Jacquelyn Bertrand

LIM-kinase1 hemizygosity implicated in impaired visuospatial constructive cognition.

To identify genes important for human cognitive development, we studied Williams syndrome (WS), a developmental disorder that includes poor visuospatial constructive cognition. Here we describe two families with a partial WS phenotype; affected members have the specific WS cognitive profile and vascular disease, but lack other WS features. Submicroscopic chromosome 7q11.23 deletions cosegregate with this phenotype in both families. DNA sequence analyses of the region affected by the smallest deletion (83.6 kb) revealed two genes, elastin (ELN) and LIM-kinase1 (LIMK1). The latter encodes a novel protein kinase with LIM domains and is strongly expressed in the brain. Because ELN mutations cause vascular disease but not cognitive abnormalities, these data implicate LIMK1 hemizygosity in imparied visuospatial constructive cognition.

Attentional Characteristics of Infants and Toddlers With Williams Syndrome During Triadic Interactions

Two studies were conducted to consider the looking behavior of infants and toddlers with Williams syndrome (WS). In Study 1, the looking behavior of a 10-month-old girl with WS during play sessions with her mother and with a stranger was compared to that of 2 groups of infants who were developing normally (ND), 1 matched for chronological age and the other for developmental age. The infant with WS spent more than twice as much time looking at her mother as the infants in either contrast group did. She also spent twice as much time looking at the stranger. In addition, during 78% of this time, her gaze at the stranger was coded as extremely intense. Looks of this intensity were virtually never made by the ND infants. In Study 2, the looking behavior of 31 individuals with WS ages 8 to 43 months during a genetics evaluation was compared to that of 319 control children in the same age range (242 with developmental delay due to causes other than WS). Twenty-three of the 25 participants with WS aged 33 months or younger demonstrated extended and intense looking at the geneticist. In contrast, none of the control participants looked extensively or intently at the geneticist. Findings are discussed in the context of previous research on arousal and focused attention during normal development and on temperament and personality of older children and adults with WS. It is argued that the unusual looking patterns evidenced by infants and toddlers with WS presage the unusual temperament and personality of older individuals with WS, and the possibility of a genetic basis for these behaviors is addressed.

GTF2I hemizygosity implicated in mental retardation in Williams syndrome: Genotype–phenotype analysis of five families with deletions in the Williams syndrome region

Most individuals with Williams syndrome (WS) have a 1.6 Mb deletion in chromosome 7q11.23 that encompasses the elastin (ELN) gene, while most families with autosomal dominant supravalvar aortic stenosis (SVAS) have point mutations in ELN. The overlap of the clinical phenotypes of the two conditions (cardiovascular disease and connective tissue abnormalities such as hernias) is due to the effect of haploinsufficiency of ELN. SVAS families often have affected individuals with some WS facial features, most commonly in infancy, suggesting that ELN plays a role in WS facial gestalt as well. To find other genes contributing to the WS phenotype, we studied five families with SVAS who have small deletions in the WS region. None of the families had mental retardation, but affected family members had the Williams Syndrome Cognitive Profile (WSCP). All families shared a deletion of LIMK1, which encodes a protein strongly expressed in the brain, supporting the hypothesis that LIMK1 hemizygosity contributes to impairment in visuospatial constructive cognition. While the deletions from the families nearly spanned the WS region, none had a deletion of FKBP6 or GTF2I, suggesting that the mental retardation seen in WS is associated with deletion of either the centromeric and/or telomeric portions of the region. Comparison of these five families with reports of other individuals with partial deletions of the WS region most strongly implicates GTF2I in the mental retardation of WS.

Interventions for children with Fetal Alcohol Spectrum Disorders (FASDS): Overview of findings for five innovative research projects

It is well established that prenatal exposure to alcohol causes damage to the developing fetus, resulting in a spectrum of disorders known as fetal alcohol spectrum disorders (FASDs). Although our understanding of the deficits and disturbances associated with FASDs is far from complete, there are consistent findings indicating these are serious, lifelong disabilities-especially when these disabilities result from central nervous system damage. Until recently, information and strategies for interventions specific to individuals with FASDs have been gleaned from interventions used with people with other disabilities and from the practical wisdom gained by parents and clinicians through trial and error or shared through informal networks. Although informative to a limited degree, such interventions have been implemented without being evaluated systematically or scientifically. The purpose of this article is to provide a brief overview of a general intervention framework developed for individuals with FASDs and the methods and general findings of five specific intervention research studies conducted within this framework. The studies evaluated five different interventions in five diverse locations in the United States, with different segments of the FASD population. Nonetheless, all participants showed improvement in the target behaviors or skills, with four studies achieving statistical significance in treatment outcomes. Important lessons emerged from these five interventions that may explain success: including parent education or training, teaching children specific skills they would usually learn by observation or abstraction, and integration into existing systems of treatment. A major implication of these research studies for families dealing with FASDs is that there are now interventions available that can address their childrens needs and that can be presented as scientifically validated and efficacious to intervention agents such as schools, social services, and mental health providers. In the field of FASD research and clinical service, a common theme reported by families has been that clinicians and professionals have been reluctant to diagnose their children because there were no known effective treatments. Results of these five studies dispel that concern by demonstrating several interventions that have been shown to improve the lives of individuals with FASDs and their families.

The association of mild, moderate, and binge prenatal alcohol exposure and child neuropsychological outcomes: a meta-analysis.

BACKGROUND The objective of this review is to evaluate the literature on the association between mild, moderate, and binge prenatal alcohol exposure and child neurodevelopment. METHODS Meta-analysis with systematic searches of MEDLINE (1970 through August 2012), EMBASE (1988 through August 2012), and PsycINFO(®) (1970 through August 2012) and examination of selected references. RESULTS From 1,593 articles, we identified 34 presenting data from cohort studies that met our inclusion criteria. Information on study population, outcomes, measurement instruments, timing and quantification of alcohol exposure, covariates, and results was abstracted. Outcomes included academic performance, attention, behavior, cognition, language skills, memory, and visual and motor development. The quality of each article was assessed by 2 researchers using the Newcastle-Ottawa Scale. Based on 8 studies of 10,000 children aged 6 months through 14 years, we observed a significant detrimental association between any binge prenatal alcohol exposure and child cognition (Cohens d [a standardized mean difference score] -0.13; 95% confidence interval [CI], -0.21, -0.05). Based on 3 high-quality studies of 11,900 children aged 9 months to 5 years, we observed a statistically significant detrimental association between moderate prenatal alcohol exposure and child behavior (Cohens d -0.15; 95% CI, -0.28, -0.03). We observed a significant, albeit small, positive association between mild-to-moderate prenatal alcohol exposure and child cognition (Cohens d 0.04; 95% CI, 0.00, 0.08), but the association was not significant after post hoc exclusion of 1 large study that assessed mild consumption nor was it significant when including only studies that assessed moderate alcohol consumption. None of the other completed meta-analyses resulted in statistically significant associations between mild, moderate, or binge prenatal alcohol exposure and child neuropsychological outcomes. CONCLUSIONS Our findings support previous findings suggesting the detrimental effects of prenatal binge drinking on child cognition. Prenatal alcohol exposure at levels less than daily drinking might be detrimentally associated with child behavior. The results of this review highlight the importance of abstaining from binge drinking during pregnancy and provide evidence that there is no known safe amount of alcohol to consume while pregnant.

The effect of different alcohol drinking patterns in early to mid pregnancy on the child’s intelligence, attention, and executive function

Please cite this paper as: Kesmodel U, Bertrand J, Støvring H, Skarpness B, Denny C, Mortensen E, the Lifestyle During Pregnancy Study Group. The effect of different alcohol drinking patterns in early to mid pregnancy on the child’s intelligence, attention, and executive function. BJOG 2012;119:1180–1190.

Drawing by children with Williams syndrome: A developmental perspective

Two studies are presented that investigate the developmental aspect of visual‐motor integration by children with Williams syndrome and normally developing children. In Study 1, drawings by 9‐ and 10‐year‐olds with Williams syndrome were compared to drawings by 2 groups of normally developing children: 1 group individually matched for chronological age and another group individually matched for mental age. In Study 2, the normal developmental course for this spatial cognitive skill was examined for 40 normally developing children ages 4 years to 7 years. In both studies, 2 drawing tasks were used: the Short Form of the Developmental Test of Visual Motor Integration (VMI) and drawing then copying a flower, house, and elephant from the Boston Diagnostic Aphasia Evaluation (BDAE). Results from Study 1 indicated that, as expected, the children with Williams syndrome scored significantly lower on the VMI and produced significantly fewer recognizable drawings than did either their chronological age matches or th...

The effects of low to moderate alcohol consumption and binge drinking in early pregnancy on executive function in 5‐year‐old children

Please cite this paper as: SkogerbøÅ, Kesmodel U, Wimberley T, Støvring H, Bertrand J, Landrø N, Mortensen E. The effects of low to moderate alcohol consumption and binge drinking in early pregnancy on executive function in 5‐year‐old children. BJOG 2012;119:1201–1210.

Predictors of Intelligence at the Age of 5: Family, Pregnancy and Birth Characteristics, Postnatal Influences, and Postnatal Growth

Parental education and maternal intelligence are well-known predictors of child IQ. However, the literature regarding other factors that may contribute to individual differences in IQ is inconclusive. The aim of this study was to examine the contribution of a number of variables whose predictive status remain unclarified, in a sample of basically healthy children with a low rate of pre- and postnatal complications. 1,782 5-year-old children sampled from the Danish National Birth Cohort (2003–2007) were assessed with a short form of the Wechsler Preschool and Primary Scale of Intelligence – Revised. Information on parental characteristics, pregnancy and birth factors, postnatal influences, and postnatal growth was collected during pregnancy and at follow-up. A model including study design variables and child’s sex explained 7% of the variance in IQ, while parental education and maternal IQ increased the explained variance to 24%. Other predictors were parity, maternal BMI, birth weight, breastfeeding, and the child’s head circumference and height at follow-up. These variables, however, only increased the explained variance to 29%. The results suggest that parental education and maternal IQ are major predictors of IQ and should be included routinely in studies of cognitive development. Obstetrical and postnatal factors also predict IQ, but their contribution may be of comparatively limited magnitude.

The effects of low to moderate prenatal alcohol exposure in early pregnancy on IQ in 5-year-old children.

Please cite this paper as: Falgreen Eriksen H, Mortensen E, Kilburn T, Underbjerg M, Bertrand J, Støvring H, Wimberley T, Grove J, Kesmodel U. The effects of low to moderate prenatal alcohol exposure in early pregnancy on IQ in 5‐year‐old children. BJOG 2012;119:1191–1200.