Premorbid weight, body mass, and varsity athletics in ALS

We appreciate the interest of Dr. Vanacore in the possibly increased incidence of ALS in soccer players. How that might arise is not known. Branched chain amino acids might be toxic, but that possibility is still speculative, as are the effects of prolonged vigorous exercise and shared genetic susceptibility to both ALS and athleticism.

To prove a relationship between food and dietary supplements and ALS would require a study of the ingestion of nutritional or performance- enhancing substances in athletes engaged in many different sports. If any association with ALS were demonstrated, an investigation of the biological mechanisms could follow.

I read with interest the case-control study by Scarmeas et al. reporting a significant association between amyotrophic lateral sclerosis (ALS) and a history of varsity athletes (OR = 1.70, CI95% 1.04-2.76). [1]

In an epidemiological study performed on 24,000 professional Italian soccer players the distribution of the causes of death of 350 Italian soccer players has been analyzed in terms of SPMR (Standardized Proportional Mortality Ratio).2 Mortality for motor neuron disease (ICD - IX Revision 335.2) between 1960 and 1996 was very high (SPMR = 11.6; eight observed vs 0.69 expected cases). Six of these eight cases (75%) were under the age of 59, the corresponding proportion in the Italian general population is 32.1%. Five other cases were registered after 1996. [2]

Some hypotheses have been proposed to explain the association between ALS and sport. In particular, physical trauma or limb injury and a vigorous physical activity have been investigated but the findings were conflicting.

Among the potential explanations it should be considered that subjects with genetic susceptibility who are chronic users of dietary supplements containing branched chain amino acid (BCAA) might bear a higher risk of ALS. The BCAA (leucine, isoleucine and valine) supplementation in athletes is frequently used to stimulate the muscular protein synthesis, to improve both mental and physical performances, and to accelerate the body's recovery after particulary intense and prolonged sport activities.

This hypothesis is supported by three different arguments : a) clinical and experimental evidences show that glutamatergic transmission is implicated in the pathogenesis of ALS; b) there is a relationship between cerebral metabolism of BCAA and glutamate: recently a putative model of brain leucine metabolism ("leucine-glutamate cycle") has been proposed [3]; c) after skeletal muscle, the brain is the organ with the highest activity of two key enzymes in the catabolism of BCAA: branched chain amino transferase (BCAT) and branched chain alfa ketoacid dehydrogenase (BCKD). [4]

Two mammalian BCATs exist : mitochondrial (BCATm) and cytosolic (BCATc) isoenzymes localized in the astroglia and neurons respectively. Moreover, the BCATc was found primarily in the pyramidal neurons. [5]

ALS is a complex disease, thus several factors, known or unknown, might increase the risk of experiencing this disease. Among susceptible athletes a high assumption of BCAA might play a key role.

References

1. Scarmeas N, Shih T, Stern Y, Ottman R, Rowland LP. Premorbid weight, body mass, and varsity athletics in ALS. Neurology 2002;59:773- 775.

2. Belli S. Causes of death of Italian soccer players. Epid Prev 2003;27:12.

3. Daikhin Y, Yudkoff M. Compartmentation of brain glutamate metabolism in neurons and glia. J Nutr 2000;130:1026S-1031S.

4. Suryawan A, Hawes JW, Harris RA, Shimomura Y, Jenkins AE, Hutson SM. A molecular model of human branched-chain amino acid metabolism. Am J Clin Nutr 1998;68:72-81.

5. Hutson SM, Lieth E, LaNoue KF. Function of leucine in excitatory neurotransmitter metabolism in the central nervous system. J Nutr 2001,131:846S-850S.