The present study extends our previous work on social behavior impairment in young males with fragile X syndrome (FraX). Specifically, we evaluated whether the autistic phenomenon in FraX is expressed as a range of behavioral impairments as in idiopathic autism (Aut). We also examined whether there are behaviors, identified as items of the Autism Diagnostic Interview-Revised (ADI-R), that in FraX predispose to or differentiate subjects with autism spectrum disorder (ASD) diagnosis. Finally, regression models were utilized to test the relative contribution of reduced communication and socialization skills to ADI-R scores and diagnoses. A cohort of 56 boys (3-8 years) with FraX was examined in terms of scores on measures of cognition (IQ was a co-variate in most analyses.), autistic behavior, problem/aberrant behavior, adaptive behavior, and language development. We found that, indeed, in terms of problem behavior and adaptive skills, there is a range of severity from FraX + Aut to FraX + PDD (Pervasive Developmental Disorder) to FraX + none. ADI-R items representing "Play" types of interaction appear to be "susceptibility" factors since they were abnormal across the FraX cohort. Integrated regression models demonstrated that items reflecting complex social interaction differentiated the FraX + ASD (Aut + PDD) subgroup from the rest of the FraX cohort, while abnormalities in basic verbal and non-verbal communication distinguished the most severely affected boys with FraX + Aut from the milder FraX + PDD cohort. Models incorporating language, adaptive communication, and adaptive socialization skills revealed that socialization was not only the main influence on scores but also a predictor of ASD diagnosis. Altogether, our findings demonstrate that the diagnosis of ASD in FraX reflects, to a large extent, an impairment in social interaction that is expressed with variable severity in young males with FraX.

The present study characterizes distinctive and specific features of social behavior impairment, termed social behavior profile (SBP), in young males with fragile X syndrome (FraX). Fourteen males with FraX and autism (FraX+Aut), ages 3-8 years, were compared with either 41 FraX boys without autism (Aut), 7 age-matched males with developmental language delay and autism (DLD+Aut), or with 11 boys with non-selected (for language delay) idiopathic autism (IA), on several standardized instruments assessing social behavior and autistic features (i.e., autism diagnostic interview-revised, ADI-R). We found that FraX+Aut subjects displayed more impairment in overall cognition, problem/aberrant behavior, and adaptive behavior than the rest of the FraX cohort, even when individuals with pervasive developmental disorder (PDD) were included in the latter. Compared to both DLD+Aut and IA, FraX+Aut males were less impaired in ADI-R reciprocal social interaction (RECS) domain. However, boys with FraX+Aut were in general comparable to DLD+Aut subjects in problem/aberrant and adaptive behaviors. Based on the contrast between FraX+Aut and non-autistic FraX and DLD+Aut, we were able to identify measures (e.g., child behavior checklist (CBCL) withdrawn subscale) that better define social interaction impairment in FraX. Comparisons with DLD+Aut and IA led to the conclusion that communication impairment (COMM) and stereotypic behavior contribute relatively more to the diagnosis of autism in FraX+Aut. In agreement with recent studies, our data suggest that FraX+Aut, and more generally SBP, is a distinctive subphenotype among boys with FraX, which may share some pathophysiological mechanisms with IA.

The present study extends our previous work on characterizing the profile of social behavior abnormalities in boys with Fragile X (FraX) and autism spectrum disorder (ASD) using clinically oriented behavioral rating scales and standardized instruments. The goal was to further distinguish behavioral parameters contributing to the diagnostic classification of FraX þ ASD. The study design included two cohorts of boys with FraX (3-8 years), a larger main cohort for crosssectional analyses (n ¼ 56, 24 with ASD), and a longitudinal subset (n ¼ 30, 11 with ASD) of the main cohort with up to 3 yearly observations. The focus was on the relative contribution of delayed adaptive socialization and social withdrawal, including item components of their corresponding rating instruments, to the diagnosis of ASD in boys with FraX. Using a combination of regression analyses, we demonstrated that: (1) as delayed socialization, social withdrawal is also a correlate of FraX þ ASD; (2) items of social withdrawal scales representing avoidance were the main predictors of ASD status, particularly in older boys; (3) adaptive socialization skills reflecting rules of social behavior and recognition and labeling of emotions, linked to verbal reasoning abilities, were selectively associated with FraX þ ASD; (4) adaptive socialization is the primary determinant over time of ASD status in boys with FraX; and (5) integrated adaptive socialization-social withdrawal models allow the identification of distinctive FraX þ ASD subgroups. Altogether, our findings suggest that two distinct but interrelated social behavior abnormalities, one linked to impaired cognitive processes (delayed socialization) and the second one to disturbance in limbic circuits (avoidance), play a role in the development of ASD in boys with FraX.

Although Smith-Lemli-Opitz Syndrome (SLOS), a genetic condition of impaired cholesterol biosynthesis, is associated with autism [Tierney et al., 2001], the incidence of SLOS and other sterol disorders among individuals with autism spectrum disorders (ASD) is unknown. This study investigated 1) the incidence of biochemically diagnosed SLOS in blood samples from a cohort of subjects with ASD from families in which more than one individual had ASD and 2) the type and incidence of other sterol disorders in the same group. Using gas chromatography/mass spectrometry, cholesterol and its precursor sterols were quantified in one hundred samples from subjects with ASD obtained from the Autism Genetic Resource Exchange (AGRE) specimen repository. Although no sample had sterol levels consistent with SLOS, 19 samples had total cholesterol levels lower than 100 mg/dL, which is below the 5 th centile for children over age 2 years. These findings suggest that, in addition to SLOS, there may be other disorders of sterol metabolism or homeostasis associated with ASD. KeywordsSmith-Lemli-Opitz syndrome; hypocholesterolemia; Autism Genetic Resource Exchange; Asperger disorder; pervasive developmental disorder Smith-Lemli-Opitz syndrome (SLOS, MIM 270400) is an autosomal recessive malformation syndrome caused by a deficiency of the last step of cholesterol biosynthesis, 7-dehydrocholesterol reductase (DHCR7) [Tint et al, 1994]. Principal abnormalities include a typical facial appearance, microcephaly, hypotonia, cleft palate, hypogenitalism, 2-3 toe syndactyly, and a characteristic behavioral profile including autism, usually accompanied by mental retardation. The enzymatic deficiency manifests biochemically in blood and all tissues as a reduced level of cholesterol and increased levels of 7-dehydrocholesterol (7DHC) and its isomer, 8-dehydrocholesterol (8DHC), although a few very mildly affected patients have normal plasma cholesterol levels despite increases in 7DHC and 8DHC. This NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript sterol abnormality in turn affects the synthesis and metabolism of various sterol-derived compounds, including bile acids, adrenal steroids, neurosteroids, and the structure of sterolrich membranes, such as myelin, the plasma membrane, and various subcellular organelles.SLOS is a relatively common genetic disorder with an estimated incidence among those of European ancestry of approximately 1 in 50,000 births. SLOS has a wide spectrum of clinical and biochemical severity, from functionally normal individuals to malformed fetuses that die in utero [Lowry and Yong, 1980;Kelley and Hennekam, 2000]. Although the combined carrier frequency for several common DHCR7 null alleles of about 1.25% predicts an incidence of 1 in 25,000 births in European-derived populations, about 50% of conceptuses appear to be lost early in pregnancy [Kelley and Herman, 2001]. Most SLOS individuals who survive the newborn period are compound heterozygotes for a common DHCR7 null mutation and a mild...

To gain insight into the specificity of cerebellar vermian abnormalities reported in autism, we conducted a magnetic resonance imaging (MRI) study of boys with either of two conditions associated with autism, Down syndrome and fragile X syndrome, compared with boys with idiopathic autism and controls. The subjects, ranging in age from 3 to 9 years, included 16 boys with Down syndrome + autism and 11 boys with Down syndrome only; 13 boys with fragile X syndrome + autism and 9 boys with fragile X syndrome only; 10 boys with idiopathic autism; and 22 controls. Diagnosis of autism was based on DSM-IV criteria, confirmed primarily by the Autism Diagnostic Interview. T1-weighted midsagittal MRIs were used to measure midline structures. Intracranial area, reflecting brain size, was significantly smaller in subjects with Down syndrome. Therefore, all vermian measures were expressed as ratios to intracranial area. Analysis of covariance (covarying for age and IQ) demonstrated that posterior vermi (lobules VI-VII and VIII-X) were markedly smaller in both Down syndrome groups and those with fragile X syndrome only, whereas only lobules VI-VII were reduced in idiopathic autism. Factorial analyses of variance tested interactions between autism factor and the diagnosis of Down syndrome or fragile X syndrome. The size of lobules VI-VII/intracranial area was dependent on autism status only in fragile X syndrome, with ratios significantly larger in fragile X syndrome with autism with respect to fragile X syndrome only. We conclude that selective posterior vermis hypoplasia is seen not only in idiopathic autism but also in Down syndrome and some individuals with fragile X syndrome. However, reductions in vermian lobules VI and VII appear to be specific to idiopathic autism, whereas increased size of lobules VI and VII is associated with autism in fragile X syndrome. The latter results are consistent with MRI studies showing lobules VI-VII hyperplasia in a subset of subjects with idiopathic autism and cerebral and hippocampal enlargements in fragile X syndrome.