EL PARADIGMA EMERGENTE CON EL MODELO DE INNOVACIÓN

One of the most unusual factors infl uencing the severity of autism is a family history of anxiety and depression. Familial mood and anxiety disorders and autism have been shown to be associated in a number of studies (DeLong and Dwyer, 1988; Piven et al., 1991; DeLong, 1994; DeLong and Nohria, 1994; Smalley et al., 1995; Piven and Palmer, 1999). Smalley et al. (1995) reported a lifetime prevalence of DSM (Diagnostic and Statistical Manual of Mental Disorders-III-Revised) (American Psychiatric Association, 1987) defi ned major mood disorders in 40.3% of parents of children with autism, relative to 19.2% of parents of children with tuberous sclerosis, or of children with an unspecifi ed seizure disorder. The majority of these parents (64%) had their fi rst onset of depression prior to the birth of their child with autism. Further, 32.4% of siblings (mean age = 17 years) were found to have developed major mood disorders. Similar results were reported by Piven et al. (1999). Smalley et al. (1995) also reported that 20% of parents and 20.6% of siblings of children with autism had social phobia. Although depression occurs at higher rates in families with autism, the two disorders are not directly related. That is, in families, autism does not cause depression and depression does not cause autism (Bolton et al., 1998; Piven and Palmer, 1999).

Given the fact that one of the primary characteristics of depression is withdrawal from the environment and that social phobia is characterized by intense social withdrawal, one would expect that caregivers who suffer from these conditions would have children with autism whose outcome would be less than optimal. This expectation would be wrong. Smalley et al. (1995) found that a history of social phobia was more likely in families where the child with autism had an IQ greater than or equal to 70. Similar observations have been noted by DeLong (2004) with respect to a family history or mood disorders. We reported (Cohen and Tsiouris, 2006), based on a large sample of 122 families of young children (mean (SD) age = 5.4 (1.4) years) with an autism spectrum disorder, that a maternal lifetime history of recurrent major depression (there were no signifi cant paternal effects or maternal anxiety disorder effects) is associated with signifi cantly higher IQs (differences as great as 20 IQ points), higher adaptive skills and higher T-scores on the Receptive/Expressive Social Communication Abilities dimension of the PDDBI (p < 0.025) in these children.

Associations between recurrent major depression in the mothers and the Approach/ Withdrawal domain scores on the PDDBI were complicated but suggestive of increased anxiety and more social withdrawal in these young children. Specifi cally, teachers, but not parents, rated the children whose mothers had a history of recurrent depression as having more problems with sensory behaviors, rituals, and fears, and fewer problems with overarousal (i.e., relatively less hyperactivity), a more fearful and inhibited (internalizing) behavior style. These types of problems are suggestive of early-onset anxiety or internalizing problems. The fact that these effects were evident in the teacher but not the parent reports could refl ect separation anxiety or social phobia problems in this young age group. In the non-PDD population, social phobia and major depression have been noted to be more common among young children (mean age of 6.7 years) whose parents have a history of major depression

(Biederman et al., 2001). Thus, the children of mothers with recurrent depression in our study resembled, to some extent, their non-PDD cohorts. Unlike these chil- dren, however, their internalizing problems manifested as an increased severity of certain “autistic” behaviors.

These observations are indeed puzzling. Why would high functioning autism be linked to a lifetime history of mood disorders in their families, especially their mothers? In our study, we could not attribute the relatively increased IQ association to psychosocial factors, selection bias, or other treatments such as applied behavior analysis (ABA). While it is conceivable that those mothers with a depression history may be more intelligent and, therefore, their children with autism would be more likely to be higher functioning, IQs of the children in our study were unre- lated to maternal educational level, and type of maternal depression was unrelated to maternal educational level. Further, studies have concluded that IQs of children with autism do not correlate signifi cantly with IQs of their parents (Szatmari and Jones, 1991; Fombonne et al., 1997).

Genetic factors could be a possible explanation. Smalley et al. (1995) speculated that the association of familial mood/anxiety disorders with high functioning autism is due to greater etiological heterogeneity in children with autism who also have intel- lectual disabilities. That is, in such children, genetic and/or environmental factors unrelated to mood disorder likely play a role in contributing to causation. DeLong (2004) has made a similar argument. However, there is no a priori reason for why genes associated with intellectual disability should not also be involved in depression or social phobia. Intellectual disability is a common feature in males with fragile X syndrome. Yet, social anxiety is prominent in these males at all levels of intelligence (Cohen et al., 1988) and major depression has been reported to be common in their mothers (Thompson et al., 1996).

In our paper (Cohen and Tsiouris, 2006), we hypothesized a “genetic modifi er” model (cf. Slavotinek and Biesecker, 2003) as an explanation. In this model, “autism genes” and “depression genes” share common alleles, which interact with one another (epistatic interactions) to modify the expression of each disorder. In the case of autism, this would include a relatively “protective” effect of recurrent depression alleles on IQ in children with autism.

This modifi er model is displayed in the Venn diagram (Figure 5.1). Here, the phenotypes of autism and depression are depicted as separate entities arising from gene sets that are largely independent. However, the two disorders share some risk alleles (denoted here as DEP/AUT alleles). When these DEP/AUT alleles are present, they interact with each other to modify the expression of each disorder (the shaded regions). Therefore, this model predicts that DEP/AUT alleles should result in individuals more likely to have a specifi c autism or depression pheno- type, depending upon the number and type of these alleles, and that these DEP/ AUT alleles have a protective effect on the deleterious effects on language and IQ caused by other autism genes, accounting for the increased cognitive ability in these affected children. If this hypothesis were true, it would have clear implica- tions for prognosis and treatment. Is there any evidence that genes associated with mood and anxiety disorders have a protective effect on language and IQ in children with autism? The answer is yes.