Apolipoprotein E and Cerebral Palsy: A Cross-sectional Study of the Influence of Genetic Variation on Clinical Manifestations of CP
Abstract
Cerebral palsy (CP) is the most common neurodevelopmental disorder in children, showing
varying degrees of motor impairments, activity limitations and accompanying disturbances of
function. A long-held belief has been that the cause of CP is birth asphyxia. However, the
realization that only a small minority of CP cases can be attributed to a perinatal hypoxicischemic
event has led to an extensive search for other causes, among them genetic factors.
Although a number of genes have been investigated as possible causes of CP, the results have
been inconclusive.
The APOE gene and its protein product, apolipoprotein E (apoE), have received much
attention. apoE is the most important transporter of cholesterol and lipids in the brain,
substances that are essential for myelination, cell membrane and synapse formation.
Furthermore, apoE has also been shown to have a number of regulatory functions of
importance for normal brain development and function. The gene exists in three variants,
APOEε2, APOEε3 and APOEε4, encoding three corresponding protein isoforms, apoE2,
apoE3 and apoE4, which differ at only one or two positions in the amino acid sequence.
Because of differing internal chemical bonds, these small differences will result in
fundamental changes in the three-dimensional structure of the proteins, with subsequent
differences in receptor affinity and lipid and cholesterol binding capacity.
apoE4 has been identified as a risk factor for Alzheimer’s disease and poorer outcome
after traumatic brain injuries compared to apoE2 and apoE3, making APOE interesting as a
candidate for genetic influence in the development of CP. Several reports have, however,
suggested that apoE4 may show properties of “antagonistic pleiotropy” i.e. having protective
properties in a developing brain, but being detrimental in older people.
The aim of the research for this thesis was to study whether the APOE alleles
differentially influenced the severity of CP, assessed by gross and fine motor function,
presence of epilepsy and eating and feeding abilities making gastrostomy tube feeding
necessary. In accordance with the concept of antagonistic pleiotropy, the hypothesis was that
carriers of APOEε4 would have the least severe CP. A further aim of the thesis was to
determine whether the severity of CP would be influenced by genetic variation in six gene
transcription enhancers regulating the expression of APOE and consequently the level of apoE
protein in cerebrospinal fluid. Finally, based on the hypothesis that different allele
combinations would give varying degrees of CP severity, the combinations of APOE alleles and genetic variation in a specific transcription enhancer (rs59007384 (TOMM40B)) were
studied with regard to cerebral palsy severity.
Children registered in the Cerebral Palsy Register of Norway (CPRN) were invited to
participate and 281 families returned swabs with buccal cells for genotyping of APOE and six
transcription regulators. The results of the genetic analyses were correlated with clinical data
held in the CPRN.
There were no associations between the genetic variations studied and gross motor
function. Carriers of APOEε4 were more likely to have epilepsy, more likely to have poor
fine motor function (children with unilateral CP) and more likely to need a gastrostomy
feeding tube for adequate nutrition. Presence of a specific allele (a T-allele) in the
transcription enhancer TOMM40B increased the risk of fine motor impairment and epilepsy.
Compared to carriers of other allele combinations, carriers of no T-allele in TOMM40B and
no APOEε4 allele were found to have a favorable outcome regarding fine motor function,
epilepsy and gastrostomy tube feeding. No dose-response variation was found for other allele
combinations.
The findings did not support our main hypothesis of a protective developmental effect
of APOEε4. On the contrary, carrying APOEε4 seemed to increase the risk of more severe
CP. Thus, not only the structure of the apoE proteins, but also the amount in cerebrospinal
fluid seemed to influence the severity of CP. Our hypothesis of expected variations in CP
severity with different allele combinations was partly supported. Based on the demonstrated
association of clinical manifestations of CP with specific genetic variations and allele
combinations, the studies in this thesis support the concept of genetic influence on the
severity of cerebral palsy.