Williams Syndrome Individuals Research Articles

Neuronal Gtf2i deletion alters mitochondrial and autophagic properties

Gtf2i encodes the general transcription factor II-I (TFII-I), with peak expression during pre-natal and early post-natal brain development stages. Because these stages are critical for proper brain development, we studied at the single-cell level the consequences of Gtf2i’s deletion from excitatory neurons, specifically on mitochondria. Here we show that Gtf2i’s deletion resulted in abnormal morphology, disrupted mRNA related to mitochondrial fission and fusion, and altered autophagy/mitophagy protein expression. These changes align with elevated reactive oxygen species levels, illuminating Gtf2i’s importance in neurons mitochondrial function. Similar mitochondrial issues were demonstrated by Gtf2i heterozygous model, mirroring the human condition in Williams syndrome (WS), and by hemizygous neuronal Gtf2i deletion model, indicating Gtf2i’s dosage-sensitive role in mitochondrial regulation. Clinically relevant, we observed altered transcript levels related to mitochondria, hypoxia, and autophagy in frontal cortex tissue from WS individuals. Our study reveals mitochondrial and autophagy-related deficits shedding light on WS and other Gtf2i-related disorders.

Neuroanatomical correlates of social approach in Williams Syndrome and down syndrome

Individuals with Williams Syndrome (WS) or Downs Syndrome (DS) are often described as hypersociable, friendly and overly trusting of others. This hypersociability is a major concern for parents/caregivers due to the associated increased risk of exploitation and victimisation. Two brain regions - the amygdala and the orbitofrontal cortex (OFC) - have been implicated in driving this hypersociability in WS, and in the general population and have associations with emotional evaluation, threat detection and social motivation. However, there has been little neuroimaging research on this topic, especially in DS, to date. The aim of the present study was to investigate the potential neuroanatomical and neuropsychological correlates of hypersociability in WS and DS. Twelve individuals with WS (M = 22 years of age) and eleven individuals with DS (M = 26 years of age) completed a neuropsychological battery of executive functioning and social measures, including informant ratings on an ecologically measure of social approach. Clinical groups and twelve typically developing controls (M = 23 years) underwent a magnetic resonance imaging scan to investigate volumetric differences in the OFC and the amygdala. As expected, WS individuals displayed the highest overall social approach, especially in relation to need to approach strangers and drive to interact with strangers, as well as inappropriate/overfriendly behaviours. Both groups rated similarly in terms of social trust and unconditional positive regard. Emotion recognition abilities were similar across groups, with the DS group displaying some difficulties with negative emotions (especially anger). Inhibition and flexibility were similarly impaired across WS and DS. Compared to neurotypical controls, the DS group showed increased amygdala volumes bilaterally, while the WS group showed an enlarged right medial OFC. Approach ratings were significantly correlated with left amygdala and medial and left lateral OFC volumes in WS, and with these same regions bilaterally in DS. Results provide potential biological explanations for the hypersociability seen in WS and DS. Future research should focus on other potential neural correlates, as well as potential genetic and hormonal contributions to approach.

Audiological profile and cochlear functionality in Williams syndrome.

to evaluate cochlear functionality in Williams syndrome (WS) individuals. a study with 39 individuals, being 22 with WS aged between 7 and 17 years, 15 male and 7 female, and 17 individuals with typical development and normal hearing. All individuals were evaluated using pure tone audiometry, acoustic immittance measurements, and Transient Evoked Otoacoustic Emissions (TEOAE). The audiological profile in individuals with WS was analyzed, and TEOAE responses were compared between WS individuals without hearing loss and typical developmental individuals. The hearing loss was observed in 50% of patients, being 78.95% sensorineural and 21.05% mixed. This hearing loss was predominantly mild to moderate, affecting mainly frequencies above 3 kHz. As for TEOAE, there was a higher incidence of absence and lower amplitude responses in individuals with WS. WS individuals have hair cell dysfunction, mainly in the basal region of the cochlea. Thus, TEOAE analysis is an important clinical resource to be considered in the routine audiological evaluation.

Decomposing response times in Williams syndrome in separate cognitive processes

ABSTRACT Williams Syndrome (WS) is a rare neurodevelopmental disorder of genetic origin. The syndrome is characterised by a selective set of deficits in a number of cognitive domains. In spite of a wealth of studies, response times (RTs) of WS have attracted little attention. In the present study, we fill this gap by analysing data from a receptive vocabulary task using the Diffusion Decision Model (DDM). Our results show that the speed of accumulation, decision threshold and non-decision time parameters of WS individuals are similar to these of typically developing 5-year-old preschoolers. In addition, WS verbal intelligence scores were associated with the speed of accumulation of lexical information. Finally, the performance of WS and preschooler individuals was correlated across the vocabulary task and an additional orientation discrimination task only at the group but not at the individual level; therefore, pointing to domain-specific lexical and perceptual processing in WS.

Cognitive profile of young children with Williams syndrome.

There is very little research on the cognitive profile of young children with Williams syndrome (WS). The present study utilised the Differential Ability Scales - Second Edition to examine the early cognitive abilities of 22 young children with WS (aged 3.98 to 7.70years, 10 male and 12 female participants). Overall, IQ ranged from 38 (severely impaired) to 81.00 (low average). Consistent with Mervis et al. who looked at an older sample, over half (59.08%) of our young WS sample showed a significant and abnormal weakness in spatial ability relative to verbal ability. Moreover, 81.82% showed a significant and clinically unusual weakness in spatial ability relative to nonverbal reasoning ability. At the subtest level, only 4.55% of our sample showed a significant strength in naming vocabulary compared with verbal comprehension, while 13.64% showed a significant weakness in naming vocabulary relative to verbal comprehension. The results of the present study show cognitive heterogeneity, consistent with the literature on older children and adults with WS. There were variable levels of intellect and variable patterns of cognitive strength and weakness across both index and subtest scores. Findings highlight the need for individual assessment and management of young children with WS but also indicate that for the majority of WS individuals spatial skills are indeed an area of significant and abnormal weakness and should be a focus for early intervention.

Abnormal auditory event-related potentials in Williams syndrome

Individuals with Williams Syndrome (WS) have specific auditory characteristics, including hypoacusis and hyperacusis, and music appreciation skills. Little is known about the functionality of the central auditory nervous system (CANS) for sound processing in WS. Thus, the objective of the present study was to evaluate the functionality of the CANS in individuals with WS, based on auditory event-related potentials, as far as cognitive and behavioral aspects are concerned. The study was carried out with 17 individuals, seven females and ten males, between seven and 17 years old, with WS, and 17 individuals with typical development matched by sex and chronological age to individuals with WS. None of these individuals had middle ear impairment or hearing loss. The subjects were evaluated for intelligence quotient, loudness discomfort level, and auditory event-related potentials with Tone Burst stimuli, on the oddball paradigm; the parents also answered the MTA-SNAP-IV questionnaire. Hyperacusis was found in six WS individuals and two individuals with typical development. In the present study, WS individuals present longer latency and reduced amplitude for P1, N1, N2 and P3 components. These results, suggesting a delay and hypoactive responses of the CANS in this syndrome, that cannot be related to the cognitive or behavioral aspects of these individuals, but it indicates a cortical immaturity to process acoustic stimuli.

Visuospatial bias in line bisection in Williams syndrome.

Recently, a study using the subjective straight-ahead task showed that individuals with Williams syndrome (WS) present a bias in the representation of body perception. The aim of the present study is to examine the horizontal midline body representation in WS participants using the bisection line task, which is an important benchmark for an egocentric frame of reference. Fifteen WS participants (mean age=21.7±9.5years) were compared with two typical development control groups: one composed of 15 participants matched on chronological age and one composed of 15 children matched on mental age. The task consisted of dividing each line in a series of 18 lines into two equal halves by drawing a vertical mark with a pencil in the centre of the line. Individuals with WS presented a significant leftward bias in comparison to mental age and chronological age groups. The leftward deviation in WS could be linked to the body representation bias and difficulties in the development of the egocentric reference system. An early detection of such deviation should help in the development of targeted interventions for WS individuals to improve visual-spatial skills and learning.

Peripheral and Central Auditory Findings in Individuals with Williams Syndrome

Introduction: Williams syndrome (WS) is a rare neurodevelopment genetic condition. The syndrome may present manifestations associated with the central nervous system, hearing, and language. It is possible, as well, to observe an alteration in the central auditory system, which can be diagnosed through long-latency auditory evoked potential (LLAEP).
 Objective: The aim of this study was to describe and analyze the results obtained by peripheral and central auditory evaluation on individuals with WS, verifying if there is a relationship between audiological findings and gender, age and ear side.
 Methods: This is a cross-sectional study in which 14 individuals with WS were evaluated. The exams performed consisted of pure tone audiometry, vocal audiometry, acoustic immittance measures, LLAEP, and cognitive potential.
 Results: The sample was composed of patients from 4 to 18 years old, with a mean age of 11.6 years old (±5.3), being 9 males (64.3%) and 5 females (35.7%). We mainly verified mild to moderate degree (40-44%) of sensorineural auditory loss (35.7-42.9%), type A tympanometric curve (57.1-64.3%), and absent acoustic reflexes (57.1%). As for central auditory evaluation, the subjects showed latency delay in all of the LLAEP components. Moreover, it was evidenced a statistically significant difference when comparing ears for amplitude on cognitive potential evaluation (p = 0.032), observing higher values at the left ear. It was also observed an inverse association between age and P1 wave latency both on the right (p = 0.006) and on the left ear (p = 0.022), and this result can be related to the nervous system maturational process of the WS individuals.
 Conclusion: There are few studies investigating the central auditory pathway on WS in literature. The present study contributes to the extension of the knowledge about the central involvement of the auditory phenotype in the syndrome. However, considering the sample size, more studies are suggested to confirm these findings.

Extending the positive bias in Williams syndrome: The influence of biographical information on attention allocation.

There is evidence that individuals with Williams syndrome (WS) show an attention bias toward positive social-perceptual (happy) faces. Research has not yet considered whether this attention bias extends beyond social-perceptual stimuli to perceptually neutral stimuli that are paired with positive (trustworthy) biographical information. Fourteen participants with WS (mean age = 21 years, 1 month) learned to associate perceptually neutral faces with trustworthy (positive), neutral, or untrustworthy (negative) biographical information, before completing a dot-probe task where the same biographical faces were presented. The performance of the WS group was compared to two typically developing control groups, individually matched to the WS individuals on chronological age and mental age, respectively. No between-group bias toward untrustworthy characters was observed. The WS group displayed a selective attention bias toward trustworthy characters compared to both control groups (who did not show such a bias). Results support previous findings that indicate WS individuals show a preference for positive social-perceptual stimuli (happy faces) at the neurological, physiological, and attentional levels. The current findings extend this work to include a "top-down" positive bias. The implications of a positive bias that extends beyond social-perceptual stimuli (or "bottom-up" processes) in this syndrome are discussed.

Functional basic reading skills in Williams syndrome

ABSTRACTThis study investigated whether individuals with Williams syndrome (WS) can attain a functional level of basic reading skills. The Study also investigated broader cognitive factors associated with reading ability in individuals with WS. Thirty individuals with WS participated in this study (mean chronological age 21 years and mean mental age 7 years 7 months). The results supported our hypotheses that: firstly, reading abilities would be heterogeneous in WS; secondly, at least some WS individuals are capable of achieving a functional basic reading level; and thirdly, on average, WS individuals would find reading of nonwords more difficult than reading of regular and irregular words. Moreover, higher reading ability was found to be associated with increased outcomes in adaptive functioning, in particular, Written and Expressive Communication skills and Community Living skills, highlighting the potential benefits of developing reading abilities in WS. Although Intelligence Quotient (IQ) was related to overall basic reading ability generally, it was not found to be a determining factor in reading subtypes. Several cognitive skills known to be related to reading ability in typically developing individuals were found to be associated with reading performance and reading subtypes. Implications for appropriate reading instruction are discussed.

Hearing in Williams Syndrome: From Input to Processing

Williams Syndrome (WS) is a rare genetic disease recurrent from a microdeletion of 1.5 ~ 1.8 Mb on the long arm of the chromosome 7q11.23, involving approximately 26 to 28 genes. Although these individuals present a number of physical malformations and varying cognitive deficits, an intriguing aspect of this syndrome is high auditory sensitivity and musical appreciation, which can occur concurrently with hearing loss. Several studies in the literature have used auditory tests in order to characterize the audiological profile of these patients and, thus, to seek indications that allow us to better understand how the auditory information processing in this syndrome occurs. Thus, the present study aimed to assess and describe the main characteristics of the auditory phenotype in individuals with Williams syndrome (WS) related to sound conduction and processing by the auditory system and to search for scientific evidence of genetic factors that may affect the auditory characteristics of this population. Some genes frequently absent in WS individuals may be responsible for changes in the structures and functionality of the auditory system and the brain and may be related to some auditory characteristics observed in this population. The absence of acoustic reflexes has been reported, as well as, cochlear impairment with absence of Otoacoustic Emissions and progressive sensorineural hearing loss, mainly in the high frequencies. As for auditory processing, more studies are needed in order to better understand how sound processing occurs in these patients. Some genes that are frequently absent in WS, including ELN, GTF21 and LIMK1, may account for changes in the structures and functions of the auditory system and brain as a whole in these individuals and may be related to certain auditory characteristics observed in this population. Further studies on auditory processing are needed to better understand how sound processing occurs in these individuals.

What gestures reveal about cognitive deficits in Williams Syndrome

ABSTRACTGestures have a central role in speaking and thinking about spatial information. The goal of the present study is to examine the function of gestures in Williams Syndrome (WS), a genetic disorder characterized by spatial impairments and a preservation of communication. The study’s subjects were 11 WS individuals and 22 typically-developing controls who performed a narrative task. We analyzed offline gesture production and its relation with language and spatial information. Compared to the control groups, WS individuals produced more representational gestures that anticipated, supplemented, or gesture-only communication. Gestures produced by WS participants serve a compensatory role particularly in representing spatial contents.

The proceedings of the 15th professional conference on Williams Syndrome.

Williams Syndrome (WS) is a contiguous gene deletion disorder, caused by the deletion of approximately 26-28 genes from chromosome 7 (7q11.23). Individuals with WS have complex medical, developmental, and behavioral features, requiring multidisciplinary and interdisciplinary collaboration. Guidelines detailing the identification, evaluation, and monitoring of individuals with WS need clarification, especially for primary care providers who are first-line in their management. This report summarizes the proceedings of the 2016 Professional Conference on WS in Columbus, OH. Presentations were directed towards primary care providers and subspecialists, emphasizing evidence-based practices for treating the prevalent medical and behavioral features of WS. Included in this report are findings from a panel of cardiovascular experts discussing three case studies on treatment of hypertension and the use of sedation or anesthesia for non-cardiac procedures. Abstracts from individual expert presenters are included, covering various medical and behavioral topics, and providing updates in management of WS individuals. The following topics were discussed: differences in phenotypes of 7q11.23 deletion versus duplication, growth parameters, endocrine concerns, sleep difficulties, behaviors to monitor, and pharmacological options, the neurodevelopmental profile of WS individuals, and the importance of monitoring medical and behavioral concerns as WS individuals transition to adulthood.

Where is the 'subjective straight ahead' in Williams syndrome?

Individuals with Williams Syndrome (WS) are known to have particular difficulties when performing visuo-spatial tasks, which could be related to their difficulties in using a specific reference system to determine spatial relations. The aim of the present study was to assess the internal representation of the body's sagittal plane, which is an important benchmark for an egocentric frame of reference. The results of 18 WS individuals (mean age=20.5±9.2years) on the subjective straight ahead (SSA) task were compared with those of two healthy control groups composed of 36 participants matched on chronological age matched on chronological age (CA) and 30 young children matched on non-verbal intellectual ability (YC). Individuals with WS showed a significant left deviation on the SSA body's sagittal plane representation compared with the chronological age control group and a marginal left deviation compared with the young children control group. A comparison with the objective SA (0°) showed a significant leftward deviation in the WS group but not in the two control groups. Individuals with WS showed a significant leftward deviation in the SSA task. This bias of the body's longitudinal axe representation could have a negative impact on the use of an egocentric reference system, which could be the cause for their difficulties in defining spatial relations (e.g. location and orientation) necessary for performing spatial tasks.

An interpretative phenomenological analysis of the lived musical experiences of three Williams syndrome individuals

The purpose of this interpretative phenomenological analysis (IPA) is to understand the lived musical experiences of three individuals living with Williams syndrome (WS). We are interested in their lived musical experiences because the musical abilities of WS individuals are similar to those of normal control groups despite their severe cognitive impairments. Although there is literature on the medical manifestations of the syndrome, there is no research on their lived musical experiences. Their musical experiences need to be explored as a possible way to help them to cope with their unique challenges. In this IPA we used semi-structured interviews and the six steps of data analysis for IPA suggested by Smith et al. (2009). Four superordinate themes emerged from data analysis, namely, that: a) the participants have a passion for performance; b) music allows the participants to foster friendships; c) music allows them to cope with challenging situations; and d) they display musical dependency. The findings of this study can be used to advocate the importance of music in the everyday lives of individuals with WS.

Modeling Williams syndrome with induced pluripotent stem cells.

The development of induced pluripotent stem cells (iPSCs) like never before has opened novel opportunity to study diseases in relevant cell types. In our recent study, Williams syndrome (WS), a rare genetic neurodevelopmental disorder, that is caused by hemizygous deletion of 25-28 genes on chromosome 7, is of interest because of its unique cognitive and social profiles. Little is known about haploinsufficiency effect of those deleted genes on molecular and cellular phenotypes at the neural level due to the lack of relevant human cellular model. Using the cellular reprogramming approach, we reported that WS iPSC-derived neural progenitor cells (NPCs) has increased apoptosis and therefore increased doubling time, which could be rescued by complementation of frizzled 9, one of the genes typically deleted in WS. Moreover, WS iPSC-derived CTIP2-positive pyramidal neurons exhibit morphologic alterations including longer total dendrites and increasing dendritic spine number. In addition, WS iPSC-derived neurons show an increase in calcium transient frequency and synchronized activity likely due to increased number of dendritic spines and synapses. Our work integrated cross-level data from genetics to behavior of WS individuals and revealed altered cellular phenotypes in WS human NPCs and neurons that could be validated in other model systems such as magnetic resonance imaging (MRI) in live subjects and postmortem brain tissues.

Williams syndrome-specific neuroanatomical profile and its associations with behavioral features.

Williams Syndrome (WS) is a rare genetic disorder with unique behavioral features. Yet the rareness of WS has limited the number and type of studies that can be conducted in which inferences are made about how neuroanatomical abnormalities mediate behaviors. In this study, we extracted a WS-specific neuroanatomical profile from structural magnetic resonance imaging (MRI) measurements and tested its association with behavioral features of WS. Using a WS adult cohort (22 WS, 16 healthy controls), we modeled a sparse representation of a WS-specific neuroanatomical profile. The predictive performances are robust within the training cohort (10-fold cross-validation, AUC = 1.0) and accurately identify all WS individuals in an independent child WS cohort (seven WS, 59 children with diverse developmental status, AUC = 1.0). The WS-specific neuroanatomical profile includes measurements in the orbitofrontal cortex, superior parietal cortex, Sylvian fissures, and basal ganglia, and variability within these areas related to the underlying size of hemizygous deletion in patients with partial deletions. The profile intensity mediated the overall cognitive impairment as well as personality features related to hypersociability. Our results imply that the unique behaviors in WS were mediated through the constellation of abnormalities in cortical-subcortical circuitry consistent in child WS and adult WS. The robustness of the derived WS-specific neuroanatomical profile also demonstrates the potential utility of our approach in both clinical and research applications.

Anxiety Disorders in Williams Syndrome Contrasted with Intellectual Disability and the General Population: A Systematic Review and Meta-Analysis

Individuals with specific genetic syndromes associated with intellectual disability (ID), such as Williams syndrome (WS), are at increased risk for developing anxiety disorders. A systematic literature review identified sixteen WS papers that could generate pooled prevalence estimates of anxiety disorders for WS. A meta-analysis compared these estimates with prevalence estimates for the heterogeneous ID population and the general population. Estimated rates of anxiety disorders in WS were high. WS individuals were four times more likely to experience anxiety than individuals with ID, and the risk was also heightened compared to the general population. The results provide further evidence of an unusual profile of high anxiety in WS.

Capacity to improve fine motor skills in Williams syndrome.

Individuals with Williams syndrome (WS) are known to have difficulties in carrying out fine motor movements; however, a detailed behavioural profile of WS in this domain is still missing. It is also unknown how great the capacity to improve these skills with focused and extensive practice is. We studied initial performance and learning capacity in a sequential finger tapping (FT) task in WS and in typical development. Improvement in the FT task has been shown to be sleep dependent. WS subjects participating in the current study have also participated in earlier polysomnography studies, although not directly related to learning. WS participants presented with great individual variability. In addition to generally poor initial performance, learning capacity was also greatly limited in WS. We found indications that reduced sleep efficiency might contribute to this limitation. Estimating motor learning capacity and the depth of sleep disorder in a larger sample of WS individuals might reveal important relationships between sleep and learning, and contribute to efficient intervention methods improving skill acquisition in WS.

Personal Space Regulation in Williams Syndrome: The Effect of Familiarity.

Personal space refers to a protective barrier that we strive to maintain around our body. We examined personal space regulation in young people with Williams syndrome (WS) and their typically developing, chronological age-matched peers using a parent report questionnaire and a stop-distance paradigm. Individuals with WS were reported by their parents to be more likely to violate the personal space of others, and indeed they maintained a shorter interpersonal distance in the stop-distance paradigm. Interestingly, WS individuals failed to regulate their personal space based on the familiarity of the person they were interacting with. Findings are discussed in relation to the wider social profile associated with WS, and the possible impact of atypical personal space regulation on social vulnerability.