Psychiatric and behavioral manifestations of Williams syndrome.

PURPOSE OF REVIEW: The purpose of this review is to synthesize recent advances in the psychiatric and behavioral manifestations of Williams syndrome, a rare genetic syndrome. Recent advances have focused on more deeply characterizing the social phenotype and developing social skill interventions, improving the assessment and treatment of anxiety, and exploring eating behaviors. RECENT FINDINGS: The social cognitive phenotype in Williams syndrome, which consists of both high social drive and social cognition deficits, is present cross-culturally and may be related to reduced eye gaze. Social skills training for adults with Williams syndrome has demonstrated promise. Adapted exposure therapy and cognitive behavioral therapy programs for children and adults respectively, have been piloted in Williams syndrome. The majority of adults with Williams syndrome are either underweight or overweight, and problematic food-related behaviors likely contribute to bodyweight status. SUMMARY: Williams syndrome is associated with a number of core social and psychiatric difficulties which have a significant impact on functioning and quality of life. Recent work has begun to utilize a more nuanced understanding of the clinical presentations of these problems to develop interventions tailored to this unique population. However, larger trials, particularly those inclusive of a more diverse Williams syndrome population, are needed.

Transposons in the Williams-Beuren Syndrome Critical Region are Associated with Social Behavior in Assistance Dogs.

A strong signature of selection in the domestic dog genome is found in a five-megabase region of chromosome six in which four structural variants derived from transposons have previously been associated with human-oriented social behavior, such as attentional bias to social stimuli and social interest in strangers. To explore these genetic associations in more phenotypic detail-as well as their role in training success in a specialized assistance dog program-we genotyped 1001 assistance dogs from Canine Companions for Independence®, including both successful graduates and dogs released from the training program for behaviors incompatible with their working role. We collected phenotypes on each dog using puppy-raiser questionnaires, trainer questionnaires, and both cognitive and behavioral tests. Using Bayesian mixed models, we found strong associations (95% credibility intervals excluding zero) between genotypes and certain behavioral measures, including separation-related problems, aggression when challenged or corrected, and reactivity to other dogs. Furthermore, we found moderate differences in the genotypes of dogs who graduated versus those who did not; insertions in GTF2I showed the strongest association with training success (ß = 0.23, CI95% = - 0.04, 0.49), translating to an odds-ratio of 1.25 for one insertion. Our results provide insight into the role of each of these four transposons in canine sociability and may inform breeding and training practices for working dog organizations. Furthermore, the observed importance of the gene GTF2I supports the emerging consensus that variation in GTF2I genotypes and expression have important consequences for social behavior broadly.

Cross-sectional and longitudinal assessment of cognitive development in Williams syndrome.

Williams syndrome (WS) is a rare genetic syndrome. As with all rare syndromes, obtaining adequately powered sample sizes is a challenge. Here we present legacy data from seven UK labs, enabling the characterisation of cross-sectional and longitudinal developmental trajectories of verbal and non-verbal development in the largest sample of individuals with WS to-date. In Study 1, we report cross-sectional data between N = 102 and N = 209 children and adults with WS on measures of verbal and non-verbal ability. In Study 2, we report longitudinal data from N = 17 to N = 54 children and adults with WS who had been tested on at least three timepoints on these measures. Data support the WS characteristic cognitive profile of stronger verbal than non-verbal ability, and shallow developmental progression for both domains. Both cross-sectional and longitudinal data demonstrate steeper rates of development in the child participants than the adolescent and adults in our sample. Cross-sectional data indicate steeper development in verbal than non-verbal ability, and that individual differences in the discrepancy between verbal and non-verbal ability are largely accounted for by level of intellectual functioning. A diverging developmental discrepancy between verbal and non-verbal ability, whilst marginal, is not mirrored statistically in the longitudinal data. Cross-sectional and longitudinal data are discussed with reference to validating cross-sectional developmental patterns using longitudinal data and the importance of individual differences in understanding developmental progression.

Development of emotion comprehension in children with autism spectrum disorder and Williams syndrome.

Although research has shed light on the development of emotion comprehension in typically developing children, little is known about emotion comprehension in children who are developing atypically. Thus, this study examined the developmental trajectory of emotion understanding in non-clinical (NC) children and children with autism spectrum disorder (ASD) and Williams syndrome (WS) using a Test of Emotion Comprehension. In the test, we measured children's understanding of (I) recognition of emotions based on facial expressions, (II) external causes of emotions, (III) desire-based emotions, (IV) belief-based emotions, (V) the influence of a reminder on a present emotional state, (VI) regulating an experienced emotion, (VII) hiding an emotional state, (VIII) mixed emotions, and (IX) moral emotions. A Bayesian modeling approach was applied to compare the developmental trajectories of emotion understanding across the syndrome groups. The results revealed that NC children and children with WS followed significantly different developmental trajectories in specific aspects of emotion understanding, while children with ASD followed a very similar path to NC children. Children with ASD and NC children gradually developed an understanding of each component of emotion comprehension as they matured. However, the understanding of some components, such as desire-based emotions, hiding an emotional state, and moral emotions, in children with WS was affected by their Autism Spectrum Quotient scores. This is one of the first cross-syndrome studies to assess the development of emotion comprehension in children with ASD and WS, providing important insights for understanding the nature of disability and advancing the development of intervention programs.

Perceived Anxiety in Family Caregivers of Individuals with Autism Spectrum Disorder, Down Syndrome and Williams Syndrome during the Lockdown of the First COVID-19 Wave in Spain.

The lockdown during the first wave of COV- ID-19 in Spain has been related to higher levels of anxiety in the general population. However, the emotional impact on Spanish caregivers of individuals with neurodevelopmental disorders (NDD) has not been studied so far.

Ansiedad percibida en familiares cuidadores de personas con trastorno del espectro autista, síndrome de Down y síndrome de Williams durante el confinamiento de la primera ola por COVID-19 en España / perceived anxiety in family caregivers of individuals with autism spectrum disorder, down syndrome and williams syndrome during the lockdown of the first COVID-19 wave in Spain

Antecedentes. El confinamiento durante la primera oleada de COVID-19 en España se ha relacionado con niveles mayores de ansiedad en la población general. Sin embargo, no se ha estudiado el impacto emocional en los cuidadores de personas con trastornos del neurodesarrollo (TND).Método. Se distribuyó un cuestionario a las organizaciones que prestan apoyo a las personas con TND y sus familias. Se analizaron los datos de los cuidadores de personas con trastorno del espectro autista (TEA) (N=17), síndrome de Down (N=25) y síndrome de Williams (N=18).Resultados. Los cuidadores informaron de preocupaciones relacionadas con la situación de pandemia y confinamiento. Los cuidadores de personas con TEA mostraron mayor preocupación sobre los conflictos familiares. Los tres grupos informaron de niveles de ansiedad más altos durante el confinamiento. Predijeron la ansiedad el trastorno de ansiedad previo y el diagnóstico del hijo/a. Conclusiones. Los predictores de ansiedad en los cuidadores de individuos con TND difieren de los reportados previamente en la población general española. Los resultados sugieren que el confinamiento fue especialmente duro paralas familias de personas con TEA. Las políticas públicas deberían considerar las necesidades de las personas con TND y sus cuidadores para minimizar las consecuencias negativas de la pandemia. (AU)

Background. The lockdown during the first wave of COVID-19 in Spain has been related to higher levels of anxietyin the general population. However, the emotional impact on Spanish caregivers of individuals with neurodevelopmental disorders (NDD) has not been studied so far. Methods. An online questionnaire was distributed to Spanish organisations providing support to individuals with NDD and their families. Data from caregivers of individuals with autism spectrum disorder (ASD) (N = 17), Down syndrome (DS)(N = 25) and Williams syndrome (WS) (N = 18) were analysed. Results. All caregivers reported concerns directly related to the pandemic and lockdown situation. Caregivers of individuals with ASD showed higher level of concern about the possibility of family conflict. All three groups reported higher levels of anxiety during the lockdown. Anxiety was predicted by previous anxiety disorder and the child’s diagnosis. Conclusions. Predictors of anxiety in caregivers of individuals with NDD differ from those previously reported in the general Spanish population. The results suggest that confinement in Spain was especially demanding for families of individuals with ASD. Public policies should consider the particular needs of people with NND and their caregivers to minimise the negative consequences of the ongoing pandemic.(AU)

Neuropsychological intervention in attention and visuospatial skills in two patients with Williams syndrome with different types of genetic deletion.

Williams Syndrome (WS) is a neurodevelopmental disorder with a distinctive physical, cognitive, and behavioral profile caused by a microdeletion in the q11.23 region of chromosome 7. The neuropsychological profile of WS is characterized by intellectual disability, hypersociability, and deficits, especially in attention and visuospatial skills. Our objective was to assess the effectiveness of a neuropsychological intervention program in attention and visuospatial skills in two patients with WS (aged 7 and 13 years old) with different types of deletion (1.5 and 1.8 Mb). Cognitive, behavioral, and adaptive abilities were evaluated through various neuropsychological tests and scales; the neuropsychological intervention program was subsequently applied, and we assessed its effectiveness. Both patients initially presented significant deficits in attention and visuospatial skills. After the program, we found improvements in attention and visuospatial skills. In addition, both patients had significant clinical advances and changes in adaptive behaviors (social and self-care). These findings suggest that this intervention program could improve attention processes, visuospatial skills, and some aspects of adaptive behavior in patients with WS, regardless of deletion size. Although the sample was small, limiting the generalizability of the results, we believe this program could be a helpful resource for professionals working with individuals with WS.

Williams syndrome: reduced orienting to other's eyes in a hypersocial phenotype.

Williams syndrome (WS) is a rare genetic condition associated with high sociability, intellectual disability, and social cognitive challenges. Attention to others' eyes is crucial for social understanding. Orienting to, and from other's eyes was studied in WS (n = 37, mean age = 23, age range 9-53). The WS group was compared to a typically developing comparison participants (n = 167) in stratified age groups from infancy to adulthood. Typically developing children and adults were quicker and more likely to orient to eyes than the mouth. This bias was absent in WS. The WS group had reduced peak saccadic velocities, indicating hypo-arousal. The current study indicates reduced orienting to others' eyes in WS, which may affect social interaction skills.

Systematic Review: Emotion Dysregulation in Syndromic Causes of Intellectual and Developmental Disabilities.

OBJECTIVE: To summarize the current state of the literature regarding emotion dysregulation (ED) in syndromic intellectual disabilities (S-IDs) in 6 of the most common forms of S-IDs-Down syndrome, fragile X syndrome (FXS), tuberous sclerosis complex, Williams syndrome, Prader-Willi syndrome, and Angelman syndrome-and to determine future research directions for identification and treatment of ED. METHOD: PubMed bibliographic database was searched from date of inception to May 2021. PRISMA 2020 guidelines were followed with the flowchart, table of included studies, list of excluded studies, and checklist provided. Filters applied included human research and English. Only original research articles were included in the final set, but review articles were used to identify secondary citations of primary studies. All articles were reviewed for appropriateness by 2 authors and summarized. Inclusion criteria were met by 145 articles (Down syndrome = 29, FXS = 55, tuberous sclerosis complex = 11, Williams syndrome = 18, Prader-Willi syndrome = 24, Angelman syndrome = 8). RESULTS: Each syndrome review was summarized separately and further subdivided into articles related to underlying neurobiology, behaviors associated with ED, assessment, and targeted intervention. FXS had the most thorough research base, followed by Down syndrome and Prader-Willi syndrome, with the other syndromes having more limited available research. Very limited research was available regarding intervention for all disorders except FXS. CONCLUSION: Core underlying characteristics of S-IDs appear to place youth at higher risk for ED, but further research is needed to better assess and treat ED in S-IDs. Future studies should have a standard assessment measure of ED, such as the Emotion Dysregulation Inventory, and explore adapting established curricula for ED from the neurotypical and autism spectrum disorder fields.

Developmental characteristics of Williams-Beuren syndrome and evaluation of adaptive behavioral skills.

Background/aim: Williams-Beuren syndrome (WBS) is a rare genetic disorder with delays in language and cognitive development, but, with increased awareness of clinical features and a reliable diagnostic test, WBS is becoming more widely recognized in childhood. Adaptive behavior skills and/or maladaptive behavior are important for the prognosis of individuals with WBS. The aim of this study was to investigate the clinical and developmental characteristics of patients with WBS and further increase awareness about it by evaluating the adaptive skills and maladaptive behaviors of the patients. Materials and methods: The data of WBS patients followed-up at the Developmental Behavioral Pediatrics Unit were reviewed. Patient data on perinatal and postnatal history, developmental stages, physical and neurological examination findings were collected. The International Guide for Monitoring Child Development (GMCD) was administered to each child. In addition, semistructured interviews were conducted with the parents using the Vineland Adaptive Behavior Scales, Second edition (Vineland-II). Results: A total of 12 patients diagnosed with WBS via detection of the 7q11.23 deletion, of whom 6 were girls, were retrospectively reviewed. The mean age at the time of review was 54.6 ± 32.5 months. The mean age at first presentation to the Developmental Behavioral Pediatrics Outpatient Clinic was 15 ± 11.5 months. In the first developmental evaluation using the GMCD, there was a delay in fine and gross motor domains in 6 patients, in the language domains in 4 patients, and in all of the domains in 2 patients. Findings with Vineland-II showed socialization and communication domains as strengths, but the daily living skills and motor skills domains were weaknesses. In terms of maladaptive behavior, the patients tended to frequently have behavioral problems, neurodevelopmental disease, anxiety disorders, eating problems, and sleeping problems. Conclusion: This retrospective review of 12 patients indicated a general delay in overall development, and confirmed impairment in both adaptive and maladaptive functioning in WBS.

Investigating basic emotion knowledge of people with Williams syndrome.

BACKGROUND: Emotional recognition is a key aspect of mentalizing other people's minds. People with Williams syndrome (WS) are reported to be hypersocial and empathetic; however, few studies have investigated their emotion processing ability. AIMS: This study aimed to examine emotion knowledge in people with WS and to further understand their emotion-related mentalizing ability. METHODS AND PROCEDURES: Six basic emotions (happiness, sadness, anger, fear, disgust, and surprise) were tested by narrating scenarios targeting specific emotions. Participants with WS (n = 16, 8F/8 M, CA = 8.46, MA = 5.27) listened to each scenario and pointed to an emoticon displayed on a card. Correct percentages of each target emotion and replacement by other emotions were analyzed. Comparison groups comprised mental age-matched controls (n = 16, 8F/8 M, CA = 5.26) and chronological age-matched controls (n = 16, 8 F/8 M, CA = 8.31), sixth graders (n = 20, 10F/10M, CA = 12.04), and college students (n = 20, 10F/10M, CA = 20.03). All were Chinese-speaking participants with right handedness. OUTCOMES AND RESULTS: People with WS were delayed compared to the mental age-matched group but differed from the chronological age-matched group in emotion processing. The 6th graders showed different patterns from college students, suggesting that development of emotion processing takes time. CONCLUSIONS AND IMPLICATIONS: These findings suggest (1) a gap in the maturation of emotion knowledge between people with WS and typically developing controls, (2) a nonequivalent chronological emotion-related mentalizing ability in people with WS, and (3) developmental changes in emotion processing from childhood to adulthood.

Atypical deletion of Williams-Beuren syndrome reveals the mechanism of neurodevelopmental disorders.

Genes associated with specific neurocognitive phenotypes in Williams-Beuren syndrome are still controversially discussed. This study identified nine patients with atypical deletions out of 111 patients with Williams-Beuren syndrome; these deletions included seven smaller deletions and two larger deletions. One patient had normal neurodevelopment with a deletion of genes on the distal side of the Williams-Beuren syndrome chromosomal region, including GTF2I and GTF2IRD1. However, another patient retained these genes but showed neurodevelopmental abnormalities. By comparing the genotypes and phenotypes of patients with typical and atypical deletions and previous reports in the literature, we hypothesize that the BAZ1B, FZD9, and STX1A genes may play an important role in the neurodevelopment of patients with WBS.

Emotional modulation of episodic memory in children and adolescents with Williams-Beuren syndrome.

Children and adolescents with Williams-Beuren syndrome (WBS) have been described as having specific memory abilities and emotional reactivity. Although it is well established in the literature that emotion can enhance memory, no such studies have been undertaken in individuals with WBS. In three experiments, the present study tested whether the negative or positive emotional valence of stimuli can influence verbal, visual and visuo-spatial memory by specifically evaluating two memory components: item and associative memory. Sixteen 8- to 18-year-old individuals with WBS performed the first two experiments and, among them, twelve participated in the third. They were compared to equivalent groups of typically developing control children. Participants completed intentional-encoding tasks followed by immediate item recognition, associative recall or item recall tasks. Event-related potential measures during encoding and recognition of pictures were also added in the third experiment. Results demonstrated, for the first time, effects of emotions on visual item memory and visuo-spatial associative memory in individuals with WBS, that were similar to those observed in typically developing children. By combining behavioral and neural measures, our study provides new knowledge of the interaction between emotion and memory in WBS individuals, which seems to be unaffected by their atypical development.

Functional Neurological Symptom Disorder in Williams Syndrome: Case Series and Review of Relevant Literature.

BACKGROUND: Williams syndrome (WS) is a neurodevelopmental disorder associated with several medical and psychiatric comorbidities. OBJECTIVE: To describe the clinical presentation and treatment course of functional neurological symptom disorder (FNSD) in 3 adult patients with WS. METHODS: This report describes the clinical presentation and long-term follow-up of 3 individuals with WS and FNSD who experienced a range of clinical presentations and responses to treatment. The literature on the clinical assessment and treatment of FNSD as it applies to patients with neurodevelopmental disorders is reviewed. RESULTS: FNSD treatment strategies used in the general population were successfully adapted for these 3 patients. Literature on the diagnosis and treatment of FNSD in patients with neurodevelopmental disorders is lacking. CONCLUSIONS: FNSD may be more common in individuals with WS than previously appreciated, and future studies describing the prevalence, clinical presentation, risk factors, and treatment of FNSD in WS are needed.

Evaluating quality of life in families with Williams Syndrome patients.

BACKGROUND: Williams Syndrome is a developmental disorder characterized by a variable intellectual disability. People with Williams Syndrome need the intervention of several clinical and educational specialists throughout their life. However, little is known about the impact produced by this disability in their immediate environment, especially in families. The purpose was to know the level of quality of life described by families with Williams Syndrome. METHODS: The sample was made up of 33 families belong to Spanish Williams Syndrome Association who were evaluated using the Kidslife Scale. Their children and adolescents were between 4 and 20 years old. Eight main quality of life domains were evaluated: emotional well-being, physical well-being, material well-being, personal development, interpersonal relations, social inclusion, self-determination and rights RESULTS: The obtained data indicated that the degree and presence of intellectual disability did not homogeneously influence people's quality of life, but many variables could alter their quality of life to a greater or lesser extent. There are no significant differences between quality of life areas but significant differences appeared for level of dependence in the self-determination subarea (p < .05). CONCLUSIONS: These results led us to analyse the social and emotional implications for families and their environment.

Anxiety characteristics in individuals with Williams syndrome.

BACKGROUND: Williams syndrome anxiety research predominantly focuses on disorder prevalence and symptomatology, categorised using standardised mental health classifications. However, the use of these assessments may not fully capture the phenotypic features of anxiety in Williams syndrome. In this study, we examined characteristics of anxiety using a formulation framework. METHOD: A semi-structured interview was conducted with thirteen parents of individuals with Williams syndrome (median age: 19, age range: 12-45, 8 females). RESULTS: Various anxiety triggers were reported, including anxiety triggered by phobias, uncertainty and negative emotions in others. The range of described behaviours was diverse with both avoidant and active coping strategies for anxiety management reported. CONCLUSIONS: Many of the characteristics described were consistent with findings in the intellectual disability and typically developing literature, although novel information was identified. The study demonstrates the utility of a formulation framework to explore anxiety characteristics in atypical populations and has outlined new avenues for research.

Toward an integrative model accounting for typical and atypical development of visuospatial short-term memory.

The origin of visuospatial short-term memory (STM) impairment is poorly investigated and is generally considered to be the result of a more global visuospatial deficit. However, previous studies suggest an important influence of two elements on performance in visuospatial STM tasks, the mode of presentation (i.e., simultaneous and sequential), and the visuospatial arrangement (structured vs. unstructured). With regards to a recent proposal, the aim of this study was to examine the development of the two modes of presentation and the visuospatial arrangement of visuospatial information in STM in a hundred typically developing participants aged from 4 years old to adults. Moreover, we also examined how the model explains the pattern of visuospatial STM deficit in two neurodevelopmental syndromes with different profiles in terms of STM abilities, namely Williams syndrome and Down syndrome. We found distinct performance for sequential and simultaneous presentation only from 11 years old with better performance in simultaneous than in sequential presentation mode and a sensitivity to visuospatial arrangement that increases with age. Both syndromes presented deficits at different levels, people with Williams syndrome for visuospatial arrangement and with Down syndrome for simultaneous visuospatial information in STM. The results demonstrate the importance to consider the influence of preexisting visuospatial knowledge on STM abilities. A two processing route model of STM is an interesting framework to interpret the different results.

An Exploration of Social Cognition in Children with Different Degrees of Genetic Deletion in Williams Syndrome.

An explanation for the social dysfunction observed in Williams syndrome may be deficits in social cognition. This study explored aspects of social cognition in children with Williams syndrome with different genotypes. The 12 participants included one with a 1.1 Mb deletion that retained the GTF2IRD1, GTF2I, and GTF2IRD2 genes, seven with a 1.5 Mb deletion that preserved the GTF2IRD2 gene, and four with a 1.8 Mb deletion with loss of all three genes. The participant retaining all three genes was found to have better performance on social judgment and first-order theory of mind tasks than the group with loss of all three genes. These results may reflect the influence of the GTF2I gene family on social cognition in Williams syndrome.

Functional play in young children with autism and Williams syndrome: A cross-syndrome comparison.

Functional play during early childhood paves the way to symbolic play and social communicative skills. However, functional play is surprisingly understudied in children with developmental disorders affecting social and communicative domains, such as Autism Spectrum Disorder (ASD) and Williams syndrome (WS). To address this issue and to evaluate both the quantity and quality of functional play in children with ASD and WS, we examined different play types using fine grained behavioral analysis with a group of age and IQ-matched developmentally delayed children with ASD (n = 14) and WS (n = 14) in comparison with 12 age-matched typically developing (TD) children. Significant differences were found in the quantity of functional play in the ASD and WS groups compared to TD children, with a limited breadth of object exploration found in children with ASD. While TD children engaged more frequently in functional versus nonfunctional play, this was not the case for children with ASD and WS, who showed the same amount of functional and nonfunctional play. Furthermore, functional play behavior was associated with intellectual and adaptive function in children with WS, but not ASD. These results point to the importance of intervention strategies that focus on functional play in improving developmental outcomes for children with ASD and WS.

Peer Relationships in Children with Williams Syndrome: Parent and Teacher Insights.

Although children with Williams syndrome (WS) are reported to show a strong motivation towards social interaction, evidence suggests many experience difficulties with peer relations. Less is known regarding the characteristics of such difficulties. Parents and teachers of 21 children with WS (7- to 16 years) completed questionnaires measuring aspects of social functioning and peer interactions. Parents and teachers reported that children with WS demonstrated significantly greater peer problems than population norms, including difficulties sustaining friendships and increased social exclusion. More substantial social functioning difficulties were associated with greater peer relation problems. The study provides multi-informant evidence of peer relationship difficulties in children with WS that require further consideration within the broader WS social phenotype.