A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome.

Medical Investigation of Neurodevelopmental Disorders (M.I.N.D.), Institute, University of California-Davis Medical Center, 2825 50th Street, Sacramento, CA 95817, USA.
Journal of Neurodevelopmental Disorders (Impact Factor: 3.71). 03/2009; 1(1):33-45. DOI: 10.1007/s11689-008-9001-8
Source: PubMed

ABSTRACT Intelligence testing in children with intellectual disabilities (ID) has significant limitations. The normative samples of widely used intelligence tests, such as the Wechsler Intelligence Scales, rarely include an adequate number of subjects with ID needed to provide sensitive measurement in the very low ability range, and they are highly subject to floor effects. The IQ measurement problems in these children prevent characterization of strengths and weaknesses, poorer estimates of cognitive abilities in research applications, and in clinical settings, limited utility for assessment, prognosis estimation, and planning intervention. Here, we examined the sensitivity of the Wechsler Intelligence Scale for Children (WISC-III) in a large sample of children with fragile X syndrome (FXS), the most common cause of inherited ID. The WISC-III was administered to 217 children with FXS (age 6-17 years, 83 girls and 134 boys). Using raw norms data obtained with permission from the Psychological Corporation, we calculated normalized scores representing each participant's actual deviation from the standardization sample using a z-score transformation. To validate this approach, we compared correlations between the new normalized scores versus the usual standard scores with a measure of adaptive behavior (Vineland Adaptive Behavior Scales) and with a genetic measure specific to FXS (FMR1 protein or FMRP). The distribution of WISC-III standard scores showed significant skewing with floor effects in a high proportion of participants, especially males (64.9%-94.0% across subtests). With the z-score normalization, the flooring problems were eliminated and scores were normally distributed. Furthermore, we found correlations between cognitive performance and adaptive behavior, and between cognition and FMRP that were very much improved when using these normalized scores in contrast to the usual standardized scores. The results of this study show that meaningful variation in intellectual ability in children with FXS, and probably other populations of children with neurodevelopmental disorders, is obscured by the usual translation of raw scores into standardized scores. A method of raw score transformation may improve the characterization of cognitive functioning in ID populations, especially for research applications.

1 Bookmark
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fragile X syndrome (FXS) results from dynamic mutations leading ultimately to the absence of expression of the Fragile X Mental Retardation Protein (FMRP). It is characterized by synaptic upregulated protein synthesis and immature dendritic spines associated with altered brain plasticity and cognitive functions. Recent work in Fmr1 knockout mice has shown that lovastatin, an inhibitor of Ras-ERK1/2, normalized hippocampus protein synthesis. We hypothesize that lovastatin, as a disease-modifying drug, would counterweigh the absence of FMRP and improve behavior. Here we report a phase I study to assess the safety and efficacy of lovastatin in individuals with FXS. A total of 15 patients (13 males, 6–31 years old) were treated with escalating doses of lovastatin (up to 40 mg) for three months. Their behavior were assessed before and after treatment using the Aberrant Behavioral Checklist—Community (ABC-C) total score (primary outcome), as well as domains of the FXS validated version of the ABC-C (secondary outcomes). The treatment was well tolerated and minimal side effects were reported. Significant improvement in the primary outcome (P < 0.005), as well as in secondary outcomes, were observed in the majority of the subjects (12/15). We think that long-term sustained treatment with diseased-modifying drugs would be necessary in order to improve behavior and ultimately learning. Lovastatin, well known for its long-term security profile, would be a good candidate for that purposes. Our study showing reassuring safety data along with potential functional benefit emphasizes the need of a placebo-controlled trial to ascertain lovastatin efficacy in FXS individuals. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2014; · 2.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fragile X Syndrome (FXS) is a commonly inherited form of intellectual disability and one of the leading genetic causes for autism spectrum disorder. Clinical symptoms of FXS can include impaired cognition, anxiety, hyperactivity, social phobia, and repetitive behaviors. FXS is caused by a CGG repeat mutation which expands a region on the X chromosome containing the FMR1 gene. In FXS, a full mutation (> 200 repeats) leads to hypermethylation of FMR1, an epigenetic mechanism that effectively silences FMR1 gene expression and reduces levels of the FMR1 gene product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that is important for the regulation of protein expression. In an effort to further understand how loss of FMR1 and FMRP contribute to FXS symptomology, several FXS animal models have been created. The most well characterized rodent model is the Fmr1 knockout (KO) mouse, which lacks FMRP protein due to a disruption in its Fmr1 gene. Here, we review the behavioral phenotyping of the Fmr1 KO mouse to date, and discuss the clinical relevance of this mouse model to the human FXS condition. While much remains to be learned about FXS, the Fmr1 KO mouse is a valuable tool for understanding the repercussions of functional loss of FMRP and assessing the efficacy of pharmacological compounds in ameliorating the molecular and behavioral phenotypes relevant to FXS.
    Intractable & rare diseases research. 11/2014; 3(4):118-33.
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study was designed to examine longitudinal change in nonverbal cognitive abilities across adolescence for 20 males with Down syndrome (DS). We used hierarchical linear modeling to examine the rate of change in performance on the subtests of the Leiter-R Brief IQ across four annual time points and to determine the relation between maternal IQ and level and rate of change in performance. Results indicated no significant change in IQ (standard scores) with age in the sample, suggesting IQ stability during adolescence for individuals with DS, although several participants performed at floor level on the standard scores for the Leiter-R, limiting interpretation. Growth scores, however, provide a metric of absolute ability level, allow for the examination of change in Leiter-R performance in all participants, and minimize floor effects. Results from the analysis of growth scores indicated significant gain in absolute nonverbal cognitive ability levels (growth score values) over time for the adolescents with DS, although the growth varied by subdomain. Maternal IQ did not explain variability in cognitive performance or change in that performance over time in our sample of adolescents with DS.
    Research in Developmental Disabilities 08/2014; 35(11):2933-2941. · 3.40 Impact Factor

Full-text (2 Sources)

Available from
May 21, 2014