In an important paper, Wakefi eld et al. (1998) revealed an apparent link between gastrointestinal (GI) distress (including food intolerance, diarrhea, and/or abdomi- nal pain) in children (12 case reports) and an autistic-like regression with loss of acquired skills (notably social and communication) and, less frequently, the appear- ance of stereotypic and self-injurious behaviors. This autistic regression followed the GI distress either immediately or gradually over a period of a few weeks.
Unfortunately, the Wakefi eld et al. (1998) paper became a source of controversy. In eight of the 12 cases, the authors noted that the GI distress and subsequent autis- tic regression followed delivery of the measles-mumps-rubella (MMR) vaccination. Specifi cally, in these eight cases, the GI distress along with other symptoms includ- ing fever, delirium, and/or convulsions were part of an adverse reaction to the MMR vaccination. The autistic regression appeared an average of 6.3 days after the onset of the reaction. The authors clearly state “We did not prove an association between measles, mumps, and rubella vaccine and the syndrome described” but despite this caution, the report triggered a debate about the possible link between MMR and autism. This debate soon expanded to include a possible association between one of the constituents of the MMR vaccine, organic mercury, and autism.
The observations of Wakefi eld et al. (1998) are of interest because they replicate aspects of Kanner’s (1943b) original case descriptions of autism associated with fre- quent illness, food intolerance, and adverse reactions to a vaccination. There have been attempts to refute the basic observations of Wakefi eld et al. (1998), whose report focused on autistic regression and not the overall prevalence of autism. For example, Dales et al. (2001) compared the percentage of children immunized with MMR on a year-by-year basis in California over the years 1980 to 2000 with the number of diag- nosed cases of autism. They observed that the percentage of children being immunized remained very stable while, during these same years, the absolute number of cases of autism increased dramatically. Although no correlation coeffi cient or any other statisti- cal analysis was provided, they concluded that there was no relationship between the two and that the MMR vaccination was not associated with autism. Interestingly, there was an increase in the population of California over that 20-year period and, therefore, a comparable increase in the absolute number of MMR vaccinations delivered. This seems to indicate that the Dales et al. (2001) data refl ect that the increased numbers of autism cases were associated with increased administration of MMR. However, the simplest conclusion is that the increase in the number of cases of autism was associ- ated with an increase in the population of California. In any case, the link between the MMR vaccination and autistic regression was not addressed by Dales et al. (2001).
Taylor et al. (1999) reviewed autism cases in the United Kingdom born between 1979 and 1998, comparing the incidence before and after October 1988, when the MMR vaccine was introduced. They report that there was a dramatic increase in the incidence in autism in their population starting 3 years after the introduction of the MMR vaccination but concluded that there was no association between autism and the MMR vaccination because, by 1992, the vaccine coverage had already stabilized (while the autism rate was still climbing).
Madsen et al. (2002) assessed a large population of children born in Denmark between 1991 and 1998. They divided their population into those children who received the MMR vaccination and those who did not. They then looked for a diag- nosis of autism or autism spectrum disorder in these two groups and concluded that there was strong evidence against the hypothesis that the MMR vaccination causes autism. Of interest, however, is that there were about 27% more cases of autism diagnosed over the age of 3 in the vaccinated group as compared to the unvaccinated group. More important, they failed to specifi cally examine autistic regression, pre- ferring instead to combine all cases of autism. This controversy continues with most
recent reports continuing to emphasize the safety of the MMR vaccine (Demicheli et al., 2005; Honig et al., 2008). Nonetheless, one consequence of the MMR contro- versy is that there has been increased awareness that early exposure to environmental toxicants may place certain individuals at risk for autism.
As noted, about one-third of those diagnosed with autism experience autistic regression, having apparently normal development interrupted at some point by a dramatic setback with a loss of acquired skills. Yet even in these cases, as well as for the remaining two-thirds of the cases where autism appears to be the result of a neurodevelopmental defect present at birth (Kanner, 1943b), it remains true that the etiology of autism remains unknown. Evidence for a genetic contribution for the disorder is clear, but no single gene has been identifi ed; rather, a constellation of gene polymorphisms appears to increase the risk for individuals. The controversy surround- ing the link between autism and the MMR vaccination suggested the involvement of an environmental toxicant exposure as a second factor, at least for autistic regression. Other studies have linked autism to prenatal exposure to toxicants such as thalidomide or valproic acid (VPA) (Rodier et al., 1997). Based upon these observations, together with the fact that autism fails to reach 100% concordance rates in monozygotic twins, a hypothesis has been developed that the etiology of autism may arise as the result of a gene by environment interaction with a gene polymorphism(s) enhancing the sensitivity of individuals to the deleterious effects of environmental toxicants (London and Etzel, 2000). Based upon our observations in humans (Ming et al., 2005, 2008a) and mice (Wagner et al., 2006; Ming et al., 2008b), we have advanced this hypothesis with the proposal that autism is the result of a gene by environ- ment interaction where the environmental toxicant triggers oxidative stress while the genetic defi ciency affects the ability of the individual to respond effectively to the deleterious effects of oxidative stress (Ming et al., 2008b). Toward this end, we have developed an animal model of autism and have used this model to assess the effects of gene alterations (Cheh et al., 2006) as well as early exposure to toxicants such as VPA (Wagner et al., 2006; Yochum et al., 2008) and mercury (Wagner et al., 2007) on neurobehavioral development.