Our findings support the notion that those with co-morbid FXS and autism represent a distinct subtype of FXS, with more impairment in receptive language and theory of mind even when controlling for their lower non-verbal IQ relative to those with only FXS. The greater cognitive impairments observed in those with co-morbid FXS and autism continues into adolescence and young adulthood; and the autism seen in those with FXS appears to be the same as idiopathic autism.

The Autism Diagnostic Interview-Revised was used to examine diagnostic profiles and age-related changes in autism symptoms for a group of verbal children and adolescents with FXS, with and without autism. After controlling for nonverbal IQ, statistically significant between-group differences for lifetime and current autism symptoms were found for the Communication and Restricted Interests/Repetitive Behaviors domains, but not the Reciprocal Social Interaction domain. Effect sizes for differences in Reciprocal Social Interaction also were smaller than effect sizes for the other domains with one exception. Overall, severity of autism symptoms improved with age for all participants, with the least improvement noted for Restricted Interests and Repetitive Behaviors. FMRP did not account for unique variance in autism symptoms over and above nonverbal IQ. KeywordsFragile X syndrome; autism; diagnosis; intellectual disability; behavioral phenotype Autism Spectrum Disorder in Children and Adolescents with Fragile X Syndrome: Within-Syndrome Differences and Age-Related ChangesFragile X syndrome (FXS) is the most common inherited cause of intellectual disability. In general, prevalence rates have been reported as 1 in 4000 males and 1 in 8000 females (Crawford et al., 2001); however, recent studies have yielded rates closer to 1 in 2500 (Fernandez-Carvajal., Walichiewicz, Xiaosen, Pan, Hagerman, & Tassone, 2009;Hagerman, 2008). FXS is caused by an expansion of a repetitive CGG nucleotide sequence in the FMR1 gene, located on the X chromosome (Kaufmann & Reiss, 1999). This expansion causes methylation and transcriptional silencing of the gene, resulting in a reduction or absence of the protein that is normally produced (Kaufmann, Cortell, Kau, et al., 2004). This protein (FMRP) is critical for the regulation of processes involved in synaptic maturation, axonal guidance, and experience-dependent learning (Darnell, Warren, & Darnell, 2004;Hagerman, Ono, & Hagerman, 2005). Behaviors characteristic of autism are frequent in FXS, with many individuals meeting diagnostic criteria for autism (Hagerman, 1999 NIH Public Access Author ManuscriptAm J Intellect Dev Disabil. Author manuscript; available in PMC 2011 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript prevalence of autism in FXS at 25%, although recent studies utilizing diagnostic criteria for the full spectrum of autism disorders (i.e., inclusive of PDD-NOS) have reported rates approaching 50% (Demark, Feldman, & Holden, 2003;Kaufmann et al, 2004;Philofsky, Hepburn, Hayes, Hagerman, & Rogers, 2004). In the present study, we were interested in within-syndrome differences in, and the age-related trajectories of, autism symptoms in FXS.Although the association between FXS and autism has been well documented, the developmental course of autism within FXS is not well understood. It is not known whether the symptoms of autism are stable across development in FXS or whether there is an abatement of symptoms with age as has been observ...

We consider possible causes of these maternal differences, the implications for clinical practice, needs for future research, and the importance of understanding child and contextual factors as well as the dynamics leading to these differences.

Receptive and expressive language profiles were examined for a group of verbal male children and adolescents who had fragile X syndrome along with varying degrees of autism symptoms. A categorical approach for assigning autism diagnostic classification, based upon the combined use of the ADI-R and ADOS, and a continuous approach for representing autism symptom severity, based upon ADOS severity scores, were utilized in two separate sets of analyses. All analyses controlled for nonverbal IQ and chronological age. Nonverbal IQ accounted for significant variance in all language outcomes with large effect sizes. Results of the categorical analyses failed to reveal an effect of diagnostic group (FXS+AUT, FXS-No AUT) on standardized language test performance. Results of the continuous analyses revealed a negative relationship between autism symptom severity and all of the standardized language measures. Implications for representing autism symptoms in FXS research are considered.

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