Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by delayed/abnormal language development, deficits in social interaction, repetitive behaviors and restricted interests. The heterogeneity in clinical presentation of ASD, likely due to different etiologies, complicates genetic/biological analyses of these disorders. DNA microarray analyses were conducted on 116 lymphoblastoid cell lines (LCL) from individuals with idiopathic autism who are divided into three phenotypic subgroups according to severity scores from the commonly used Autism Diagnostic Interview-Revised questionnaire and age-matched, nonautistic controls. Statistical analyses of gene expression data from control LCL against that of LCL from ASD probands identify genes for which expression levels are either quantitatively or qualitatively associated with phenotypic severity. Comparison of the significant differentially expressed genes from each subgroup relative to the control group reveals differentially expressed genes unique to each subgroup as well as genes in common across subgroups. Among the findings unique to the most severely affected ASD group are 15 genes that regulate circadian rhythm, which has been shown to have multiple effects on neurological as well as metabolic functions commonly dysregulated in autism. Among the genes common to all three subgroups of ASD are 20 novel genes mostly in putative noncoding regions, which appear to associate with androgen sensitivity and which may underlie the strong 4:1 bias toward affected males.

Heterogeneity in phenotypic presentation of ASD has been cited as one explanation for the difficulty in pinpointing specific genes involved in autism. Recent studies have attempted to reduce the "noise" in genetic and other biological data by reducing the phenotypic heterogeneity of the sample population. The current study employs multiple clustering algorithms on 123 item scores from the Autism Diagnostic Interview-Revised (ADI-R) diagnostic instrument of nearly 2000 autistic individuals to identify subgroups of autistic probands with clinically relevant behavioral phenotypes in order to isolate more homogeneous groups of subjects for gene expression analyses. Our combined cluster analyses suggest optimal division of the autistic probands into 4 phenotypic clusters based on similarity of symptom severity across the 123 selected item scores. One cluster is characterized by severe language deficits, while another exhibits milder symptoms across the domains. A third group possesses a higher frequency of savant skills while the fourth group exhibited intermediate severity across all domains. Grouping autistic individuals by multivariate cluster analysis of ADI-R scores reveals meaningful phenotypes of subgroups within the autistic spectrum which we show, in a related (accompanying) study, to be associated with distinct gene expression profiles.

Despite the identification of numerous autism susceptibility genes, the pathobiology of autism remains unknown. The present “case-control” study takes a global approach to understanding the molecular basis of autism spectrum disorders based upon large-scale gene expression profiling. DNA microarray analyses were conducted on lymphoblastoid cell lines from over 20 sib pairs in which one sibling had a diagnosis of autism and the other was not affected in order to identify biochemical and signaling pathways which are differentially regulated in cells from autistic and nonautistic siblings. Bioinformatics and gene ontological analyses of the data implicate genes which are involved in nervous system development, inflammation, and cytoskeletal organization, in addition to genes which may be relevant to gastrointestinal or other physiological symptoms often associated with autism. Moreover, the data further suggests that these processes may be modulated by cholesterol/steroid metabolism, especially at the level of androgenic hormones. Elevation of male hormones, in turn, has been suggested as a possible factor influencing susceptibility to autism, which affects ∼4 times as many males as females. Preliminary metabolic profiling of steroid hormones in lymphoblastoid cell lines from several pairs of siblings reveals higher levels of testosterone in the autistic sibling, which is consistent with the increased expression of two genes involved in the steroidogenesis pathway. Global gene expression profiling of cultured cells from ASD probands thus serves as a window to underlying metabolic and signaling deficits that may be relevant to the pathobiology of autism.

Eighteen preschool children diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders Third Edition Revised (DSM III-R) as having Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) were compared to 176 children with DSM III-R Autistic Disorder (AD), and to 311 non-autistic children with developmental language disorders (DLD) (N = 201) or low IQ (N = 110). All children were partitioned into "high" and "low" cognitive subgroups at a nonverbal IQ of 80. Within cognitive subgroups, the 18 PDD-NOS children did not differ significantly from either the DLD or the AD children in verbal and adaptive skills and obtained scores intermediate between those of these groups. The PDD-NOS did not differ from the AD children in maladaptive behaviors. Both the PDD-NOS and AD children had many more of these behaviors than the non-autistic comparison groups. Children in the "high" and "low" cognitive subgroups of AD, but not of PDD-NOS, differed substantially on most measures, with the children with lower cognitive scores significantly more impaired on all measures. Similarity of PDD-NOS children to AD children in maladaptive behaviors and an intermediate position between autistic and non-autistic groups on virtually all measures explains the difficulty clinicians encounter in classifying children with PDD and raises questions about the specificity of these diagnostic subtypes of the autistic spectrum.

Typically, children with disabilities are evaluated clinically by a number of professionals with different backgrounds whose task is to provide a diagnosis and an intervention plan. This study was carried out to describe interrater agreement for pairs of independent observers rating with different instruments the behaviors of 505 communicatively impaired autistic and nonautistic preschool children. Observers were parents, teachers, neurologists, and psychiatrists. Parents and teachers responded to behavioral questionnaires, neurologists filled out the mental status part of a standardized neurologic evaluation, and psychiatrists an observational questionnaire. All four types of observers rated sociability, language, play, attention, stereotyped, and other aberrant behaviors. Agreement between pairs of raters was significant but moderate. Owing to range restriction with smaller numbers of subjects, agreement decreased for ratings of subsamples divided according to diagnosis, cognitive level, or age. There were some differences among observers' ratings of the severity of particular categories of behaviors, with physicians generally viewing the children as more severely impaired and teachers as least impaired. Interrater agreement was not enhanced when parents and teachers rated similarly worded behavioral items. Modest interrater agreement in this study, like agreement among disparate raters of children's behaviors in other studies, suggests that observers are sensitive to different aspects of behavior and that their ratings are more likely to be complementary than unreliable.

This study assessed the relationship between fluency and language demand in children with epilepsy, a group known to demonstrate depressed language skills. Disfluency type and frequencies were analyzed in elicited narratives from 52 children. Half of these children had localization-related epilepsy (CWE), while the others were age- and gender-matched typically developing (TD) peers. CWE were found to be significantly more disfluent overall than their matched TD peers during narrative productions, and demonstrated a higher proportion of stutter-like disfluencies, particularly prolongations. The current study adds to an emerging literature that has found depressed language skills and listener perceptions of verbal ability in children with chronic seizure activity, and contributes to the small but growing literature that suggests that disfluency during spoken language tasks may be a subtle marker of expressive language impairment.