Participation in Contact or Collision Sports in Athletes With Epilepsy, Genetic Risk Factors, Structural Brain Lesions, or History of Craniotomy

Vincent J. Miele, M.D.; Julian E. Bailes, M.D.; Neil A. Martin, M.D.

Disclosures

Neurosurg Focus. 2006;21(4) 

In This Article

Genetic Risk Factors

With the completion of the human genome map, our understanding of the influence of molecular biology on an athlete's ability and susceptibility to injury is expanding. More than 900 genetic tests are available (Appendix); many could have applications in athletes. The best-known susceptibility gene for head injury is APOE*E4.

Apolipoprotein E is important for lipoprotein transport and cholesterol homeostasis by its promotion of the recognition and catabolism of APOE-containing lipoproteins (for example, β–very-low-density lipoprotein, very-low-density lipoprotein, intermediate-density lipoprotein, and high-density lipoprotein) by the low-density lipoprotein receptors, the E/α2M receptor LRP1, gp330/megalin, and the very-low-density lipoprotein receptor. It is synthesized predominantly by astrocytes and microglia and thus is highly expressed in the brain. The APOE gene, located on chromosome 19, occurs in three common allelic forms, APOE*E2, *E3, and *E4.[44] In several studies the APOE*E4 allele has been linked to poor outcomes following TBI.[18,23,32,39,43,48,70,75]

Attention was first focused on this gene when it was linked to late-onset familial and sporadic Alzheimer disease.[21,67] The neuropathological similarities between chronic TBI and Alzheimer disease led to the discovery of the possible link between sports-related brain injury and APOE*E4.[22,24,64,76,79] Chronic TBI is a worrisome complication of contact or collision sports during which the participant sustains repetitive blows of variable force to the head. In 1997, a study performed in 30 boxers revealed that those with the APOE*E4 gene and high exposure to the sport were at an increased risk of neurological dysfunction compared with those without the gene. In this study it was also found that all of the boxers in whom severe neurological impairment developed possessed the APOE*E4 allele.[39] The association between this gene and a higher risk of chronic TBI was strengthened by a second study performed in 1997 in a nonboxing population of patients who had suffered a neurotrauma.[75]

The pathophysiological mechanism for this association may be that β-amyloid is deposited in the brain to a greater extent after head trauma in individuals with the *E4 allele.[35,56,65] The allele may also affect the efficiency of neuronal repair, which is suggested by the poorer outgrowth of neurites observed in cell cultures containing APOE*E4[60] after traumatic injury, which could lead to the accumulation of residual tissue damage after repeated episodes of trauma.[40] The presence of APOE*E4-related alterations in the neuronal cytoskeleton, increased susceptibility to reactive oxygen species in association with APOE*E4, and altered intracerebral cholesterol trafficking are other mechanisms proposed to be the cause of increased susceptibility to chronic TBI in the athlete with the APOE*E4 gene.[44]

The link between APOE*E4 and chronic TBI is not universally accepted. Most studies relating to mild TBI in sports have included a relatively small population of patients, and this has been a major criticism. In addition, investigators have relied on brief cognitive assessments or coarse measures of global functioning, thereby limiting their conclusions. In other prospective studies on the role of the APOE*E4 allele in mild to moderate brain injury in which a more detailed evaluation of neuropsychiatric outcome was performed, no association was found between the presence of the APOE*E4 allele and poor outcome across all measures.[17]

The relationship between this gene and an increased risk of chronic TBI has major implications. Should all athletes in contact or collision sports be tested for APOE*E4 as a part of a preparticipation physical; and should those with positive results be banned from participation? The genetic profile of an athlete could be useful in determining if the participant is predisposed to a particular injury. If this information is known before participation, the athlete could be properly counseled concerning his or her risks, given special techniques and equipment to minimize risk, and offered alternative sporting activities. On the other hand, several social concerns exist with regard to DNA-based testing. When testing is performed, who should be allowed to have access to the acquired information? Should sports regulatory agencies have access to information on an individual's APOE*E4 status before granting a boxing license? If an individual is discovered to carry a less than desirable gene for a specific sport, how would it affect his or her ability to participate psychologically, and will this information create a new form of discrimination? Should parents, coaches, and even sports agents be allowed to request genetic testing on minors and/or clients? If genes and gene therapies are allowed to be patented, will this limit accessibility and create unfair advantages between athletes?

The time may come when biotechnology firms buy the rights to sports stars' genetic codes. If the prescreening of fetuses occurs, how can selective terminations of pregnancies be prevented if less-than-ideal genetic markers are discovered by parents and/or governments seeking high-performance athletes? Will managers and agents be allowed to see an athlete's genetic profile before they sign an athlete to a contract or agree to train him or her? These profiles could potentially be used to weed out athletes who are predisposed to injury or who have a limited ability to perform. The Americans with Disabilities Act, which was signed into law in 1990, made it illegal to discriminate against disabled workers. The Federal Equal Employment Opportunity Commission has ruled that this act also protects people from discrimination on the basis of their genetic profile.

Because the connection between the APOE*E4 gene and sports-related head injury is still not decided, discussion of these ethical and legal issues seems somewhat premature. Nevertheless, although these quandaries seem distant, the current rate of growth in the field of genetics demands that these ethical and legal issues be evaluated now. To address these concerns, the National Center for Human Genome Research, the National Institutes of Health, and the Human Genome Program of the Department of Energy have established the Joint Working Group on Ethical, Legal, and Social Issues associated with mapping and sequencing the human genome. This group is currently developing policy recommendations for the necessary protections that must be put in place as new genetic tests are developed.

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