Autism in fragile X syndrome: a category mistake?

OBJECTIVE: Many investigators now routinely classify children with fragile X syndrome (FXS) according to whether or not they also meet diagnostic criteria for autism. To determine whether this classification is appropriate, we examined the profiles of autistic behaviors shown by boys and girls with FXS. METHOD: Individuals with FXS, aged 5 to 25 years, were assessed on two established measures of autism, the Social Communication Questionnaire (SCQ) and the Autism Diagnostic Observation Schedule (ADOS). RESULTS: We found that 35.1% of boys and 4.3% of girls with FXS scored in the "autism" category on both instruments. Analysis of the symptom profile indicated that both boys and girls with FXS showed lower rates of impairment on communication and reciprocal social interaction items than the reference autism samples on the measures. Furthermore, a regression model showed that IQ was significantly negatively associated with the SCQ total score in both boys and girls with FXS, when controlling for age, medication use, and FMRP levels. CONCLUSIONS: These data suggest that there are significant differences in the profile of social and communicative symptomatology in FXS compared with individuals diagnosed with idiopathic autism. Given these differences, the implementation of standard autism interventions for individuals with FXS may not be optimal. Maintaining the conceptual distinction between FXS (an established biological disease) and idiopathic autism (a phenomenologically defined behavioral disorder) may also facilitate the development of more targeted and thus effective interventions for individuals with FXS in the future.

Developmental trajectories and correlates of sensory processing in young boys with fragile X syndrome.

BACKGROUND AND PURPOSE: No longitudinal study on sensory processing in children with fragile X syndrome (FXS) exists. This study examined developmental trajectories and correlates of sensory processing from infancy through preschool years in 13 boys with FXS. METHOD: Participants were assessed using observational and parent-report measures 2-6 times between 9 and 54 months of age. RESULTS: Over time, an increasing proportion of boys displayed sensory processing that differed significantly from test norms. Observational measures were more sensitive than parent-reports early in infancy. Age and developmental quotient significantly predicted levels of hyporesponsiveness; there was a trend for hyperresponsiveness to increase with age. Baseline physiological and biological measures were not predictive. CONCLUSIONS: Sensory processing problems are observable early and grow increasingly problematic from infancy through the preschool ages. Early identification and intervention may attenuate long-term difficulties for children with FXS.

Psychological well-being of mothers of youth with fragile X syndrome: syndrome specificity and within-syndrome variability.

BACKGROUND: Research on parental well-being has focused largely on Down syndrome and autism; however, fragile X syndrome is likely to pose different challenges for parents compared with these other diagnostic conditions. Moreover, there is considerable variability among youth with fragile X syndrome; for example, 25% to 33% of affected youth meet criteria for a co-morbid diagnosis of autism. It is likely that parents of youth with fragile X syndrome will experience different degrees and patterns of stress, depending on whether their offspring do or do not have a co-morbid diagnosis of autism. In the present study, we compared mothers of three groups of young males on measures of psychological well-being and stress: those with fragile X syndrome and a co-morbid diagnosis of autism; those with fragile X syndrome alone; and those with Down syndrome. METHOD: The sample consisted of mothers of adolescent and young adult males with fragile X syndrome and co-morbid autism (n=9), fragile X syndrome alone (n=19), and Down syndrome (n=19). We screened all youth for autism using the Autism Behavior Checklist, which was completed by mothers, fathers and teachers, and the youth who scored above the suggested cut-off were evaluated by a licensed psychologist to determine autism status. The three groups of youth did not differ in chronological age (16.4, 15.8 and 16.0 years, respectively) or non-verbal mental age (3.8, 3.9 and 3.8 years, respectively). Several self-report measures were completed by mothers. These measures assessed current mental health status (e.g. the Center for Epidemiological Studies Depression Scale), perceptions of their son's and family's functioning (e.g. the Positive Affect Index, which measures closeness felt by the mother to her son and also reciprocated closeness felt by the son towards the mother, as perceived by the mother), and approach to coping with their son's disability [e.g. the Multidimensional Coping Inventory (COPE), which measures emotion-focused and problem-solving focused coping]. RESULTS: The results suggest that fragile X syndrome creates more challenges to maternal psychological well-being than Down syndrome, and that the combination of fragile X syndrome and autism can be particularly challenging. Differences among groups, however, were manifested mainly as concerns about the affected son and about relationships within the family rather than as lower levels of mental health. Thus, mothers of sons with fragile X syndrome, regardless of the son's autism status, reported more pessimism about the son's future and more conflict within the family than mothers of sons with Down syndrome. Additionally, mothers of sons with fragile X syndrome and co-morbid autism reported lower levels of reciprocated closeness than the other two groups of mothers. CONCLUSION: 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.

Is fragile X syndrome a pervasive developmental disability? Cognitive ability and adaptive behavior in males with the full mutation.

In addition to mental retardation (MR), fragile X [fra(X)] syndrome has been associated with various psychopathologies, although it appears that the link is secondary to MR. It has been proposed that individuals with the full mutation be classified as a subcategory of pervasive developmental disorders (PDD). If fra(X) males are to be categorized as PDD, how do they compare with other types of developmental disabilities? We examined 27 fra(X) males aged 3-14 years, from 4 sites in North America. Measures of cognitive abilities were obtained from the Stanford-Binet Fourth Edition (SBFE), while levels of adaptive behavior were evaluated using the Vineland Adaptive Behavior Scales (VABS). Control subjects were sex-, age-, and IQ matched children and adolescents ascertained from the Developmental Evaluation Clinic (DEC) at Kings County Hospital. At the DEC, control subjects were diagnosed as either MR (n = 43) or autistic disorder (AD; n = 22). To compare subjects' adaptive behavior (SQ) with their cognitive abilities (IQ), a ratio of [(SQ/IQ) x 100] was computed. Results graphed as cumulative distribution functions (cdf) revealed that the cdf for AD males, who by definition are socially impaired, was positioned to the left of the cdf for MR controls, as expected. Mean ratio for AD males (70) was lower than for MR males (84). On the other hand, the cdf for fra(X) males was positioned far to the right of either AD or MR controls (mean ratio = 125). Statistical tests showed that SQ of fra(X) males was significantly higher than controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Longitudinal changes in IQ among fragile X males: clinical evidence of more than one mutation?

Longitudinal changes in IQ among mentally retarded (MR) fragile X [fra(x)] males have been reported previously. While age is associated with decline in IQ, not all males are so affected. This suggests that there may be more than one subtype of affected fra(X) male. Therefore, we examined the distribution of standardized difference scores (Zdiff) in IQ to determine if subjects were from an admixture of at least 2 populations. Cluster analysis of Zdiff scores was used to partition subjects into 2 groups. Goodness-of-fit tests indicated that scores were more likely to come from an admixture. Discriminant functions (DF) were calculated to determine predictive validity of Zdiff scores. To eliminate the effect of skewing, a power transform was applied to Zdiff scores and DFs recomputed. Zdiff and transformed scores provided similar results. The mean and variance for one group showed no differences in test-retest scores as would be expected from examining any population while the mean for the second group indicated significant decline in IQ nearly 4 standard errors below the first test score. These results suggest that there may be clinical evidence for 2 types of fra(X) mutation: One which causes MR but is static, and a second mutation which causes MR but is dynamic and contributes to an apparent longitudinal decline in cognitive function.

Mode of inheritance influences behavioral expression and molecular control of cognitive deficits in female carriers of the fragile X syndrome.

The effect of mode of inheritance on expression of fragile X syndrome [fra(X)] was investigated in nonretarded female carriers. Examination included cognitive and molecular measures. A priori predictions about cognitive impairment and size of an unstable region of DNA containing a CGG repeat on the X chromosome were tested in age and education matched heterozygotes grouped according to parental inheritance. Nine carriers with a maternal fra(X) chromosome, 11 carriers with a paternal fra(X) chromosome and 15 control mothers of children with non X-linked developmental disabilities were tested. Inheritance was established through DNA linkage analysis. Cognitive skills were assessed using the Wechsler Adult Intelligence Scale-Revised and the Benton Visual Retention Test. Molecular status was assessed by Southern blot analysis of genomic DNA digested with Eco RI and Eag I, and probed with StB 12.3. Results supported the inheritance models' predictions. Heterozygotes who inherited the fra(X) from their fathers appeared to be a homogeneous group. They were indistinguishable from controls on cognitive measures and all had genomic insertions of less than 500 base pairs. In contrast, heterozygotes who inherited the fra(X) chromosome from their mothers appeared to be made up of 2 sub-populations. They were as a group deficient in measures of attention and visual memory, but not other measures, with scores of some women consistently below the other subjects. Further, they had some members with greater than 500 base pair inserts.(ABSTRACT TRUNCATED AT 250 WORDS)

The behaviour of fragile X and other aberrations during recovery from low folate conditions.

Whole blood from two mentally retarded fra-X brothers was grown in low folate medium where fra-X expression was enhanced. Bromodeoxyuridine was added to mitigate the low folate conditions and metaphases were sampled sequentially, and stained for replication banding, through one cell cycle of recovery. The replication bands allowed detailed analysis of the cell cycle and the allocation of individual cells to precise sub-phases. Various classes of fra-X and all other types of chromosomal aberrations were scored in these classified cells. The fra-X does not conform in morphology to any of the known simple chromatid intrachange types, which were often present within the same cells, but the subsequent fall in frequency once bromodeoxyuridine was added closely paralleled that of the conventional aberrations. Normal folate level frequencies of fra-X are restored by the time early S-phase cells (sub-phase SkI) reach metaphase. When sub-phased cells are rearranged in true chronological sequence, there is a suggestion of a sudden fall in frequency between SkII-III (about 70% of the transit of S). This suggests that the critical point for low folate enhancement occurs in this region of the S-phase. This is somewhat earlier than the band-appearance distribution curve for Xq27 which lies within sub-phase SkIV.