The Prader-Willi syndrome Profile: validation of a new measure of behavioral and emotional problems in Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare, neurodevelopmental disorder caused by the lack of expression of paternally imprinted genes on chromosome 15q11-13. PWS features a complex behavioral phenotype, including hyperphagia, anxiety, compulsivity, rigidity, repetitive speech, temper outbursts, aggressivity, and skin-picking. Questionnaires exist for measuring hyperphagia, but not for the aggregation of other problems that are distinctive to PWS. A PWS-specific tool is needed for phenotypic research, and to help evaluate treatment efficacy in future clinical trials aimed at attenuating PWS's hyperphagia and related problems. In this 4-phase study, we leveraged our expertise in PWS with feedback from families and specialists to validate the PWS Profile, a novel, informant-based measure of behavioral and emotional problems in this syndrome. RESULTS: The authors developed a bank of 73 items that tapped both common and less frequent but clinically significant problems in PWS (Phase 1). An iterative feedback process with families and stakeholders was used to ensure content and construct validity (Phase 2). After adding, omitting, or revising items, in Phase 3, we pilot tested the measure in 112 participants. Results were reviewed by an international team of PWS specialists and revised again (Phase 3). The final, 57-item Profile was then administered to 761 participants (Phase 4). Principal component factor analyses (n = 873) revealed eight conceptually meaningful factors, accounting for 60.52% of test variance, and were readily interpretated as: Rigidity, Insistence; Aggressive Behaviors; Repetitive Questioning, Speech; Compulsive Behaviors; Depression, Anxiety; Hoarding; Negative Distorted Thinking; and Magical Distorted Thinking. Factors were internally consistent and showed good test-retest reliability and convergent validity with existent measures of behavioral problems. Profile factors were not related to IQ, BMI, or parental SES. Three Profile factors differed across PWS genetic subtypes. Age and gender differences were found in only one Profile factor, Hoarding. CONCLUSIONS: The PWS Profile is a valid, psychometrically-sound questionnaire that already has shown responsivity to treatment in a previous clinical trial. The Profile can extend the reach of future clinical trials by evaluating the impact of novel agents not only on hyperphagia, but also on the emotional and behavioral problems that characterize PWS.

The Feasibility and Effectiveness of a Novel, On-Line Social Skills Intervention for Individuals With Prader-Willi Syndrome.

Introduction: People with neurodevelopmental disabilities, including Prader-Willi syndrome (PWS), are at heightened risk for the negative sequalae of loneliness, including depression and anxiety. While societal factors such as stigma or limited social opportunities contribute to loneliness, so too do deficits in social cognition and social skills. People with PWS have specific difficulties recognizing affect in others, accurately interpreting social interactions, and taking the perspectives of others. These features, combined with hyperphagia, rigidity, and insistence on sameness conspire to impede the abilities of people with PWS to make and sustain friendships and reduce feelings of loneliness. Methods: We developed and administered an intervention, Building Our Social Skills (BOSS), that aimed to improve social skill deficits in PWS. The 10-week intervention was administered on-line via Zoom to 51 young people with PWS in the U.S. (M age = 20.8, SD = 6.42). Two clinicians co-led groups of 6-8 participants in 30-min sessions, 3 times per week, and also trained 4 graduate students to co-lead groups with high fidelity. We used a pre-post intervention and 3-month follow-up design, with no control group, and mitigated this design limitation by triangulating across informants and methodologies. Specifically, parents completed the widely used Social Responsiveness Scale (SRS) and Child Behavior Checklist (CBCL), and participants were individually interviewed about their friendships and loneliness. Interview responses were reliably coded by independent raters. Results: Repeated measure multivariate analyses, with baseline values entered as covariates, revealed significant pre-to post-test improvements in the SRS's social cognition, motivation and communication subscales (p's < 0.001), with large effect sizes ( n p 2 = 0.920, 0.270, and 0.204, respectively). Participant and parental reports of loneliness were correlated with the CBCL's Internalizing domain, specifically the Anxiety/Depressed subdomain. Over time, parents reported getting along better with peers, increased contact with friends, more friends and less loneliness. Participants also reported significantly less loneliness and more friends. Conclusions: This mixed method, proof-of-concept study demonstrated the feasibility of delivering an on-line social skills intervention to young people with PWS. As no differences were found between clinician vs. graduate student outcomes, the BOSS curriculum holds considerable promise for wider dissemination and implementation in the PWS community.

Molecular Classes and Growth Hormone Treatment Effects on Behavior and Emotion in Patients with Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a complex genetic disorder with three genetic classes. Patients with PWS are characterized by severe hypotonia, developmental delay, behavioral problems, learning disabilities and morbid obesity in early childhood if untreated. Data were collected through Rare Disease Clinical Research Network (RDCRN) from four study centers which evaluated patients with PWS. The Behavior Assessment System for Children 2nd edition (BASC-2) was chosen to provide behavioral assessment. Data from 330 participants ((64% 15q11-q13 deletion (DEL), 36% maternal disomy 15 (UPD)) were separated into three age groups and analyzed, 68% of whom were still actively receiving recombinant human growth hormone (rhGH) treatment. When comparing the BASC results by molecular subtype, parent-reported aggression was higher for the deletion than for the UPD cohort (p = 0.007). Participants who were on rhGH treatment showed lower scores for parent-reported hyperactivity and aggression (p = 0.04, 0.04, respectively), and a trend for anger control (p = 0.06) and teacher-reported attention problems and aggression (p = 0.01, 0.004, respectively). Additional adjusted analyses were undertaken and significant differences were noted in the GH versus non-GH treated groups for only teacher-reported aggression, which increased in the No GH treated patient group (p = 0.03). This study showed documented differences in PWS behavior by molecular class and rhGH treatment. RhGH therapy may be beneficial for certain behaviors in patients with PWS; however, observed differences need more studies for confirmation in the future.

A Longitudinal RCT of P-ESDM With and Without Parental Mindfulness Based Stress Reduction: Impact on Child Outcomes.

This randomized controlled trial (NCT03889821) examined Mindfulness Based Stress Reduction (MBSR) in conjunction with the Parent-implemented Early Start Denver Model (P-ESDM). A previous report described improved metrics of parental distress (Weitlauf et al. in Pediatrics 145(Supplement 1):S81-S92, 2020). This manuscript examines child outcomes. 63 children with ASD (< 36 months) and their parents received 12 P-ESDM sessions. Half of parents also received MBSR. Longitudinal examination of whole sample means revealed modest improvements in autism severity, cognitive, and adaptive skills. There was not a significant time × group interaction for children whose parents received MBSR. Future work should examine more proximal markers of child or dyadic change to enhance understanding of the impact of providing direct treatment for parents as part of early intervention initiatives.

'The cure for us is a lot of things': How young people with Prader-Willi syndrome view themselves and future clinical trials.

BACKGROUND: Despite work on the self-identities of people with intellectual disabilities, research has yet to describe the self-perceptions of people with Prader-Willi syndrome (PWS). The perspectives of those with PWS are also important for rapidly evolving clinical trials aimed at treating symptoms of PWS. METHOD: Twenty-one young people with PWS were administered a semi-structured interview that assessed how they perceive their syndrome and clinical trials. Transcribed interviews were reliably coded using content-driven, applied thematic analyses. RESULTS: Five themes emerged: struggles with chronic hunger and food-seeking that impede goals and relationships; struggles with anxiety and outbursts, schedule changes and school; distancing from PWS; needs for clinical trials that cure PWS, reduce hunger or anxiety, and lead to improved outcomes; and needs for advocacy and awareness of PWS. CONCLUSIONS: Findings shed new light on the self-perceptions of those with PWS and have important implications for current interventions and future clinical trials.

Training Healthcare Professionals to Work With People With Intellectual and Developmental Disabilities.

This study assessed 155 healthcare providers, from nine disciplines, who work professionally with people with intellectual and developmental disabilities (IDD). Using a national, web-based survey, respondents rated their experience, comfort, and competence in treating individuals with different disability types and preferred methods of continuing education; respondents also provided suggestions for attracting others to work with the IDD population. Findings revealed that experiences, comfort, and competence were all higher concerning persons with autism spectrum disorder (ASD) and intellectual disability (ID), lower for those with deaf-blindness. Overall, levels of experience exceeded levels of comfort, which in turn exceeded levels of competence. The most helpful venues for continued training involved day-to-day contact with persons with IDD, which also characterized open-ended responses. Research and practical implications are discussed.

Evaluating Sleep Disturbances in Children With Rare Genetic Neurodevelopmental Syndromes.

BACKGROUND: Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared with typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS), and Prader-Willi (PWS) syndromes to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes with each other, and with typically developing controls. METHODS: Children were recruited from the Rare Diseases Clinical Research Network consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including Pediatric Sleep Questionnaire (Sleep-Disordered Breathing), Children's Sleep Habits Questionnaire (CSHQ), and Pediatric Daytime Sleepiness Scale. RESULTS: Sleep data were analyzed from 714 participants, aged two to 18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared with individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances, which were associated with each of the genetic syndromes. CONCLUSIONS: Individuals with RTT, AS, and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.

Behavioral features in Prader-Willi syndrome (PWS): consensus paper from the International PWS Clinical Trial Consortium.

Prader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder associated with a characteristic behavioral phenotype that includes severe hyperphagia and a variety of other behavioral challenges such as temper outbursts and anxiety. These behaviors have a significant and dramatic impact on the daily functioning and quality of life for the person with PWS and their families. To date, effective therapies addressing these behavioral challenges have proven elusive, but several potential treatments are on the horizon. However, a limiting factor for treatment studies in PWS is the lack of consensus in the field regarding how to best define and measure the complex and interrelated behavioral features of this syndrome. The International PWS Clinical Trials Consortium (PWS-CTC, www.pwsctc.org ) includes expert PWS scientists, clinicians, and patient advocacy organization representatives focused on facilitating clinical trials in this rare disease. To address the above gap in the field, members of the PWS-CTC "Behavior Outcomes Working Group" sought to develop a unified understanding of the key behavioral features in PWS and build a consensus regarding their definition and description. The primary focus of this paper is to present consensus definitions and descriptions of key phenotypic PWS behaviors including hyperphagia, temper outbursts, anxiety, obsessive-compulsive behaviors, rigidity, and social cognition deficits. Patient vignettes are provided to illustrate the interrelatedness and impact of these behaviors. We also review some available assessment tools as well as new instruments in development which may be useful in measuring these behavioral features in PWS.

Influence of molecular classes and growth hormone treatment on growth and dysmorphology in Prader-Willi syndrome: A multicenter study.

Prader-Willi syndrome (PWS) is a complex genetic disorder with three molecular classes but clinical ascertainment is based on distinctive features. The prevalence of dysmorphic features was studied in 355 PWS participants (61% deletion, 36% maternal disomy [UPD], and 3% imprinting defects) from the National Institute of Health PWS Rare Diseases Clinical Research Network. The effect of growth hormone (GH) treatment on growth and dysmorphic features was compared. Among participants, upslanting palpebral fissures were seen in 23%; strabismus in 42%; abnormal dentition in 32%; small hands in 63% and small feet in 70%; hypopigmentation in 30%; striae in 32% and skin picking in 26%. Compared to those with UPD, participants with deletions were found to be heavier (p = 0.002), had smaller head circumference (HC) (p = 0.009), higher incidence of a flat occiput (p = 0.005); low-anterior hairline (p = 0.04); abnormal dentition (p = 0.009); abdominal striae (p = 0.045), nail abnormalities (p = 0.050), and fair-haired (p < 0.001). Participants in both genetic groups receiving GH were taller (p = 0.005), had larger HCs (p = 0.005), and longer hands (p = 0.049). This study suggested that PWS genetic subtypes and GH treatment can influence growth and dysmorphic features that may impact clinical diagnosis of PWS, such as stature, head shape and appearance of the eyes, nose, and genitalia.

Mindfulness-Based Stress Reduction for Parents Implementing Early Intervention for Autism: An RCT.

BACKGROUND AND OBJECTIVES: Systems of care emphasize parent-delivered intervention for children with autism spectrum disorder (ASD). Meanwhile, multiple studies document psychological distress within these parents. This pilot longitudinal randomized controlled trial compared the parent-implemented Early Start Denver Model (P-ESDM) to P-ESDM plus mindfulness-based stress reduction (MBSR) for parents. We evaluated changes in parent functioning during active treatment and at follow-up. METHODS: Participants included children (<36 months old) with autism spectrum disorder and caregivers. Participants were randomly assigned to P-ESDM only (n = 31) or P-ESDM plus MBSR (n = 30). Data were collected at baseline, midtreatment, the end of treatment, and 1, 3, and 6 months posttreatment. Multilevel models with discontinuous slopes were used to test for group differences in outcome changes over time. RESULTS: Both groups improved during active treatment in all subdomains of parent stress (ß = -1.42, -1.25, -0.92; P < 0.001), depressive symptoms, and anxiety symptoms (ß = -0.62 and -0.78, respectively; P < 0.05). Parents who received MBSR had greater improvements than those receiving P-ESDM only in parental distress and parent-child dysfunctional interactions (ß = -1.91 and -1.38, respectively; P < 0.01). Groups differed in change in mindfulness during treatment (ß = 3.15; P < .05), with P-ESDM plus MBSR increasing and P-ESDM declining. Treatment group did not significantly predict change in depressive symptoms, anxiety symptoms, or life satisfaction. Differences emerged on the basis of parent sex, child age, and child behavior problems. CONCLUSIONS: Results suggest that manualized, low-intensity stress-reduction strategies may have long-term impacts on parent stress. Limitations and future directions are described.

Early Diagnosis in Prader-Willi Syndrome Reduces Obesity and Associated Co-Morbidities.

Prader-Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11-q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity in PWS. We studied 352 subjects with PWS, recruited from the NIH Rare Disease Clinical Research Network, to determine if age at diagnosis, ethnicity, gender, and PWS molecular class influenced the age they first become heavy, as determined by their primary care providers, and the age they first developed an increased appetite and began seeking food. The median ages that children with PWS became heavy were 10 years, 6 years and 4 years for age at diagnosis < 1 year, between 1 and 3 years, and greater than 3 years of age, respectively. The age of diagnosis and ethnicity were significant factors influencing when PWS children first became heavy (p < 0.01), however gender and the PWS molecular class had no influence. Early diagnosis delayed the onset of becoming heavy in individuals with PWS, permitting early GH and other treatment, thus reducing the risk of obesity-associated co-morbidities. Non-white individuals had an earlier onset of becoming heavy.

Profiles and trajectories of impaired social cognition in people with Prader-Willi syndrome.

INTRODUCTION: People with Prader-Willi syndrome (PWS) have a distinctive behavioral phenotype that includes intellectual disability, compulsivity, inattention, inflexibility and insistence on sameness. Inflexibility and inattention are at odds with the cognitive flexibility and attention to social cues needed to accurately perceive the social world, and implicate problems in social cognition. This study assessed two social cognition domains in people with PWS; emotion recognition and social perception. We identified changes in social cognition over an approximate two-year time period (M = 2.23 years), relative strengths and weakness in social cognition, and correlates and predictors of social cognition. METHODS: Emotion recognition and social perception were examined at two time points in 94 individuals with PWS aged 5 to 62 years (M = 13.81, SD = 10.69). Tasks administered included: standardized IQ testing; parent-completed measures of inattention and inflexibility; standard emotion recognition photos (fear, sadness, anger, happy); and videotaped social perception vignettes depicting negative events with either sincere/benign or insincere/hostile interactions between peers. RESULTS: An atypical trajectory of negative emotion recognition emerged, marked by similar levels of poor performances across age, and confusion between sad and anger that is typically resolved in early childhood. Recognition of sad and fear were positively correlated with IQ. Participants made gains over time detecting social cues, but not in forming correct conclusions about the intentions of others. Accurately judging sincere intentions remained a significant weakness over time. Relative to sincere intentions, participant's performed significantly better in detecting negative social cues, and correctly judging trickery, deceit and lying. Age, IQ, inattention, and recognition of happy and sad accounted for 29% of variance in social perception. CONCLUSION: Many people with PWS have deficits in recognizing sad, anger and fear, and accurately perceiving the sincere intentions of other people. The impact of these deficits on social behavior and relationships need to be better understood.

Birth seasonality studies in a large Prader-Willi syndrome cohort.

Prader-Willi syndrome (PWS) is generally due to sporadic paternal deletions of the chromosome 15q11-q13 region followed by maternal disomy 15. Advanced maternal age is more commonly seen in those with maternal disomy 15. Environmental factors (e.g., drug use, occupational chemical exposure, infectious agents, and irradiation) could account for chromosome changes. Previous evidence of differences in male and female gametogenesis could suggest an environmental role in the causation of the paternal 15q11-q13 deletion seen in PWS. Certain occupations such as hydrocarbon-exposing occupations (e.g., landscaping, farming, and painting) and viral exposure (e.g., human coronavirus 229E causing upper respiratory infections in adults with an incorporation site in the human genome at chromosome 15q11) can be seasonal in nature and contribute to chromosome damage. To assess, we reviewed birth seasonality data in a large cohort of individuals with PWS recruited nationally (N = 355) but no significant differences were seen by month between those with the 15q11-q13 deletion compared with maternal disomy 15 when analyzing quarterly seasonal patterns. Although early evidence supported birth seasonality differences in PWS, a larger number of individuals in our recent study using advanced genetic testing methods did not find this observation.

Molecular genetic classification in Prader-Willi syndrome: a multisite cohort study.

BACKGROUND: Prader-Willi syndrome (PWS) is due to errors in genomic imprinting. PWS is recognised as the most common known genetic cause of life-threatening obesity. This report summarises the frequency and further characterises the PWS molecular classes and maternal age effects. METHODS: High-resolution microarrays, comprehensive chromosome 15 genotyping and methylation-specific multiplex ligation probe amplification were used to describe and further characterise molecular classes of maternal disomy 15 (UPD15) considering maternal age. RESULTS: We summarised genetic data from 510 individuals with PWS and 303 (60%) had the 15q11-q13 deletion; 185 (36%) with UPD15 and 22 (4%) with imprinting defects. We further characterised UPD15 findings into subclasses based on the presence (size, location) or absence of loss of heterozygosity (LOH). Additionally, significantly older mothers (mean age=32.5 years vs 27.7 years) were found in the UPD15 group (n=145) compared with the deletion subtype (n=200). CONCLUSIONS: We report on molecular classes in PWS using advanced genomic technology in the largest cohort to date. LOH patterns in UPD15 may impact the risk of having a second genetic condition if the mother carries a recessive mutant allele in the isodisomic region on chromosome 15. The risk of UPD15 may also increase with maternal age.

Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. METHODS: Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. RESULTS: Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. CONCLUSION: I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

Multicentre study of maternal and neonatal outcomes in individuals with Prader-Willi syndrome.

INTRODUCTION: Prader-Willi syndrome (PWS) is a complex genetic disorder associated with three different genetic subtypes: deletion of the paternal copy of 15q11-q13, maternal UPD for chromosome 15 and imprinting defect. Patients are typically diagnosed because of neonatal hypotonia, dysmorphism and feeding difficulties; however, data on the prenatal features of PWS are limited. OBJECTIVE: The aim of the study was to identify and compare frequencies of prenatal and neonatal clinical features of PWS among the three genetic subtypes. METHODS: Data from 355 patients with PWS from the Rare Diseases Clinical Research Network PWS registry were used to analyse multiple maternal and neonatal factors collected during an 8-year multisite study. RESULTS: Among our cohort of 355 patients with PWS (61% deletion, 36% UPD and 3% imprinting defect) 54% were born by caesarean section, 26% were born prematurely and 34% with a low birth weight (frequencies 32%, 9.6% and 8.1%, respectively, in the general population). Fetal movements were reported as decreased in 72%. All babies were hypotonic, and 99% had feeding difficulties. Low Apgar scores (<7) were noted in 17.7% and 5.6% of patients, respectively, compared with 1% and 1.4%, respectively, in the general population. Maternal age and pre-pregnancy weight were significantly higher in the UPD group (p=0.01 and <0.001, respectively). CONCLUSION: We found a higher rate of perinatal complications in PWS syndrome compared with the general population. No significant differences in the genetic subtypes were noted except for a higher maternal age and pre-pregnancy weight in the UPD subgroup.

Eye Tracking as a Marker of Hyperphagia in Prader-Willi Syndrome.

This study examined the feasibility of eye tracking measures as markers of hyperphagia in 42 children and adults with Prader-Willi syndrome (PWS). Gaze data collected during free visual exploration of complex displays revealed that food images may not have an overall superior salience in PWS. However, increased attention to food in the context of other high-interest items was associated with higher scores on caregiver reports of hyperphagia. The study also provided preliminary evidence of test-retest reliability of eye tracking measures, suggesting that gaze characteristics may be a promising objective marker of food-related interests in PWS.

Attentional rather than sensory differences characterize auditory processing in Williams syndrome.

Individuals with Williams Syndrome (WS) exhibit an atypical auditory profile. Across two experiments, we used event-related potentials (ERPs) in a three-stimulus auditory oddball task to examine early sensory (P1, N1, P2) and later cognitive (P3a, P3b) stages of cortical auditory processing in adults with WS and age-matched typical peers. In Study 1, piano chords served as standard, target, and novel stimuli; whereas, in Study 2, a variety of non-piano sounds comprised the novel stimuli. Across both experiments, there were no group differences in the earliest stages of sensory encoding (P1, N1), along with evidence for atypically large P2 responses in participants with WS. Persons with WS exhibited larger than typical P3a responses when the novel stimuli were perceptually distinct from the standard and the target stimuli (Study 2), but not when task-relevant and -irrelevant stimuli were perceptually similar (Study 1). Further, the WS group demonstrated reduced goal-directed attention (attenuated P3b response). These group differences in ERPs were not directly related to IQ. Our results in the context of an active discrimination task point to a more complex profile of auditory processing in persons with WS than previously reported, with group differences emerging during the later stages of stimulus categorization and evaluation, but not within early stimulus detection and feature encoding.

Prader-Willi syndrome and early-onset morbid obesity NIH rare disease consortium: A review of natural history study.

We describe the National Institutes of Health rare disease consortium for Prader-Willi syndrome (PWS) developed to address concerns regarding medical care, diagnosis, growth and development, awareness, and natural history. PWS results from errors in genomic imprinting leading to loss of paternally expressed genes due to 15q11-q13 deletion, maternal disomy 15 or imprinting defects. The 8 year study was conducted at four national sites on individuals with genetically confirmed PWS and early-onset morbid obesity (EMO) with data accumulated to gain a better understanding of the natural history, cause and treatment of PWS. Enrollment of 355 subjects with PWS and 36 subjects with EMO began in September 2006 with study completion in July 2014. Clinical, genetic, cognitive, behavior, and natural history data were systematically collected along with PWS genetic subtypes, pregnancy and birth history, mortality, obesity, and cognitive status with study details as important endpoints in both subject groups. Of the 355 individuals with PWS, 217 (61%) had the 15q11-q13 deletion, 127 (36%) had maternal disomy 15, and 11 (3%) had imprinting defects. Six deaths were reported in our PWS cohort with 598 cumulative years of study exposure and one death in the EMO group with 42 years of exposure. To our knowledge, this description of a longitudinal study in PWS represents the largest and most comprehensive cohort useful for investigators in planning comparable studies in other rare disorders. Ongoing studies utilizing this database should have a direct impact on care and services, diagnosis, treatment, genotype-phenotype correlations, and clinical outcomes in PWS.

Diagnoses and characteristics of autism spectrum disorders in children with Prader-Willi syndrome.

BACKGROUND: A small percentage of people with autism spectrum disorders (ASD) have alterations in chromosome 15q11.2-q3, the critical region for Prader-Willi syndrome (PWS). Data are limited, however, on the rates and characteristics of ASD in PWS. Previous estimates of ASD in PWS (25 to 41%) are questionable as they are based solely on autism screeners given to parents. Inaccurate diagnoses of ASD in PWS can mislead intervention and future research. METHODS: One hundred forty-six children and youth with PWS aged 4 to 21 years (M = 11) were assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). An expert clinical team-made best-estimate ASD diagnoses based on ADOS-2 videotapes, calibrated severity scores, and children's developmental histories and indices of current functioning. Children were also administered the Kaufman Brief Intelligence Test-2, and parents completed the Repetitive Behavior Scale-Revised and Vineland Adaptive Behavior Scales. Scores were compared across children with PWS + ASD versus PWS only. The performance of an ASD screener, the Social Communication Questionnaire (SCQ) and the ADOS-2 were evaluated in relation to best-estimate diagnoses. RESULTS: Best-estimate diagnoses of ASD were made in 18 children, or 12.3% of the sample, and the majority of them had the maternal uniparental disomy (mUPD) PWS genetic subtype. Compared to the PWS-only group, children with PWS + ASD had lower verbal and composite IQ's and adaptive daily living and socialization skills, as well as elevated stereotypies and restricted interests. Regardless of ASD status, compulsivity and insistence on sameness in routines or events were seen in 76-100% of children and were robustly correlated with lower adaptive functioning. The SCQ yielded a 29-49% chance that screen-positive cases will indeed have ASD. The ADOS-2 had higher sensitivity, specificity and predictive values. Communication problems were seen in children who were ADOS-2 positive but deemed not to have ASD by the clinical team. CONCLUSIONS: Autism screeners should not be the sole index of probable ASD in PWS; children need to be directly observed and evaluated. Compulsivity and insistence on sameness are salient in PWS and likely impede adaptive functioning. Most children with PWS only evidenced sub-threshold problems in social interactions that could signal risks for other psychopathologies.