Richard C. Deth, Ph.D.
Professor of Pharmacology
Northeastern University
Boston, Massachusetts
Summary
The developmental disorder autism has both genetic and environmental origins, and its forty-fold increase during the past two decades reflects an increased role for environmental factors. It has been proposed that increased use of vaccines containing the ethylmercury derivative thimerasol is the major contributing factor. Published research from my laboratory has revealed that thimerosal is an exceptionally potent inhibitor of biochemical pathways that transfer single carbon atoms between molecules. These “methylation” pathways are critically involved in several important functions including the regulation of gene expression and the molecular mechanism of attention. Recent studies from my lab indicate that thimerosal exerts its toxic effect on methylation by interfering with formation of the active form of vitamin B12, also known as cobalamin. Dietary B12 must be converted to methylB12 (methylcobalamin) in order to assist in the transfer of single-carbon methyl groups from the folic acid pathway by the enzyme known as methionine synthase. By reducing methylB12 formation, thimerosal inhibits this enzyme and thereby interferes with methylation events. Autistic children have abnormal plasma levels of methylation-related metabolites and exhibit higher frequencies of genetic mutations that affect this pathway. These genetic risk factors make them less able to detoxify thimerosal and also increase their sensitivity to its mechanism of toxicity. In many cases, autism can be effectively treated by the administration of methylB12 along with other agents that augment methylation capacity. Taken together, these facts indicate that increased exposure to thimerosal has combined with genetic risk factors in a sensitive subpopulation to cause the recent rise in autism.
Outline
1. The Puzzle of Autism
2. Physiological and Biochemical Roles of Methylation
3. Activity of Methionine Synthase
4. Effects of Thimerosal and Heavy Metals
5. Autism-associated Metabolic and Genetic Abnormalities
6. Methylation-related Treatments for Autism
7. Conclusions
1. The Puzzle of Autism
Autism is a pervasive developmental disorder characterized by deficits in language, attention, cognition and learning, frequently accompanied by abnormal behavior including social isolation, repetitive activity and emotional lability. Severe deficits may be recognized at birth, but a failure to achieve standard milestones during initial years of life remains the primary basis of diagnosis in most cases. While the underlying cause(s) remains obscure for many developmental disorders, metabolic abnormalities (e.g. Lesch-Nyhan Syndrome and adenylsuccinate lyase deficiency) or impaired methylation-dependent gene silencing and/or imprinting (Rett and Fragile-X Syndromes) (1-4) suggest biochemical mechanisms that may be involved. Development disorders can also be caused by exposure to toxins (e.g. ethanol, in fetal alcohol syndrome; heavy metals, in lead poisoning) (5,6), although the precise molecular mechanisms underlying their toxicity are not known. The recent increase in the incidence of autism has led to speculation that environmental exposures including vaccine additives (i.e. aluminum and the ethylmercury-containing preservative thimerosal) might contribute to the triggering of this developmental disorder (7).
Based upon a high concordance in twin studies, genetic factors are thought to play an important role in causing autism. However, it is clear that the recent dramatic rise in autism rates is not caused by a genetic phenomenon. The more likely scenario is that autism is caused by the interaction of genetic risk factors with environmental risk factors and the importance of the environmental factors has increased during the past twenty years. As illustrated in Fig. 1, the “Puzzle of Autism” therefore is the challenge of understanding exactly which genes provide the inborn risk, and which environmental factor(s) is serving as the trigger. The molecular mechanism at the intersection of genetic and environmental factors should be capable of accounting for the observed symptoms of autism, and knowledge of this mechanism should help identify effective treatments for autism. The findings summarized in this report indicate that impairment in the biochemical pathways that allow for the transfer of single carbon groups (i.e. methylaion) is a major factor contributing to the cause(s) of autism.
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