Blink rate in boys with fragile X syndrome: preliminary evidence for altered dopamine function.

BACKGROUND: Dopamine, a neurotransmitter involved in motor and cognitive functioning, can be non-invasively measured via observation of spontaneous blink rates. Blink rates have been studied in a number of clinical conditions including schizophrenia, autism, Parkinsons, and attention deficit/hyperactivity disorder with results implicating either hyper or hypo dopaminergic states. METHODS: This study examined spontaneous blink rate in boys with fragile X syndrome (FXS). Blink rates of boys (4-8 years old) with FXS (n = 6) were compared with those of age-matched typically developing boys (n = 6) during active and passive tasks. Blink rates (blinks per minute) for each task were compared between the two groups. Then, the relation between blink measures and core FXS-related features [problem behaviours, arousal, fmr 1 protein (FMRP)] were examined within the group of boys with FXS. RESULTS: Blink rate in boys with FXS was significantly higher than typically developing boys during passive tasks. Within the FXS group, there were significant correlations between blink rate and problem behaviours and physiological arousal (i.e. heart activity) but not with FMRP. CONCLUSIONS: Observed differences in spontaneous blink rate between boys with and without FXS and the relation between blink rate and physiological and behavioural measures in boys with FXS suggests that further work examining dopamine dysfunction as a factor in the pathophysiology of FXS may be warranted.

Cardiovascular indices of physiological arousal in boys with fragile X syndrome.

In this study, the relationship between physiological arousal, as indexed by heart rate variability, was examined in boys with fragile X syndrome (FXS) and typically developing boys matched on chronological age. In addition, the relationship of heart activity to clinical and molecular factors in the group of boys with FXS was examined. Results suggest that boys with FXS have higher levels of heart activity during the passive phases, as reflected in shorter heart periods. This high level of heart activity appears to be due to increased sympathetic activity and reduced parasympathetic activity. Boys with FXS did not display the expected patterns of heart activity in response to phases of increasing challenge, and sympathetic and parasympathetic systems did not appear coordinated in these boys with FXS. Clinical factors may be related to neural regulation of heart activity while molecular factors do not appear to be.

Autistic behavior, FMR1 protein, and developmental trajectories in young males with fragile X syndrome.

In the context of a longitudinal study, we assessed the relationship between ratings of autistic behavior, FMR1 protein expression (FMRP), and the developmental trajectories of 55 young males with fragile X syndrome. Autistic behavior, as measured by the Childhood Autism Rating Scale, was not related to FMRP expression. However, autistic behavior was a significant predictor of both developmental status and developmental change. Boys with both autistic behavior and fragile X syndrome functioned at significantly lower levels of development and grew at significantly slower rates than those without autistic behavior. FMRP expression accounted for less variance in developmental level than did autistic behavior, and was not significantly related to slope (developmental change over time). No autistic behavior x FMRP interaction was found.

Variability in FMRP and early development in males with fragile X syndrome.

To test the hypothesis that variability in development in fragile X syndrome is related to FMRP (the protein deficient in this syndrome expression), we studied 53 males between 23 and 98 months of age. For the entire group, which included males with either mosaism, partially methylated full mutation, and fully methylated full mutation, FMRP expression ranged from 1% to 40% and accounted for a small but significant amount of variance in level, but not rate, of total development as well as motor, social, adaptive, cognitive, and language development. For males with a fully methylated full mutation, the association was in the hypothesized direction, but not statistically significant. Findings support the hypothesized relationship between FMRP and individual capabilities but suggest that other factors also play a major role.

Early development, temperament, and functional impairment in autism and fragile X syndrome.

We compared the developmental status, functional abilities, and temperament of 31 young boys with fragile X syndrome (FXS) who did not have autism, matched on chronological age, gender, and race, with 31 boys with autism but no FXS. Children with autism exhibited a more variable profile of development in comparison with a relatively flat profile for children with FXS. Children with autism were significantly more delayed in social skills and were rated by observers as exhibiting a greater degree of impairment in cognitive, communication, and social skills. On temperament ratings, both groups were slower to adapt, less persistent, and more withdrawing than the reference group. Boys with FXS were rated as more active than the referent group, whereas boys with autism were rated as less intense, more distractible, having a higher threshold for response, and less rhythmic than the reference group. A smaller three-group analysis compared boys with FXS, boys with autism, and boys with both FXS and autism. Children with both autism and FXS were substantially more delayed than children with autism or FXS alone.

Behavioral style of young boys with fragile X syndrome.

To study the behavioral style or temperament of 45 boys, aged 47 to 88 months, with full-mutation fragile X syndrome (FXS), 102 parent ratings on the Behavioral Style Questionnaire (McDevitt and Carey 1978) were recorded. These ratings were analysed with a variety of statistical techniques. Considerable variability was evident in temperament profiles; consequently, a characteristic profile was not identified for FXS. Boys with FXS differed significantly from the reference sample on five of nine temperament dimensions. They were more active and less intense, approachable, adaptable, and persistent. No significant differences were found in distractibility, rhythmicity, mood, or sensory threshold. Only 16 of the 45 boys in the sample could be classified as easy, difficult, or slow to warm up. There was no link between severity of developmental disability and temperament ratings. This supports the theory that intelligence and temperament are separate constructs. Scores on temperament dimensions were stable over time. Our results suggest that many of the behaviors observed in boys with FXS may be related to temperament. Consequently, parent counseling and environmental modifications should be considered as first line treatment. The question of whether the behavior problems observed in boys with FXS are innate or whether they result from poorness of fit between child and environment is an important issue that needs further study.

Early developmental trajectories of males with fragile X syndrome.

Findings from a prospective longitudinal study of 46 boys with fragile X syndrome between the ages of 24 and 72 months were reported. Hierarchical linear modeling was used to construct and evaluate overall developmental trajectories and scores in five domains: Cognition, Communication, Adaptive, Motor, and Personal-Social. The children varied widely, with significant differences across individuals in both mean rate and level of performance. Overall development was significantly delayed, with a slope of .48--approximately half the rate expected for typically developing children. No differences were found in rates of growth across the five domains. Significant differences were found, however, in mean levels of performance. At every age tested, Motor and Adaptive scores were higher than Communication and Cognitive.

Autistic behavior in young boys with fragile X syndrome.

A sample of 57 boys with fragile X syndrome (fraX) between the ages of 24 and 133 months was rated using the Childhood Autism Rating Scale (CARS) to assess the extent to which autism and autistic features were evident in a young population. Fourteen subjects (approximately 25% of the sample) scored above the cutoff for autism, suggesting a relatively high incidence of autistic behavior. All but 2 of these 14 were in the mildly or moderately autistic range, however, and only a few items received severe ratings, suggesting that severe autism is relatively rare in fraX, at least during the early years. The CARS resulted in a continuum of autistic ratings in the fraX population, but no particular items on the CARS contributed disproportionately to autism ratings. A visual comparison of ratings on an autistic, non-fraX sample revealed similar profiles of ratings, suggesting that differentiating fraX and autism on the basis of CARS ratings is not likely. Within the fraX group, chronological age and socioeconomic status did not correlate with CARS ratings, but severity of delay was strongly related, such that more severely delayed children scored higher (more autistic) on the CARS.

Ocular status of boys with fragile X syndrome: a prospective study.

PURPOSE: The purpose of this study was to determine whether the high rates of ocular problems described in previous retrospective reports of individuals with fragile X syndrome were present in a prospective sample of young boys. Fragile X syndrome is currently considered the leading hereditary cause of mental retardation, with prevalence estimates of 1:2500 to 1:5000 males. METHODS: Forty-eight boys with fragile X syndrome between the ages of 2.5 and 11 years were evaluated for ocular abnormalities. They received complete ophthalmic evaluations including assessment of visual acuity, cycloplegic refraction, ocular motility assessment, and dilated fundus examination. RESULTS: Approximately 25% of the children had clinically significant ocular findings that included refractive errors (17%, primarily hyperopia and astigmatism) and strabismus (8%). Of the 42 children with quantifiable visual acuities, only 1 child, with diagnoses of nystagmus and hyperopia, had a Snellen visual acuity that was not within normal limits for his age. Three of the 5 children with gross measures of visual acuity had clinically significant findings: 2 had hyperopia greater than 3.5 diopters and 1 had esotropia. The other 2 children with gross measures of acuity and the 1 child without visual acuity assessment had cycloplegic refractions of +1.25 to +1.5 and ocular motility appeared normal. CONCLUSIONS: These results suggest that previous reports of high rates of vision problems, particularly strabismus, in boys with fragile X syndrome may have resulted from selection bias. Although we did observe a higher prevalence of strabismus than that found in the general population (8% vs 0.5% to 1%), the proportion of children having strabismus in our sample was much smaller than that reported in other studies of children with fragile X syndrome (30% to 40%). However, 17% of the sample did have significant refractive errors. In addition to evaluating the ocular motility of children with fragile X syndrome, cycloplegic refraction should also be performed to determine whether refractive problems are present.