Decreased cerebellar posterior vermis size in fragile X syndrome: correlation with neurocognitive performance.

We examined whether posterior vermis size is smaller in individuals with fragile X syndrome (fra X) than in control subjects and whether this decreased size is associated with cognitive performance. Cognitive and behavioral dysfunctions have been identified in fra X; however, underlying neuropathogenic mechanisms remain unclear. MRI was used to investigate the posterior fossa in 32 males with fra X, 28 males with other causes of cognitive disability (CD), and 38 males with normal development (ND) as well as and in 37 females with fra X and 53 female control subjects. Among females with fra X, neurocognitive correlates of posterior vermis size were examined. Posterior vermis size (cross-sectional area) in males with fra X was significantly smaller compared with CD and ND groups, particularly when corrected for intracranial area. Posterior vermis size corrected for intracranial area was significantly smaller in females with fra X compared with control subjects. Compared with males with fra X and non-fra X control subjects, posterior vermis size in females with fra X was intermediate. After statistically removing the effect of mean parental IQ, posterior vermis size predicted a significant proportion of the variance (10 to 23%) of performance on full-scale, verbal, and performance IQ; block design; categories achieved on the Wisconsin Card Sorting Test; and the Rey inventory score. The size of the posterior vermis is significantly decreased in fra X, more so in males than in females. In females with fra X, posterior vermis size predicts performance on selected cognitive measures.

A process approach to describing mathematics difficulties in girls with Turner syndrome.

OBJECTIVE: To expand on previous reports of mathematics difficulty in girls with Turner syndrome (TS). METHODS: Mathematics performance was examined by evaluating the types of errors made on mathematics achievement subtests by 29 girls with TS, 26 girls with fragile X syndrome (another genetic condition associated with mathematics difficulty), and 41 girls with neither disorder. Correlations between mathematics achievement scores and measures of IQ, attention, and visuospatial skills were also examined. RESULTS: Relatively low mathematics achievement was evident in girls with TS before 10 years of age, and a higher percentage of girls with TS made operation (57%) and alignment (48%) errors on a mathematics calculations test than did girls with fragile X syndrome (19% and 14%, respectively). No group differences were found for procedural or multiplication table errors. Girls with TS attempted more "unfamiliar" problems than did girls with fragile X syndrome or girls in the comparison group. Mathematics achievement scores in girls with TS were positively correlated with Judgment of Line Orientation and Wechsler Intelligence Scale for Children-Revised Third Factor scores; these correlations differed from those in the other groups. CONCLUSIONS: The qualitative group differences observed further support the concept of specificity of the TS phenotype and illustrate the importance of a process approach to assessment.

Preliminary evidence for a cognitive phenotype in Barth syndrome.

Barth syndrome (BTHS) is a rare, X-linked, recessive disorder that affects almost exclusively males. It is characterized by short stature, cardioskeletal myopathy, cyclic neutropenia, increased excretion of 3-methylglutaconic acid in the urine, and moderate hypocholesterolemia. The objective of the present study was to assess whether BTHS presents with a cognitive phenotype. Preliminary data were collected from five kindergarten or first-grade boys with BTHS. An abbreviated psychoeducational test battery was administered to each boy, and parents of each boy completed standardized behavior rating scales. Data from 120 boys of similar age or grade level were used for one comparison group; a subset of this sample comprised a comparison group that was individually matched on age and grade level to one of the five boys with BTHS. Preliminary data reflect a higher incidence of cognitive difficulties in boys with BTHS relative to both comparison groups. Boys with BTHS had significantly lower visual spatial skills, but comparable reading-related skills, when compared with either group. Although based on a small sample size, the preliminary data presented in this work are the first indication of a cognitive phenotype associated with BTHS.

Neuropsychological profiles of three sisters homozygous for the fragile X premutation.

Fragile X syndrome (fraX) is associated with an amplification of a CGG repeat within the fraX mental retardation (FMR-1) gene. We describe an exceptional family in which 3 adult sisters are homozygous for the FMR-1 premutation. Each sister inherited 2 premutation alleles (ca. 80 CGG repeats) from their biologically unrelated parents. The 3 sisters were administered measures of executive function, visual spatial, memory, and verbal skills. Deficiencies in the first 2 of these domains have been reported among females with the full mutation. The sisters' performances were compared with available normative data and with published group means for females affected by fraX. These women did not appear to have verbal or memory difficulties. None of the women demonstrated a global executive function deficit, and none had global deficits in spatial ability. The profiles of these sisters are consistent with reports that the fragile X premutation does not affect cognitive performance.

Problem solving limitations among cytogenetically expressing fragile X women.

Neurocognitive deficits among fragile X individuals have been reported for both high and low functioning individuals. Recent findings from our research suggest a specific neurocognitive phenotype among fragile X women that is characterized by deficits on tests of frontal lobe functioning. In this paper, we examine in more detail the performance of 10 cytogenetically expressing women and 10 control women on 2 problem solving measures considered sensitive to frontal lobe functions: the Contingency Naming Test and the Tower of Hanoi. The results pertaining to each test suggest that fragile X women, relative to control women, are less able to solve a problem when the difficulty of the problem is increased by requiring simultaneous consideration of additional information. These findings have important implications for remediation strategies designed for affected fragile X individuals.

Maximizing the sensitivity of a screening questionnaire for determining Fragile X at-risk status.

Parents of 55 preschool and school-aged children with the FMR1 full mutation (fM) completed a brief screening questionnaire. Parents of 55 additional children, each of whom was individually matched for sex, age, and IQ to one of the 55 children with Fragile X syndrome, also completed a questionnaire. Items on the questionnaire concerned behavior, rather than physical features or family history, associated with Fragile X syndrome. Children with the fM were more likely than controls to be on prescription medication, to have poor eye contact, to be described as nervous or anxious, and to regularly engage in repetitive movements and/or repetitive speech. Moreover, children with the fM received higher total scores on the questionnaire than their matched controls. These results suggest that questions about behavior are useful in the diagnostic evaluation of Fragile X syndrome, especially in the absence of the recognizable physical features associated with this condition.

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.

High functioning fragile X males: demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression.

Fragile X (fra(X)) males with a standardized IQ score of 70 or higher represent a high functioning (HF) or nonretarded fra(X) male group. This group, which does not include nonpenetrant males, has received little research attention to date. Of 221 fra(X) males who had been evaluated through The Children's Hospital in Denver since 1981 and had completed cognitive or developmental testing, 29 (13%) were high functioning by the above definition. We found that HF males on the whole had a lower cytogenetic score and were younger than retarded fra(X) males, but there was no difference between these two groups in the number of typical fra(X) physical manifestations present. FMR-1 DNA testing was performed on 134 fra(X) males and methylation status was determined for 51 of these. A greater percentage of HF males had a mosaic pattern or an incompletely methylated full mutation than did retarded males. A unique DNA pattern, an unmethylated fully expanded mutation, was discovered in 3 of the highest functioning fra(X) males. Protein studies performed on 2 of these males demonstrated the presence of FMR-1 protein, albeit at lower levels than normal. FMR-1 protein was not present in retarded fra(X) males. Significant FMR-1 protein expression may be responsible for higher cognitive functioning in the 2 males with unmethylated fully expanded mutations compared to retarded fra(X) males.

Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1.

To address the controversy regarding the relationship between cognitive impairment (lowering of IQ) and magnetic resonance imaging (MRI) characteristics (T2-weighted hyperintensities or unidentified bright objects [UBOs]) in children with neurofibromatosis-1 (NF-1), we used a pairwise NF-1/ sibling design; we set out to predict the lowering of IQ in each child with NF-1 as a discrepancy from the IQ of an unaffected sibling (D-SIQ). Our multiple regression model included the age of the child with NF-1, familial or sporadic nature of the NF-1, number of locations in the child's brain occupied by T2-weighted hyperintensities (UBOs), and the volumetric percentage of brain tissue occupied by T2-weighted hyperintensities (UBOs). Only the number of locations occupied by UBOs accounted for IQ lowering (D-SIQ) in children with NF-1 (42% of the variance in D-SIQ). This is the first report to confirm that a continuum of lowered IQs in NF-1-affected children exists in relation to the distribution of UBOs (range 0-7), not just presence (vs. absence) of any UBOs.

Behavioral and psychiatric disorders in adult male carriers of fragile X.

OBJECTIVE: In the present study we examined the incidence of psychiatric and behavioral problems among male carriers of the fragile X gene. METHOD: Retrospective data on carrier males were gathered using the family informant method. Each of 56 fragile X carrier women was interviewed about her father by an examiner blind to the father's carrier status. The interviewer administered measures of (1) behaviors related to DSM-III-R Axis I disorders, (2) adult attention-deficit hyperactivity disorder (ADHD) behaviors, (3) parental bonding skills, and (4) abusive behaviors. The endorsements from 24 women with fragile X fathers were compared with endorsements from 32 women with nonfragile X fathers. RESULTS: The results show a higher incidence of psychopathology among the fragile X males (relative to nonfragile X fathers) for behaviors related to adult ADHD, parental bonding, abuse; and particularly for alcohol abuse/dependence and obsessive-compulsive disorder behaviors. CONCLUSIONS: These findings support the hypotheses that some "nonpenetrant" males may indeed be mildly affected carriers and that there is a broad spectrum of involvement among carrier males.

Specific frontal lobe deficits among women with the fragile X gene.

The neurocognitive phenotype of fragile X and its relation to cytogenetic expression were examined among 10 fragile X women with > or = 2% expression, 10 0% obligate carriers, and 10 controls. Measures were obtained for intellectual ability, achievement, and verbal, nonverbal, memory, and frontal lobe functions. Results show that no group demonstrated deficits on verbal, nonverbal, or memory measures. In contrast, when controlling for effects of IQ, the expressing fragile X women exhibited (1) deficits on measures of frontal lobe functioning, and (2) enhanced performance on verbal, but not figural, memory. Frontal lobe deficits may account for behavioral and cognitive manifestations of fragile X.

Social cognition skills among females with fragile X.

Emotion perception and perspective-taking skills were examined among women with or without the fragile X gene. The performance of 56 control women was compared to the performance of 46 women who were carriers of the fragile X gene. Twenty-seven of the carrier women had 0-1% cytogenetic expression and did not appear affected by the gene, whereas the remaining 19 women had > or = 2% cytogenetic expression and did appear affected by the gene. The emotion perception task employed was one for which deficits have been reported among individuals with autism. The results show that performance on this emotion-perception test and the perspective-taking measure was significantly related to full-scale IQ scores, but not to fragile X group status when effects of IQ were removed. Thus the results do not support the hypothesis that perspective-taking or emotion perception deficits are a component of the fragile X phenotype in females and represent an important differentiation between fragile X and autism.

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.

Neuromotor functioning in children with Tourette syndrome with and without attention deficit hyperactivity disorder.

Neuromotor function was assessed in 94 children of normal intelligence with Tourette syndrome, Tourette syndrome and attention-deficit hyperactivity disorder (ADHD), or ADHD only, using the Physical and Neurological Examination of Subtle Signs (PANESS). Time to complete six motor movements was analyzed separately by side (left and right) and complexity (simple and patterned). All groups performed faster on their preferred, dominant side. Although all groups took longer to complete patterned versus simple movements, the group with ADHD had a larger discrepancy for complexity than the other two groups. The speed for simple and patterned tasks was at or faster than age expectations for 54% of tasks in the group with Tourette syndrome but only 15% of tasks in the other two groups. More children in the group with Tourette syndrome (76%) than the groups with Tourette syndrome with ADHD (54%) or ADHD (54%) or ADHD only (65%) performed movements within normal time limits for age. Findings suggest that Tourette syndrome is not associated with motor slowing.

The neurocognitive phenotype of female carriers of fragile X: additional evidence for specificity.

The specificity of the neurocognitive profile among women with the fragile X gene, in relation to cytogenetic expression, was examined among 22 women with > or = 2% expression, 35 0% obligate carriers, and 60 controls. Measures were obtained for intellectual ability; achievement; and verbal, nonverbal, memory, and executive functions. Findings show that no group consistently demonstrated global deficits in the verbal, nonverbal or memory domains. In contrast, even when controlling for the effects of IQ, the expressing women exhibited (1) deficits on measures of executive function, (2) deficits in measures of attention and visual-spatial skills, and (3) enhanced performance on verbal, but not figural, memory. No deficits were seen among obligate carriers. This study supports the notion that executive function deficits and/or visual-spatial skills may account for the behavioral and cognitive manifestations of fragile X.

No widespread psychological effect of the fragile X premutation in childhood: evidence from a preliminary controlled study.

This study was designed to examine the effect of the fragile X premutation (pM) on cognitive function and behavior. Participants included 14 children (7 males, 7 females) with the fragile X pM and 14 children without the fragile X pM (and without the fragile X full mutation [fM]), each of whom was matched by age and gender with one of the participants from the pM group. The children ranged in age from 3 years, 1 month, to 17 years, 11 months. Participants were individually administered measures of intellectual functioning, academic achievement, and visual motor integration. Parent rating scales of problem behaviors were completed. Group differences were examined using nonparametric statistics. No statistically significant differences were found between the premutation and nonpremutation groups. The results from this study are consistent with the hypothesis that the premutation does not, in general, have an effect on a child's development. However, this does not preclude cases where specific factors may lead to a specific phenotype.

The FMR1 and FMR2 mutations are not common etiologies of academic difficulty among school-age children.

The prevalence of the fragile X mental retardation (FMR) 1 and FMR2 full mutations (fM) was examined among 1014 school-age children with academic difficulties but without mental retardation. Both Southern blot and polymerase chain reaction analyses for FMR1 and FMR2 were performed on samples obtained from these children. No fM genes were found, and one FMR1 premutation was identified. The distribution of allele sizes for both genes was comparable to those reported for other clinical and normal population samples. These results suggest that neither the FMR1 nor the FMR2 mutation is a common etiology of academic failure among school-age children without mental retardation and that the prevalence of the FMR1 premutation is no more frequent in children with academic failure than it is in the general population.

Math learning disability and math LD subtypes: evidence from studies of Turner syndrome, fragile X syndrome, and neurofibromatosis type 1.

The present study examined whether indicators of math learning disability are observed in 5- and 6-year-olds with neurofibromatosis type 1 (NF1) and in 5- to 6-year-old girls with Turner syndrome or fragile X syndrome. Data from 14 girls with Turner syndrome, 9 girls with fragile X syndrome, and 11 children with NF1 were compared to data from control participants matched on age, sex, IQ score, and grade level. The results indicate that girls with fragile X syndrome or Turner syndrome are significantly more likely to have specific math difficulties relative to their control group, with a larger effect size demonstrated by the group with Turner syndrome. Young children with NF1 had a heterogeneous profile not suggestive of specific math disability. The results are discussed in terms of their implications for understanding math disability subtypes and the identification of math difficulty in the early school years.

The utility of kindergarten teacher ratings for predicting low academic achievement in first grade.

The purpose of this study was to assess the predictive value of kindergarten teachers' ratings of pupils for later first-grade academic achievement. Kindergarten students were rated by their teachers on a variety of variables, including math and reading performance, teacher concerns, and amount of learning relative to peers. These variables were then analyzed with respect to outcome measures for math and reading ability administered in the first grade. The teachers' ratings of academic performance were significantly correlated with scores on the outcome measures. Analyses were also carried out to determine sensitivity, specificity, and predictive values of the different teacher ratings. The results indicated high overall accuracy, sensitivity, specificity, and negative predictive value for the ratings. Positive predictive value tended to be lower. A recommendation to follow from these results is that teacher ratings of this sort be used to determine which children should receive cognitive screening measures to further enhance identification of children at risk for learning disability. However, this recommendation is limited by the lack of empirically supported screening measures for math disability versus well-supported screening tools for reading disability.