Family environment and cognitive abilities in girls with fragile-X syndrome.

BACKGROUND: There remains some variance in cognitive ability that is unexplained in children with fragile-X syndrome (FXS). Studies in typically developing children suggest that family environment might be one contributor to this unexplained variance. However, the effect of family environment in relation to cognition in atypical children with FXS has been relatively unexplored to date. METHODS: The present authors examined the putative genetic and environmental factors associated with cognition in a group of age-matched children consisting of 26 females with FXS and 31 typically developing children. All subjects were administered the Wechsler Intelligence Scale for Children-Revised; and the subjects' parents were administered the Wechsler Adult Intelligence Scale-Revised, and completed the Hollingshead Index of Social Status and the Moos & Moos Family Environment Scale. RESULTS: Using a multiple regression analytic strategy, the present authors found that family environment contributed significantly to cognitive abilities in typically developing girls, but did not have a unique contribution to cognitive abilities in girls with FXS. There was a suggestion that, for girls with FXS, socio-economic status, a measure of sociocultural environment, was correlated with IQ. CONCLUSIONS: The present study provides a basis for future research on the environmental contributions to cognitive abilities, particularly work related to verbal cognition.

Brain anatomy, gender and IQ in children and adolescents with fragile X syndrome.

This study utilized MRI data to describe neuroanatomical morphology in children and adolescents with fragile X syndrome, the most common inherited cause of developmental disability. The syndrome provides a model for understanding how specific genetic factors can influence both neuroanatomy and cognitive capacity. Thirty-seven children and adolescents with fragile X syndrome received an MRI scan and cognitive testing. Scanning procedures and analytical strategies were identical to those reported in an earlier study of 85 typically developing children, permitting a comparison with a previously published template of normal brain development. Regression analyses indicated that there was a normative age-related decrease in grey matter and an increase in white matter. However, caudate and ventricular CSF volumes were significantly enlarged, and caudate volumes decreased with age. Rates of reduction of cortical grey matter were different for males and females. IQ scores were not significantly correlated with volumes of cortical and subcortical grey matter, and these relationships were statistically different from the correlational patterns observed in typically developing children. Children with fragile X syndrome exhibited several typical neurodevelopmental patterns. Aberrations in volumes of subcortical nuclei, gender differences in rates of cortical grey matter reduction and an absence of correlation between grey matter and cognitive performance provided indices of the deleterious effects of the fragile X mutation on the brain's structural organization.

Behavior phenotype in the RSH/Smith-Lemli-Opitz syndrome.

The behavior phenotype of Smith-Lemli-Opitz syndrome (SLOS) was studied by assessing behavior, social, and communication abilities, sensory hyperreactivity, and the deficits associated with autistic disorder. Fifty-six SLOS subjects, age 0.3 to 32.3 years, were evaluated by multiple age-dependent questionnaires and telephone interviews. Of the 56 subjects, 50 (89%) had a history of repeated self-injury: 30 (54%) bit themselves; 27 (48%) head-banged; and 30 (54%) threw themselves backward in a highly characteristic upper body movement ("opisthokinesis"). Forty-seven of these subjects were also evaluated by direct observation and by direct interview of the parent or caregiver. Of 11 subjects 10 years or older, three (27%) had a stereotypic stretching motion of the upper body accompanied by hand flicking. Additional measures showed sensory hyperreactivity, temperament dysregulation, sleep disturbance, and social and communication deficits. Nine of 17 subjects (53%) met the diagnostic criteria for autistic disorder by the Autism Diagnostic Interview-Revised (ADI-R) algorithm questions [Lord et al., 1993, 1994]. Thus, SLOS is a metabolic disorder that can be associated with autism and other behavioral characteristics that define a distinctive and diagnostically important behavioral disorder.

Social functioning among girls with fragile X or Turner syndrome and their sisters.

Social behaviors among two genetically homogeneous groups--girls with fragile X (fraX) or Turner syndrome (TS)--were examined to address the role of family environment versus biological determinants of social dysfunction in girls with these disorders. Using a sibling pair design, girls with fraX or TS were compared with their own sisters on measures of IQ and social functioning. The 8 girls with fraX and the 9 girls with TS had lower FSIQ scores and higher ratings of social and attention problems relative to their own sisters. Girls with fraX also had higher ratings of withdrawn behaviors, relative to their own sisters. The unaffected sisters were not rated as demonstrating any difficulties in these areas, relative to controls. Correlations between problem ratings and FSIQ were not statistically significant. Although these preliminary findings do not indicate a lack of familial impact on social development in girls with either disorder, the results provide preliminary evidence that social dysfunction reported for girls with fraX or TS cannot be attributed solely, nor primarily, to global aspects of the family environment.

Autistic behaviors among girls with fragile X syndrome.

Reports of autistic behaviors were examined for 30 school-age girls with fragile X (fraX) and 31 age- and IQ-matched controls through a structured interview administered to each girl's parent(s). IQ scores were obtained for each participant; anxiety, neuroanatomical, and molecular-genetic data were derived for girls with fraX. Girls with fraX had significantly more autistic behaviors than controls. These behaviors were qualitatively similar to those reported for boys with fraX, but were not correlated with IQ. Anxiety in girls with fraX was positively correlated with abnormal social and communication behaviors; posterior cerebellar vermis area was negatively correlated with measures of communication and stereotypic/restricted behaviors. Severity of stereotypic/restricted behaviors was negatively correlated with the prevalence of active non-fraX chromosomes. Thus anxiety and posterior cerebellar area measures had distinct associations with subsets of autistic behaviors; these associations may have important implications for understanding the neurobiology of autism.

Cognitive, behavioral, and neuroanatomical assessment of two unrelated male children expressing FRAXE.

Standardized cognitive, behavioral, and neuroanatomical data are presented on 2 unrelated boys with the FRAXE (FMR2) GCC expansion mutation. In the context of normal IQ, both boys had a history of developmental delay, including significant problems with communication, attention, and overactivity. Additionally, one child was diagnosed with autistic disorder. Data from these 2 cases are compared to analogous information from previous reports about individuals with the FRAXE or FRAXA (FMR1) mutation. These comparisons support the idea that FRAXE is associated with nonspecific developmental delay and possibly high-functioning autism.

Contribution of the FMR1 gene mutation to human intellectual dysfunction.

The degree to which genetic factors influence human intelligence remains a matter of some controversy. However, there is little doubt that single gene mutations can significantly alter brain development and function. For example, mutations affecting the FMR1 gene cause the fragile X syndrome, the most prevalent known inherited cause of intellectual dysfunction. The most common mutation occurring in the FMR1 locus involves expansion of a trinucleotide (CGG)n repeat sequence within the promoter region of the gene. Between 6 and 54 repeats are typically observed in individuals from the general population. When > or = 200 CGG repeats are present, the expanded repeat sequence and an adjacent CpG island are usually hypermethylated, Aa phenomenon associated with transcriptional silencing of the gene and commonly referred to as the FMR1 full mutation. The intermediate range of repeats (approximately 50 to 200 CGGs), referred to as the premutation, is characterized by the absence of hypermethylation within the promoter region and normal phenotype. Some individuals have a combination of methylated and unmethylated alleles of differing size and are referred to as having mosaic status. Most males with the FMR1 full mutation function in the mentally retarded range of intelligence; in contrast, females with the FMR1 full mutation show a broader range of intelligence, from mental retardation to normal IQ.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurodevelopmental effects of X monosomy: a volumetric imaging study.

Thirty girls with Turner syndrome (TuS) were compared with 30 individually age-matched controls on volumetric brain measures derived from magnetic resonance imaging and on measures of psychological functioning. As expected, girls with TuS performed more poorly on visual-spatial and intellectual measures relative to controls, and were rated by their parents as having more significant problems in attention and social behaviors. Although no group differences in overall cerebral or subcortical volumes were observed, the regional distribution of gray and white matter differed across groups in both right and left parietal regions. Differences in total tissue volume ratios were seen for both right and left parietal areas, but differences in individual gray and white matter ratios were seen exclusively in the right parietal regions. In general, girls with TuS had a smaller proportion of tissue (gray and white) within the right and left parietal regions, and a larger proportion of tissue within the right inferior parietal-occipital region relative to girls in the control group. These data suggest a potentially important role for X chromosome genes and/or sex steroids in the development and specialization of brain structure and function.

Specification of the neurobehavioral phenotype in males with fragile X syndrome.

OBJECTIVE: A controlled clinical study was designed to identify the neurobehavioral profile that is specific to males with fragile X syndrome. DESIGN: Thirty-one males with fragile X syndrome and 30 age and IQ-matched male controls were evaluated with instruments that assess multiple domains of adaptive functioning and problem behaviors. The Vineland Adaptive Behavior Scales and the Aberrant Behavior Checklist were selected for their dimensional scaling of behavioral ratings. RESULTS: Parent and Teacher versions of the Aberrant Behavior Checklist demonstrated a profile of behaviors specific to males with fragile X syndrome characterized by significantly higher levels of hyperactivity, stereotypic movements, and unusual speech. The Vineland Adaptive Behavior Scales revealed no fragile X-specific profile of adaptive skills development. CONCLUSIONS: The distinct pattern of aberrant behavior observed among males with fragile X emphasizes the importance of drawing subtype distinctions within the classification of individuals with mental retardation on the basis of underlying etiology. For clinical research, specifying the fragile X phenotype is a vital part in the effort to elucidate the neurodevelopmental pathways of normal behavior and psychopathology. Understanding the fragile X symptom pattern is essential for designing symptom-specific treatment interventions, as well as for research into the efficacy of interventions strategies.

An analysis of two discrepancy-based models and a processing-deficit approach in identifying learning disabilities.

The incidence of learning disabilities (LD) in a research center sample of 107 boys and 103 girls between 6 and 12 years of age was calculated using Wechsler IQ and Woodcock-Johnson cluster scores in a regression model (REG) and a reliability model (REL). The REL method identified LD three times more often than the REG method, and all those identified by REG were also identified by REL. When stratified by IQ, REG and REL identified similar percentages in the lowest IQ group; however, REG identified at a lower rate as IQ increased. All 87 children identified with reading disabilities (both REL-RD and REG-RD) were weak to a similar extent on phonemic awareness. Comorbid elevated attention ratings were found in 62% of children with RD; 26% had elevated attention ratings but no linguistic processing deficits, and 21% had at least one linguistic processing deficit but no attentionally suspect rating.

Molecular-neurobehavioral associations in females with the fragile X full mutation.

In this study, young females with the fragile X [fra(X)] full mutation (fM) were assessed using quantitative measures of mutation amplification size (Amp) as well as the ratio of active normal X chromosome to total normal X chromosome (activation ratio-AR). Neurobehavioral assessments of females with the fM were performed and included specific and general measures of cognitive and behavioral/developmental functioning. To investigate molecular-behavioral associations, Amp and AR were used as independent variables, while cognitive and behavioral scores were used as dependent variables. Significant correlations were observed between both molecular variables (Amp and AR) and measures of cognitive functioning, with AR showing the most consistent and robust correlations. As AR increased, overall IQ and specific subtest and area scores from the cognitive tests increased. Conversely, as Amp increased, the overall IQ and specific subtest and area cognitive scores decreased. No significant associations were observed between AR or Amp and measures of behavior or development. The molecular-cognitive associations were generally consistent with the cognitive profile previously described in studies comparing females with fra(X) to age-matched controls. Amp and AR were not associated with one another, nor were they associated with the same cluster of cognitive measures. Though this report does not conclusively show that AR and Amp can be used to clinically assess the risk of a female with the fM for cognitive disability, the evidence presented does suggest that these molecular variables, especially AR, reflect important underlying genetic factors contributing to the fra(X) phenotype.

Psychiatric disorders associated with fragile X in the young female.

Seventeen females with the fragile X mutation and 17 non-fragile X females group-matched on age (range 4 to 27 years), IQ (range 34 to 126), and socioeconomic status were compared on Diagnostic and Statistical Manual of Mental Disorders (3rd ed, revised) criteria for selected psychiatric disorders. Additional comparisons were made on level of social development and parent and teacher ratings of maladaptive behaviors. Correlations of genetic testing data with psychiatric and behavioral variables were investigated. Consistent with hypotheses, females with the fragile X mutation showed a greater frequency of avoidant disorder and mood disorders compared with control subjects. Females with the fragile X mutation also showed greater frequency of stereotypy/habit disorder when compared with control subjects. Contrary to predictions, females with the fragile X mutation did not show higher frequencies of attention deficit hyperactivity disorder or undifferentiated attention deficit. They showed greater deficits in their interpersonal socialization skills and were rated by their parents and teachers as significantly more withdrawn and depressed when compared with control subjects. The size of the DNA insertion associated with the genetic abnormality was correlated with IQ, severity of attention problems, and anxiety/withdrawal symptoms. Evidence from this study points to an association between a specific genetic syndrome and characteristic developmental and psychiatric difficulties. Implications for the clinician are discussed.

Chromosome fragility and psychopathology in obligate female carriers of the fragile X chromosome.

The relationship between fragility (the percentage of cells exhibiting the fragile X chromosome abnormality) and psychopathological conditions was investigated in a sample of 40 obligate female carriers of the fragile X chromosome. Subjects were categorized by those with positive fragility greater than 0% (n = 19) and those with 0% fragility (n = 21). Compared with women with 0% fragility, it was expected that women with positive fragility would have a higher likelihood of manifesting a spectrum of social and psychological disability previously shown to be associated with fragile X syndrome in women. It was also expected that within the group with positive fragility, degree of fragility would be related to severity of symptoms. Results partially supported the hypotheses: women with fragility over 0% were more likely to be assigned a diagnosis of schizotypal features, were rated higher on symptoms associated with the schizophrenia spectrum, and scored lower on IQ, level of healthiest functioning, education, and socioeconomic status than women with 0% fragility. Subsequent comparisons with a control group indicated that the group with 0% fragility and normal controls did not differ on these variables. Within the group with positive fragility, increasing fragility was related to greater severity of symptoms and lower IQ, education, socioeconomic status, and levels of adaptive functioning, as predicted. Contrary to expectations, positive fragility was not associated with proportion of affective disorder diagnoses or ratings on affective disorder symptoms. The results of the study provide evidence that degree of fragility is a potentially important predictor of psychopathology among women with normal IQ who are carriers of the fragile X chromosome abnormality.

Cognitive profiles associated with the fra(X) syndrome in males and females.

Twenty-three fragile X [fra(X)] males (mean IQ 50, mean age 10 years) and 11 fra(X) females (mean IQ 84, mean age 11.3 years) were administered the Stanford-Binet Intelligence Scale, 4th ed. (S-B). The cognitive profiles generated from the S-B indicated a pattern of subtest strengths and weaknesses that was similar for both groups. Consistent weaknesses in both groups were found in quantitative skills and short-term memory recall for visually presented, abstract stimuli, whereas a consistent strength was observed for short-term memory recall of visually presented, meaningful stimuli. Strengths in verbal labeling and comprehension and deficits in spatial visualization and visual-motor coordination were identified by the S-B for the male group but not for the female group. Fragility in the female group was negatively correlated with the S-B score for the short-term memory area and the combined S-B scores for the verbal reasoning and quantitative reasoning areas. The specific, S-B-identified cognitive strengths and weaknesses associated with the fra(X) condition are potentially useful indicators for investigation of specific cognitive process deficits associated with the fra(X) condition and the design of appropriate educational interventions for fra(X) children.

Neuroanatomy of fragile X syndrome: the posterior fossa.

The occurrence and specificity of posterior fossa abnormalities as measured from magnetic resonance images of the brain were investigated in a group of 14 males with fragile X syndrome and comparison groups consisting of 17 males with other causes of developmental disability and 18 males with normal IQs. The size of the posterior cerebellar vermis was significantly decreased and the fourth ventricle significantly increased in the group of males with fragile X syndrome compared with males in both comparison groups. These neuroanatomical abnormalities appeared to be secondary to hypoplasia rather than atrophy.

Rating problem behaviors in outpatients with mental retardation: use of the Aberrant Behavior Checklist.

Parent and teacher ratings of behavior problems of an outpatient sample of 110 children, adolescents, and young adults with IQs ranging from severe mental retardation to borderline were obtained using a modified version of the Aberrant Behavior Checklist (ABC). Using factor analytic techniques, the five-factor structure of the parent data corresponded extremely well with the five factors originally obtained from staff ratings of mentally retarded inpatients (i.e., Irritability, Withdrawal, Hyperactivity, Stereotypies, and Inappropriate Speech). Factor content was virtually identical between the parent and original ABC data with differences involving only one or two items per scale. The teacher data also revealed a factor structure that corresponded to the same five factors as the parent and original data. Although the teacher and parent factors showed a high degree of similarity, the teacher data suggested that the Stereotypies and Inappropriate Speech factors of the parent and original analyses were not the same constructs for teacher respondents. Age was related to the withdrawal factor for parent data; level of intellectual functioning was the only subject characteristic related to factor scale scores in both parent and teacher data. Test-retest reliabilities were adequate to excellent for all factors for both parent and teacher data. Parent-teacher cross-informant reliabilities were adequate for at least four of the factors. The results of the report indicate that the ABC is a useful, reliable instrument for assessing maladaptive behaviors in young, developmentally disabled outpatients.

Maternal regulation of children's problem-solving behavior and its impact on children's performance.

This study focused on a social interaction theory of the development of cognitive self-regulation. Specifically, the effect of mother-child interaction on the child's ability to problem solve was investigated. The general predictions were (1) children who interacted with their mothers throughout a problem-solving task would subsequently exhibit improved independent performance over practice-control children, who received corrective feedback from a female experimenter at the end of the task; (2) mothers would be more responsible for task activities, would more often regulate their child's task behaviors, and offer more specific verbal content when task demands on child competence increased than when they decreased. 60 3- and 5-year-olds either worked with their mothers or practiced alone and were given corrective feedback on a sorting task in which miniature pieces of furniture were placed in a doll house. As predicted, children who interacted with their mothers subsequently created more correct, adult-like groupings independently than children who received corrective feedback. Mothers displayed more task responsibility and regulation with younger children and when task demands on children of both age groups increased. Maternal verbal content became less specific when task demands decreased. Child performance was related to (1) variation in maternal regulation of the child; and (2) degree of specificity of maternal verbal content.