El proceso de enseñanza de los PIP requiere una didáctica integradora global, en la cual se tomen en cuenta los siguientes aspectos:

Since our paper was published, my collaborators and I have recruited additional boys on whom we have both PDDBI and MAOA-uVNTR data. Some of this infor- mation has been reported elsewhere (Holden et al., 2006). We currently have data on 115 simplex and multiplex families who have sons who are positive for autism or autism spectrum disorder on the ADI-R or ADOS-G, have autism scores on the PDDBI greater than 36 (a cutoff that agrees well with the above measures as well as with clinical diagnosis of autism), have no other medical explanation for their disorder, who were born full-term, and who were in the correct age range for the PDDBI (18 months to 12.5 years of age). For multiplex families, only the earliest born affected male was selected for analysis. Of the 115 mothers, 4 were homozygous for the 3-repeat allele, 63 were heterozygous for the 3- and 4-repeat alleles (34 boys with the 3-repeat allele and 29 with the 4-repeat allele), and 48 were homozygous for the 4-repeat allele. Due to the small sample size of the homozygous

FIGURE 5.2 This fi gure shows the similarity in parent and teacher profi les for the signifi - cant PDDBI domain T-scores (mean ± 95% confi dence interval) across 3-repeat and 4-repeat MAOA-uVNTR genotypes (see text). Note that the domain names differ slightly from the current version of the PDDBI (Cohen and Sudhalter, 2005) and these changes are noted below. Vertical lines separate the SENSORY (stereotypies) domain (higher scores indicate increased severity) from the Receptive-Expressive Social Communication Abilities domains (where higher scores indicate increased ability) and from the overall Autism Score (higher scores indicate increased severity). Soc Appr, Social Approach domain; LMRL, Learning, Memory and Receptive Language domain; Sem/Prag Abil is a component of the Expressive Language domain. (From Cohen, I.L. et al., Clin. Genet., 64, 190, 2003. With permission.)

Informant × Subscale × MAOA

Me an ( ± 95 % C l) St er eoty pie s Soc Ap p r L MR L Se m /Prag Ab il A uti sm S cor e Parent St er eoty pie s Soc Ap p r L MR L Se m /Prag Ab il A uti sm S cor e Teacher 70 65 60 55 50 45 40 35 3-repeat 4-repeat

3-repeat mothers, their data were dropped from the rest of the analyses yielding three groups: (1) 3_34, i.e., 3-repeat boys from heterozygous mothers; (2) 4_34, or 4-repeat boys from heterozygous mothers; and (3) 4_44 or 4-repeat boys from homozygous 4-repeat mothers. If the associations with the MAO-A were maternal in nature, we would predict that groups 1 and 2 would be similar and both would differ from group 3. If the associations were strictly due to the alleles inherited by the boys, then group 1 would differ from groups 2 and 3, with the latter groups similar to one another. If the boys’ and the mothers’ alleles interacted, then all three groups would differ from one another.

Data were analyzed with multivariate analyses of variance (MANOVAs) with domains within each dimension of the PDDBI serving as the dependent variables. Analysis of variance (ANOVA) was used to analyze the overall Autism Composite score. Family status (simplex or multiplex) also served as a predictor to control for the effects of living with a sibling having autism. Post-hoc analyses were used to compare groups.

Within the Receptive/Expressive Social Communication Abilities dimension, higher levels of ability in association with the 4-repeat allele were predicted based on our previous data. This was confi rmed for the Social Approach Behaviors domain (SOCAPP; a measure of nonvocal social skills such as eye contact, gesture, play, and empathy), Expressive Language domain (EXPRESS; a measure of phonological, semantic and pragmatic verbal ability), and the Learning, Memory and Receptive Language domain (LMRL; a measure of memory and receptive skills) except that these were indeed maternal in nature. The 3_34, 4_34, and 4_44 groups had mean SOCAPP (SE) T-scores of 44.9 (2.1), 47.2 (2.3), and 51.1 (1.6). Thus, there was about a 0.5 SD difference between the 4_44 group and the other two groups (p < 0.022) who did not differ from each other. Similar effects were present for the other two domains. Interestingly, the LMRL domain has the highest correlation with IQ (r (74) = 0.77; Cohen and Sudhalter, 2005) and the difference across groups for this domain was the largest: the 3_34, 4_34, and 4_44 groups had mean (SE) T-scores of 47.5 (2.2), 47.3 (2.4), and 54.6 (1.7). Thus, there was almost a 1 SD difference between the 4_44 group and the other two groups (p < 0.014). These results confi rm our earlier fi ndings but indicate that these differences are maternal in nature.

Within the Approach/Withdrawal Problems dimension of the PDDBI, signifi - cant differences (p < 0.05) were evident across the three groups for three domains: Sensory/Perceptual Approach Behaviors (SENSORY), replicating our original observation; Ritualisms/Resistance to Change (RITUAL; a measure of engaging in rituals or resisting changes in routines or in the environment); and Specifi c Fears (FEARS; a measure of overall anxiety, sensitivity to noises, separation prob- lems, etc.). The SENSORY effect was not maternal with the 3_34 group showing higher T-scores (mean (SE) = 52.7 (1.7)) than the 4_34 or 4_44 groups (mean = (SE) 48.1 (1.8) and 48.4 (1.4), respectively, p < 0.05). All of these scores were in the autism range but the means differed by about 0.5 SD. However, the RITUAL and FEARS effects were maternal in nature. The 3_34, 4_34, and 4_44 groups had mean (SE) RITUAL T-scores of 50.8 (1.5), 47.7 (1.7), and 53.6 (1.3) and mean (SE) FEARS T-scores of 50.2 (1.6), 48.0 (1.8), and 54.6 (1.4). Thus, again, there was about a 0.5 SD difference between the 4_44 group and the other two groups

(p < 0.005). Conceptually, both fears and ritualistic behaviors are related to one another as “internalizing” behaviors. Indeed, obsessive–compulsive disorder is characterized in the DSM as an anxiety disorder.

A nonmaternal effect was present, however. Boys with the 3-repeat allele had higher SENSORY scores, as noted, and higher Autism Composite Scores, a mea- sure of overall severity, as predicted based on our previous data. The Autism Composite was worse in boys with the 3-repeat allele by about 0.5 SD (p < 0.028). The 3_34, 4_34, and 4_44 groups had mean (SE) T-scores of 55.2 (1.6), 49.6 (1.7), and 50.9 (1.4).

5.7 SUMMARY AND CONCLUSIONS

These results are consistent with the maternal depression effects cited above. This particular MAOA polymorphism (or a closely linked site) is associated with anxiety- like behaviors in children with autism and with adaptive abilities in socialization and language, and these effects are maternal in nature. Recurrent major depression in the mothers of these children is also associated with the same behavior pattern. Thus, the “maternal environment” seems to play a role in modulating internalizing behaviors and social and language skills in these children. Mothers homozygous for the higher-activity 4-repeat MAOA allele have children on the autism spectrum who appear to be relatively better off compared to children with autism who have heterozygous mothers, irrespective of their MAO genotype in that they are “higher functioning,” a good prognosticator for future development.

It should be noted that our results were specifi c to only certain behaviors; there was no “global” association of these alleles with the full spectrum of behaviors characteristic of autism. Thus, we did not fi nd evidence for any associations of these MAOA alleles with PDDBI domains assessing social pragmatic problems and repetitive language (or aggression, at this age). The association with the global autism score was quantitative in nature and unlikely to be associated with an actual difference in diagnostic category. The 3-repeat cases were simply “more autistic,” by 0.5 SD, than the other two groups whose scores were at the expected mean for children with autism. Therefore the notion that genes affect only certain behaviors linked to autism is supported by our data.

Recent data indicate that this MAOA-uVNTR polymorphism is also associ- ated with brain size differences in autism. Davis et al. (2008) reported in an MRI study that cerebral gray and white matter volume was increased in children with autism having the low-activity 3-repeat allele (n = 12) versus those with the high activity 4-repeat allele (n = 17). Thus, there is an association of this polymorphism with brain growth in autism. These researchers did not determine if their effects were maternal in nature or not but they did note that MAOA is expressed early in development.

Taken together, these studies are consistent with the idea that alleles associated with depression are protective for cognitive functioning in children on the autism spectrum but enhance internalizing problems. These effects are maternal in nature, and, given the MRI data, likely prenatal in origin. Indeed, as noted, the primary substrate for MAO is serotonin and Cote et al. (2007) noted that this molecule plays

a strong role in development prior to its role as a neurotransmitter. In mice, these researchers reported that this morphogen effect is maternal, i.e., that embryonic development is dependent on serotonin that is of maternal, and not fetal, origin. They also noted (Cote et al., 2007, p. 333), with respect to autism, that “it is conceivable that variations in maternal serotonin levels exert subtle effects on brain development during early ontogeny irrespective of the proper levels of peripheral serotonin in the affected child.” Our data are consistent with this notion. Perhaps genes like MAOA that may affect maternal serotonin levels during early gestation mitigate some of the deleterious effect of other autism genes (or autism predisposing prenatal stress or epigenetic factors) on cognitive development but enhance the child’s disposition to react with intense anxiety to the environment. This behavior pattern is typically seen in Asperger’s type individuals. These fi ndings suggest it may be benefi cial to explore the use of maternal and child genotyping for these alleles in order to predict the therapeutic effi cacy of medications affecting the serotonin system or MAOA activity.

It should also be noted that the notion that prenatal factors are involved in autism has been of increasing interest to the research community. Studies have noted increased risk for development of autism in association with a variety of birth complications (Kolevzon et al., 2007; Durkin et al., 2008; Kinney et al., 2008; Limperopoulos et al., 2008; Pinelli and Zwaigenbaum, 2008; Schendel, 2008; Schendel and Bhasin, 2008; Tsuchiya et al., 2008; Williams et al., 2008).

My colleagues and I (Karmel et al., 2008) have reported on factors associated with the later diagnosis of autism in neonatal intensive care unit (NICU) infants. Such infants were more likely than the rest of the cohort to be of low birth weight, to have shorter gestations, to show evidence for greater CNS involvement, to be male, and to have more educated mothers. We also noted that, by 4 months of age, the group that went on to develop autism had a greater preference for high frequency visual stimulation than a matched cohort, suggesting unique problems with the attention- arousal system in these infants. In fact, this preference was strongly correlated with a variety of domains on the PDDBI in a subgroup of these children (n = 12) who were seen at an average age of 4 years. When compared with other autistic children seen by me who were not in a NICU, the NICU children, at 4 years of age, showed higher RITUAL and AGGRESS (aggressiveness and irritability) domain scores, suggesting long-term infl uences of these birth complications on certain aspects of their behav- iors. It would be interesting to analyze the MAOA genotypes of these children and their mothers to see if there is an association with the severity of their disorder, the specifi c type of birth complication or their interaction.

In summary, our data indicate that, by assuming that autism is a syndrome com- prised of several different behavioral categories that can be independently infl uenced by many different factors, and by having appropriate assessment tools, it is possible to determine which variables modulate their severity and the magnitude of these effects. Further, to the extent that these variables yield similar effects, it may be possible to determine what they have in common. Our data indicate that a maternal lifetime history of recurrent depression and the high activity alleles of the MAOA- uVNTR polymorphism yield similar PDDBI profi les, and both may theoretically be linked through a common effect on prenatal serotonin levels.

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