Genetic evidence that stress-activated p38 MAP kinase is necessary but not sufficient for UV activation of HIV gene expression.

We have examined the role of stress-activated p38 MAP kinase in regulating human immunodeficiency virus (HIV) gene expression in response to ultraviolet light (UV). We found that UV activated p38 in HeLa cells harboring stably integrated copies of an HIVcat plasmid to levels similar to those obtained by hyperosmotic shock. However, hyperosmotic shock resulted in one order of magnitude smaller increase in CAT activity than treatment with UV. The specific p38 inhibitor SB203580 significantly decreased (>80%) UV activation of HIV gene expression whereas PD98059, a specific MEK-1 inhibitor did not, suggesting that p38 is specifically involved in the HIV UV response and little to no contribution is provided by MEK-1 and the p42/p44 MAP kinase pathway. Whereas increased binding of NF-kappaB to an oligonucleotide spanning the HIV enhancer was observed after UV, as expected, this binding was not affected by SB203580. Furthermore, UV activation of HIV gene expression in cells having the cat reporter gene under control of an HIV promoter deleted of the enhancer (-69/+80) produced results indistinguishable from those using HIVcat/HeLa cells with an intact HIV promoter (-485/+80), suggesting that SB203580 acts through the basal transcription machinery. Northern blot analysis of steady-state RNA from HIVcat/HeLa cells revealed an almost complete inhibition of UV activation with SB203580 at the RNA level. Similarly, the UV response was almost completely obliterated at the CAT and RNA levels in HIVcat/HeLa cells stably transfected with a plasmid expressing a kinase-inactive mutant of p38 (isoform alpha), without affecting NF-kappaB activation, providing strong genetic evidence that p38, at least the alpha isoform, is necessary for UV activation of HIV gene expression and that NF-kappaB activation alone is insufficient. These results firmly establish p38 MAP kinase as a key modulator of HIV gene expression in response to UV that acts independently of NF-kappaB.

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.

Corpus callosum morphology in children with Tourette syndrome and attention deficit hyperactivity disorder.

The aim of this study was to investigate the morphology of the corpus callosum (CC) in Tourette syndrome (TS) and attention deficit hyperactivity disorder (ADHD) to determine whether these conditions affect distinct regional differences. Seventy-seven children and adolescents, aged 6 to 16 years, comprised the four research groups--16 patients with TS, 21 patients with TS plus ADHD, 13 patients with ADHD, and 27 unaffected control subjects. A semiautomated, computer-assisted procedure was used to measure the total area, five subregions, centerline length, perimeter, and bending angle of the CC. MRI data were analyzed using several statistical methods, primarily two-tailed analysis of variance to test the effects of TS and ADHD status, while controlling for the influence of age, gender, and total intracranial area (an estimate of brain size). TS was associated with significant increases in the area of four of five subdivisions, the total area, and the perimeter of the CC. ADHD was associated with a significant decrease in the area of the rostral body. There were no interactions between TS and ADHD factors. These findings suggest that the area of the CC is larger in children with TS, and that this difference is independent of age, handedness, intracranial area, and the diagnosis of ADHD. Our findings support hypotheses that the neurobiologic mechanisms in TS and ADHD involve frontal/subcortical circuits.

Neuropsychological status of children with Tourette's syndrome with and without attention deficit hyperactivity disorder.

To determine the frequency of learning disabilities (LD) and describe the neuropsychological profile of children with Tourette's syndrome (TS) with and without attention deficit hyperactivity disorder (ADHD), we analyzed psychosocial, psychoeducational, and neuropsychological data from 65 children between the ages of 6 and 14 years selected from a larger study of LD. Three groups were formed: TS only, TS+ADHD, and TS +/- ADHD. The third group was composed of children whose ADHD status was not as strongly confirmed by the three different instruments used for ADHD diagnosis. From other (non-TS) research projects in the Center, a comparison group of 27 unaffected siblings who had no diagnosis of ADHD was formed. All children were unmedicated at the time of assessment and had the full set of data available for analysis. LDs were present in 23% of the total TS sample, but LD was not present in the TS-only group. All TS groups had scores at or below 1 SD from the mean on measures of choice reaction time, but the TS-only group was significantly poorer on a measure of executive function (letter word fluency). We discuss the implication of the finding in the TS-only group in terms of a slowing of linguistic productivity.

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)

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.

A behavioral neurogenetics approach to developmental disabilities: gene-brain-behavior associations.

This review provides a discussion of behavioral neurogenetics' contribution to understanding neurodevelopmental pathways in learning and developmental disabilities. A brief overview is given of several common neurogenetic disorders with various genetic etiologies including Down syndrome, Turner syndrome, Prader-Willi syndrome, Angelman syndrome, and Tourette's syndrome. Special emphasis is placed on fragile X syndrome as representative of a newly-discovered class of genetic conditions characterized by an unstable trinucleotide repeat. A spectrum of cognitive, behavioral, and social-emotional phenotypic features associated with fragile X syndrome is examined. Also included are findings from recent neuroimaging research and a discussion of the need for the classification of symptoms on the basis of underlying genetic/medical conditions.

The effects of X monosomy on brain development: monozygotic twins discordant for Turner's syndrome.

Monosomy for the X chromosome is the most frequent cause of Turner's syndrome, a common clinical syndrome associated with particular physical and neurobehavioral features. The results from comprehensive assessment of prepubertal monozygotic female twins discordant for X monosomy are presented. Zygosity was established with DNA Fingerprinting and no evidence of chromosomal mosaicism was seen in either child. Physical features in the affected twin were relatively mild with respect to the full spectrum of physical malformations and disabilities associated with Turner's syndrome. The neurobehavioral phenotypes of the twins were compared. Although both sisters scored in the superior range of intelligence, the affected twin's Performance IQ was 18 points less than her sister, whereas Verbal IQ showed only a 3-point difference between the sisters. Other relative differences were noted within the executive, visuospatial, and visuomotor domains of function. Behavioral evaluation indicated greater problems with attention, hyperactivity, and anxiety in the affected twin. Quantitative analysis of brain anatomy revealed evidence of both general and regional effects of X monosomy on neurodevelopment. Cerebrospinal fluid volume was increased by 25% in the affected twin compared with her sister with a corresponding decrease in gray matter volume. The right frontal, right parietal-occipital, and left parietal-perisylvian regions showed the greatest discrepancy between the sisters with respect to increased cerebrospinal fluid and decreased gray matter volumes in twin with X monosomy. Differences in the posterior fossa were also noted with a 50% relative increase in the volumes of the fourth ventricle and cisterna magna and a 10 to 15% relative reduction in size of the cerebellar vermis, pons, and medulla in the affected twin. The association between the neurobehavioral and neuroanatomical findings in the affected twin is discussed. The unique nature of the naturally occurring genetic phenomenon seen in this twin pair provides an opportunity to more fully elucidate the neurobehavioral phenotype associated with X monosomy and Turner's syndrome.