABLE 4 Distribution of APOE Genotypes Among Children With CP and Matched Control Subjects

 
Overall, carriage of an {varepsilon}4 allele was associated with more than threefold elevated risk (Table 5) for CP, compared with matched control subjects (OR: 3.4; 95% CI: 1.4–8.7). This risk was higher for children with quadriplegia/triplegia (OR: 5.5; 95% CI: 1.2–35.9) but not for children with diplegia or hemiplegia. Within the entire study group (n = 418), 7 had the rare {varepsilon}4{varepsilon}4 genotype (5 case subjects and 2 control subjects). Compared with the control group, APOE genotype distribution in the CP cohort was not in Hardy-Weinberg equilibrium.23


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  		TABLE 5 APOE Genotype According to Subtype of CP and Comparison with Matched Control Subjects

 
To determine whether birth weight contributed to elevated risk in carriers of the {varepsilon}4 allele, a subanalysis was restricted to children with CP who were born at normal birth weight (n = 69; 33% of all case subjects) and their matched control subjects (also born at normal birth weight). Risk for CP was higher for case subjects who were born at normal birth weight and carried the {varepsilon}4 allele (McNemar's OR: 3.3; 95% CI: 0.9–15.2), but results fell slightly short of statistical significance (P = .09, McNemar's {chi}2 test).

Carriage of an {varepsilon}2 allele was associated with a 12-fold elevated risk for CP (95% CI: 1.6–247.2). Thirteen children (6%) with CP had ≥1 {varepsilon}2 allele, compared with a single child (0.5%) in the control group (Table 5). Nine of the 13 case subjects with an {varepsilon}2 allele had diplegia, but no control subjects with an {varepsilon}2 allele were available to quantify risk for this subtype (Table 5). Among children born at normal birth weight, 5 case subjects and 1 control subject carried an {varepsilon}2 allele (McNemar's OR: 5.0; 95% CI: 0.6–113.1).

Among children with quadriplegia/triplegia, carriage of the {varepsilon}4 allele increased risk for more-severe motor impairment. Within the sample of case subjects who received their physical therapy services at our facility (n = 141), distribution of the {varepsilon}4 allele could be examined only among the patients with quadriplegia/triplegia (n = 58). In this subgroup, 8 children carried the {varepsilon}4 allele, and the frequency of the {varepsilon}4 allele increased with the severity of motor impairment (P = .007, {chi}2 test for trend). Of 64 children with diplegia, 7 carried the {varepsilon}4 allele, and all 7 were rated as having mild diplegia. Similarly, among 19 children with hemiplegia, only 2 carried the {varepsilon}4 allele (1 with mild hemiplegia and 1 with moderate hemiplegia).

OFC was measured as a surrogate assessment of intelligence and neurologic development. No control subjects were microcephalic. However, 40 (21%) of the 188 children with CP for whom OFC measurements were available were microcephalic. In that group, 8 (20%) carried the {varepsilon}4 allele. Among the 148 normocephalic children with CP, 16 (11%) carried the allele. Carriage of an {varepsilon}4 allele and associated microcephaly missed statistical significance but suggested a possible association (P = .10, Fisher's exact test).

More children with CP had quadriplegia/triplegia (41%) or diplegia (41%), compared with hemiplegia (18%) (Table 5). However, the proportion of children carrying the {varepsilon}4 allele did not differ among those with quadriplegia/triplegia (n = 12; 14%), diplegia (n = 10; 12%), or hemiplegia (n = 3; 8%). This suggests that, although statistical significance was obtained only for children with quadriplegia/triplegia in this study, risk from carriage of the {varepsilon}4 allele may apply to the other spastic subtypes as well. The proportion of children carrying the {varepsilon}2 allele was higher only for children with diplegia, which suggests that the {varepsilon}2 allele may confer higher risk for diplegia than for the other subtypes.

There was a significant association between the subtype of CP and the presence of comorbid conditions. More children with quadriplegia/triplegia (41%) had a seizure disorder, compared with children with hemiplegia (34%) or diplegia (9%) (P < .001, {chi}2 test). However, among the 35 children with quadriplegia/triplegia and seizure disorder, only 3 (9%) carried the {varepsilon}4 allele (P = .18, Fisher's exact test). Cognitive deficits were also more frequent among children with quadriplegia/triplegia (14%), compared with children with diplegia (12%) or hemiplegia (5%). Visual deficit rates were higher for children with quadriplegia/triplegia or hemiplegia (each 26%), compared with children with diplegia (17%). Thus, carriage of the {varepsilon}4 or {varepsilon}2 allele was not associated with the presence of seizures, cognitive, or visual deficits.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
Carriage of the APOE {varepsilon}4 or {varepsilon}2 allele is associated with increased risk for CP significantly, compared with gender- and race-matched control subjects. More children with CP, particularly those with the quadriplegia/triplegia subtype, carried the {varepsilon}4 allele. In children with quadriplegia/triplegia, severity of motor impairment was associated significantly with carriage of the {varepsilon}4 allele. Similarly, among all children with CP, there was a trend toward increased risk for microcephaly for those carrying the {varepsilon}4 allele. This finding implies that carriage of the {varepsilon}4 allele may predict cognitive development15 in children with CP, but this issue requires additional study. Carriage of the {varepsilon}2 allele also seems to increase risk for CP but may affect only the diplegia subtype. Moreover, this association must be interpreted with caution, given the rarity of the {varepsilon}2 allele, which is carried by as little as 0.4% of the population.21 Taken together, these data implicate the APOE {varepsilon}4 and {varepsilon}2 genotypes as susceptibility factors in modulating neurologic outcomes after perinatal brain injury. It should be noted that only 18% of the CP cohort carried either the {varepsilon}2 or {varepsilon}4 allele. Other genetic susceptibility factors in the larger population of children with CP remain to be identified.

To our knowledge, the only other study of APOE genotypes and CP published to date was a case-control study from Brazil that matched subjects solely on the basis of gender and reported a fourfold risk for CP for individuals with the {varepsilon}4 allele. Ages were not reported, and the study might have included few children. The limited sample size (40 case subjects and 40 control subjects) precluded analyses according to subtype and severity of CP.24 Nonetheless, our findings extend those of the previous study, and the {varepsilon}4 allele carriage rate in our study is comparable to {varepsilon}4 allele carriage rates reported in studies of children, which ranged from 4%25 to 17%.26

The prevalence rates of seizures and visual disorders in the current study closely approximate the median percentages of these impairments in population-based studies of CP (25% and 21%, respectively).27,28 Compared with population-based data,28 the percentages of children with speech and hearing disturbances were lower in our cohort. This difference may reflect the greater convenience for families to seek treatment for these disorders in their own neighborhoods. The prevalence of mental retardation in our study is lower than that reported in population-based studies (range: 31%–75%).29

The association of quadriplegia/triplegia both with APOE genotype and with seizures, cognitive problems, and vision problems could be taken to indicate a similar association of carriage of the {varepsilon}4 or {varepsilon}2 allele with these comorbid conditions in children with CP. The lack of any statistically significant association between carriage of either the {varepsilon}4 or {varepsilon}2 allele and these coconditions in the present study does not rule out an effect of APOE genotype. The sample size in this study was not powered to test this hypothesis, which merits investigation in a larger study.

The pathogenesis of CP in term infants is multifactorial,1,2,5 but a number of lines of evidence implicate inflammatory pathways.6,30–32 ApoE is produced in the brain,33 where it serves to protect against injury through multiple mechanisms.10,25 This function is isoform specific, and the E4 isoform is less effective than E2 or E3 in attenuating the inflammatory response to brain injury.34,35 The increased risk for CP in carriers of the {varepsilon}4 allele is consistent with a model in which a prenatal or perinatal insult results in a central nervous system inflammatory response that may attenuate injury initially but is not regulated effectively by the E4 protein.

APOE genotype may also be linked to vascular mechanisms of cerebral injury leading to CP. Meta-analyses12 and neuroradiologic studies36 suggested increased susceptibility to ischemic stroke in carriers of the {varepsilon}4 allele. Carriage of the {varepsilon}4 allele may also affect outcomes after hemorrhagic stroke.37 These associations may require confirmation in larger studies.38

Other mechanisms may contribute to the increased neurologic injury in carriers of the {varepsilon}4 allele. A population-based, case-control study found increased risk for CP after perinatal exposure to neurotrophic viruses, including varicella and human herpesvirus 6 or 7.39 Interestingly, transgenic mice carrying the human {varepsilon}4 allele showed increased herpes simplex 1 virus central nervous system invasion, compared with {varepsilon}3-transgenic mice.40 The implications of these findings for treatment of CP remain to be determined, but the results are consistent with a role for apoE in regulation of the blood-brain barrier,41 potentially allowing access of neurotrophic viruses to the developing brain.

The contribution of APOE genotype to susceptibility to neurologic injury may vary with age42 and the nature of the insult.26,43 The {varepsilon}4 allele may modulate the chronic progression of injury and therefore have a more pronounced effect on outcomes for pediatric patients.42 Indeed, carriage of the {varepsilon}4 allele is associated with improved outcomes for children with malnutrition44 or traumatic brain injury45 but not intraventricular hemorrhage.46 Differences in the mechanisms of initial insults may account for variations in the role of the APOE genotype, particularly with our finding of increased risk for CP associated with the {varepsilon}4 allele.26,43

Low birth weight is a known risk factor for CP, but there is no evidence that APOE polymorphism is itself associated with low birth weight. In our study, birth weight was significantly lower for children with CP, compared with control subjects, but children with CP born at normal birth weight also carried the {varepsilon}4 allele more frequently. Therefore, low birth weight is unlikely to be a confounder of the association of APOE genotype and CP. Furthermore, if the {varepsilon}4 allele is associated with greater neurologic injury, then earlier demise of severely affected infants would strengthen the findings of our study, because such infants would not have been included in our study population.

The increased risk for CP in carriers of the rare {varepsilon}2 allele implicates additional mechanisms in the pathogenesis of CP. For instance, others have reported increased risk for neurologic injury, including dementia in Parkinson's disease43 and recurrent lobar hemorrhage,47 with this genotype in adults. However, the mechanisms leading to these associations for CP are not known and are likely to differ from those proposed for the {varepsilon}4 allele.

This study has a number of limitations. First, this was not a population-based study and therefore did not seek to ascertain all children with CP within the Chicago area or Midwest. Second, case subjects were recruited from among children with CP who were referred for orthopedic evaluation or physical therapy. These issues were addressed by confirming the diagnosis of CP and by using a matched design. Indeed, the low refusal rate suggests that there was no selective enrollment of subjects, which diminishes a potential source of bias. Last, the severity of CP was not assessed with a published scale. However, there is no generally accepted, standardized system that classifies severity of motor disability in CP, and the popular gross motor function classification system does not rate severity of hemiplegia adequately nor has it been validated for ages above 12 years.48 The scale we used is familiar to therapists at our institution and shows excellent agreement among the therapists.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
Risk and severity of CP were elevated in children carrying either the {varepsilon}4 or {varepsilon}2 allele. These data implicate apoE and thereby neuroinflammatory processes in the pathogenesis of CP. Additional epidemiologic studies are needed in other populations to confirm these associations and to evaluate the role of apoE in specific pathogenetic pathways for development of CP after perinatal brain injury.


   ACKNOWLEDGMENTS
 
This work was supported by the Children's Memorial Research Center Seed Grant Program and the United Cerebral Palsy Research and Educational Foundation (grant R-755-03).

We are indebted to the children and their families and the physicians, physical therapists, and gait analysts in the Department of Physical Therapy, Division of Rehabilitative Services, Children's Memorial Hospital. Nurses and physicians in the Children's Memorial Hospital network contributed control subjects for the study.


   FOOTNOTES
 
Accepted Sep 28, 2006.

Address correspondence to Mark S. Wainwright, MD, PhD, Division of Neurology, No. 51, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614. E-mail: m-wainwright{at}northwestern.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 REFERENCES
 

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