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Genetic Susceptibility to Brain Injury in Sports: A Role for Genetic Testing in Athletes

Barry D. Jordan MD, MPH

THE PHYSICIAN AND SPORTSMEDICINE - VOL 26 - NO. 2 - FEBRUARY 98


Technological advances in molecular biology during the next millennium may cause an explosion of genetic information about athletes' predisposition to illness and injury. Recent discoveries about a possible genetic predisposition to brain injury in boxers may be the tip of the iceberg, with far-reaching implications for members of the sports medicine community.

Evidence for Inherited Susceptibility

Chronic traumatic brain injury (CTBI), which occurs primarily among retired boxers after long exposure to the sport, is also known as dementia pugilistica, chronic traumatic encephalopathy, or "punch-drunk" syndrome. The condition represents the cumulative long-term neurologic consequence of repetitive concussive and subconcussive blows to the head. A milder form of CTBI can occur in American football, ice hockey, rugby, soccer, or any sport associated with traumatic brain injury. Clinically, CTBI is characterized by slurred speech, gait ataxia, memory impairment, behavior and/or personality changes, parkinsonism, and/or incoordination (1-6). On postmortem examination, CTBI shares several neuropathologic features with Alzheimer's disease (7-11).

Recent evidence suggests that apolipoprotein E epsilon-4 (apo E-e4), a susceptibility gene for late-onset familial and sporadic Alzheimer's disease (12,13), may also be associated with an increased risk of CTBI in boxers (14). In a survey of 30 boxers, those who harbored an apolipoprotein E epsilon-4 allele and had high exposure to the sport (more than 12 professional bouts) exhibited greater neurologic dysfunction than those without an apolipoprotein E epsilon-4 allele. In addition, all the boxers who were severely impaired possessed an apolipoprotein E epsilon-4 allele.

Also supporting the hypothesis of a genetic predisposition to the neurologic effects of boxing, Teasdale et al (15) have since reported a significant association between apolipoprotein E epsilon-4 polymorphism and outcomes following acute traumatic brain injury in a nonboxing population. In a prospective evaluation of 89 patients admitted to a neurosurgical unit, 17 (57%) of 30 patients who had the apolipoprotein E epsilon-4 allele experienced an unfavorable outcome (death, a vegetative state, or severe disability). The same was true of only 16 (27%) of 59 patients who did not have an apolipoprotein E epsilon-4 allele.

Weighty Decisions Ahead

Our recent finding of this genetic predisposition to brain injury has implications not only for the medical regulation of boxing and other contact sports but also for our awareness of a need to better understand the interaction between genetic susceptibility and environmental triggers. With future advances we may be able to identify genes that predispose athletes to other sports-related injuries. For example, we may be able to identify those who are at increased risk of rupture of the anterior cruciate ligament. With such possibilities in mind, the medical community is confronted with new possibilities for helping patients as well as with serious ethical and moral concerns about the role of genetic testing.

There are certain advantages to knowing of a genetic susceptibility to injury. Identifying athletes who are susceptible to a specific injury would give physicians the opportunity to advise them of the potential risk. Such an athlete could elect to participate in a different sport. Other options might include modification of training or playing techniques, use of specialized safety equipment, rule changes, or more rigorous medical surveillance and health status monitoring. Furthermore, the identification of genes for sports injury susceptibility may also provide a basis for novel treatment strategies, such as gene therapy.

Despite these potential benefits, identifying athletes who have a genetic predisposition to injury in sports raises important ethical and legal issues. First, the knowledge must be kept confidential. Public knowledge of an athlete's genetic risk could compromise his or her well-being and livelihood. For example, knowledge of a predisposition to disease could limit an athlete's negotiating power and/or limit the ability to obtain medical or disability insurance. Furthermore, an athlete's own knowledge of this predisposition could impose a significant psychological and emotional burden. Complicating all of this is uncertainty about the reliability of genetic testing in sports: It may be very difficult to determine the positive predictive value of a genetic test and to quantify the amount of athletic exposure that will trigger a pathobiologic response.

A Future for Genetic Testing?

Advances in molecular biology will undoubtedly expand our understanding of the interactions between inherited disease susceptibility and environmental precipitants. Any future application of such scientific knowledge in the domain of sports medicine must be accompanied by scientific validation, ethical responsibility, moral integrity, and appropriate regulatory policies. Genetic testing may be the wave of the future, but because of uncertainty about genetic and environmental interactions, its role remains to be delineated.

References

  1. Jordan BD: Chronic neurologic injuries in boxing, in Jordan BD (ed): Medical Aspects of Boxing. Boca Raton, Fla, CRC Press, 1993, pp 177-185
  2. Mendez MF: The neuropsychiatric aspects of boxing. Int J Psychiatry Med 1995;25(3):249-262
  3. Roberts AH: Brain Damage in Boxers: A Study of the Prevalence of Traumatic Encephalopathy Among Ex-professional Boxers. London, Pittman, 1969
  4. Jordan BD: Neurologic injuries in boxing, in Jordan BD, Tsairis P, Warren RE (eds): Sports Neurology, ed 2. Philadelphia, Lippincott-Raven, to be published
  5. Jordan BD: Dementia pulgilistica, in Folstein MF (ed): Neurobiology of Primary Dementia. Washington, DC, Association for Research in Nervous and Mental Disease: American Psychiatric Press, to be published
  6. Critchley M: Medical aspects of boxing, particularly from a neurological standpoint. BMJ 1957;(February 16):357-362
  7. Corsellis JA, Bruton CJ, Freeman-Browne D: The aftermath of boxing. Psychol Med 1973;3(3):270-303
  8. Roberts GW, Allsop D, Bruton C: The occult aftermath of boxing. J Neurol Neurosurg Psychiatry 1990;53(5):373-378
  9. Uhl GR, McKinney M, Hedreen JC, et al: Dementia pugilistica: loss of basal forebrain cholinergic neurons and cortical cholinergic markers, abstracted. Ann Neurol 1982;12(1):99
  10. Tokuda T, Ikeda S, Yanagesawa N, et al: Re-examination of ex-boxers' brains using immunohistochemistry with antibodies to amyloid beta-protein and tau protein. Acta Neuropathol (Berl) 1991;82(4):280-285
  11. Dale GE, Leigh PN, Luthert P, et al: Neurofibrillary tangles in dementia pugilistica are ubiquitinated. J Neurol Neurosurg Psychiatry 1991;54(2):116-118
  12. Saunders AM, Strittmatter WJ, Schmechel D, et al: Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 1993;43(8):1467-1472
  13. Corder EH, Saunders AM, Strittmatter WJ, et al: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261(5123):921-923
  14. Jordan BD, Relkin NR, Ravdin LD, et al: Apolipoprotein E epsilon4 associated with chronic traumatic brain injury in boxing. JAMA 1997;278(2):136-140
  15. Teasdale GM, Nicoll JAR, Murray G, et al: Association of apolipoprotein E polymorphism with outcome after head injury. Lancet 1997:350(9084):1069-1071

Dr. Jordan is adjunct associate professor of psychistry at the Charles R. Drew University of Medicine and an instructor of neurology at the Uersity of California at Los Angeles (UCLA) School of Medicine. Address correspondence to Barry D. Jordan, MD, Charles R. Drew University of Medicine, 1621 E 120th St, MP-19B, Los Angeles, CA 90059, e-mail to [email protected].


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