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The aim of this study was to review bariatric procedure outcomes among patients with Prader-Willi syndrome (PWS), melanocortin 4 receptor (MC4R) mutations, Bardet-Biedl syndrome, and hypothalamic obesity.Systematic published literature review used the following search terms: "Prader-Willi syndrome," "Bardet-Biedl syndrome," "hyperphagia," "bariatric surgery," "MC4R"/"melanocortin 4 receptor", "hypothalamic obesity," and "bariatric procedure." Information collected included demographics, genetics, anthropometry, procedure type, outcomes, and complications, with inclusion of case series and clinical reports given the rarity of the disorders. For PWS, postoperative weight-change percentage and BMI up to 14 years following surgery were analyzed using general linear mixed models, with descriptive outcomes for other conditions.A total of 54 publications were identified, with variable follow-up periods for 202 patients (114 with PWS, 43 with MC4R mutations, 7 with Bardet-Biedl syndrome, and 38 with hypothalamic obesity) among bariatric procedures. Weight loss of patients with PWS was greatest within 1 year of surgery, with weight-change percentage not significantly different from 0 at 5 years. Long-term results in other conditions were variable and featured suboptimal weight loss and increased reoperation risk.Bariatric procedures among hyperphagic individuals, including those with PWS, report variable results and outcomes. Benefits of bariatric surgery may be less durable in hyperphagic disorders in comparison with other patients with severe obesity.

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 (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 head circumferences (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.

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.

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.

Purpose Rearing crickets in the UK for the live pet food market is already a well-established industry. However, there is interest in also producing food for human consumption. This paper presents a life cycle assessment (LCA) of a current live pet food business. Using results from this LCA, the papers explores how current business practices could be improved to reduce environmental impacts, and discusses the potential benefits of a hybrid live pet food/human consumption business model. Methods An attributional, cradle-to-farm-gate life cycle assessment was conducted on rearing crickets for the live pet food market, with data collected on-site at a case study business. Results are reported in multiple impact categories from the ILCD 2011 Midpoint+ method. Comparison is made to the only other similar study: an LCA of rearing crickets in Thailand for human consumption (Halloran et al. J Clean Prod 156:83–94, 2017). The sources of the different environmental impacts between the two studies are explored and inefficiencies in the live pet food rearing process identified. Subsequently, scenarios are used to explore how the inefficiencies may be mitigated, and environmental impact of the live pet food production process reduced through adoption of a hybrid live pet food/human food production model. Results and discussions The environmental impact was found to be larger across all impact categories than the only known comparable study, which is for rearing crickets in Thailand for human consumption (Halloran et al. J Clean Prod 156:83–94, 2017). Some of this difference is due to the heating required for rearing crickets in a climate such as the UK, and some is due to the requirements of the live pet food market being much more demanding on resources than the human food model. The current study identifies improvements in practices that would make this contrast less stark, such as optimizing feeding practices, and the benefits of moving to a hybrid live pet food/human consumption business model. Conclusions This is the first LCA of crickets reared in the UK. The results highlight inefficiencies in the rearing process that are now being addressed by the case study business. The study also shows the potential co-benefits of a hybrid business model, in which crickets for human consumption are produced alongside crickets for the live pet food market.

BackgroundPrader-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.MethodsHigh-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.ResultsWe 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).ConclusionsWe 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.

Prader&ndash, Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11&ndash, 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 &lt, 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 &lt, 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.

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell–derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p–/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p–/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p–/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH–releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.

Prader-Willi syndrome (PWS) is a syndromic obesity caused by loss of paternal gene expression in an imprinted interval on 15q11.2-q13. Induced pluripotent stem cells were generated from skin cells of three large deletion PWS patients and one unique microdeletion PWS patient. We found that genes within the PWS region, including SNRPN and NDN, showed persistence of DNA methylation after iPSC reprogramming and differentiation to neurons. Genes within the PWS minimum critical deletion region remain silenced in both PWS large deletion and microdeletion iPSC following reprogramming. PWS iPSC and their relevant differentiated cell types could provide in vitro models of PWS.

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder associated with maladaptive social behavior, hyperphagia and morbid obesity. Orexin A is a hypothalamic neuropeptide important as a homeostatic regulator of feeding behavior and in energy metabolism through actions in the lateral hypothalamus. Dysregulation of orexin signaling may contribute to behavioral problems and hyperphagia seen in PWS and we sought to assess orexin A levels in PWS relative to controls children. Morning fasting plasma orexin A levels were analyzed in 23 children (aged 5-11 years) with genetically confirmed PWS and 18 age and gender matched healthy unrelated siblings without PWS. Multiplex immune assays utilized the Milliplex Human Neuropeptide Magnetic panel and the Luminex platform. Natural log-transformed orexin A data were analyzed using general linear model adjusting for diagnosis, gender, age, total body fat, and body mass index (BMI). Plasma orexin A levels were significantly higher (P

Prader-Willi syndrome (PWS) is a complex multisystemic condition caused by a lack of paternal expression of imprinted genes from the 15q11.2&ndash, q13 region. Limited literature exists on the association between molecular classes, growth hormone use, and the prevalence of psychiatric phenotypes in PWS. In this study, we analyzed nine psychiatric phenotypes (depressed mood, anxiety, skin picking, nail picking, compulsive counting, compulsive ordering, plays with strings, visual hallucinations, and delusions) recognized in PWS and investigated associations with growth hormone treatment (GHT), deletions (DEL) and uniparental disomy (UPD) in a cohort of 172 individuals with PWS who met the criteria for analysis. Associations were explored using Pearson chi-square tests and univariable and multivariable logistic regression analyses to control for confounding exposures. This observational study of the largest dataset of patients with PWS to date suggested the following genetic subtype and phenotype correlations in psychiatric behaviors: (1) skin picking was more frequent in those with DEL vs. UPD, (2) anxiety was more common in those with UPD vs. DEL, and (3) an increased frequency of anxiety was noted in the UPD group treated with GHT compared to the DEL group. No other significant associations were found between the genetic subtype or GHT including for depressed mood, nail picking, compulsive counting, compulsive ordering, playing with strings, and visual hallucinations. Further studies will be required before any conclusions can be reached.

Prader-Willi syndrome (PWS) is a rare genetic disorder associated with distinct abnormal behaviors including hyperphagia, profound social deficits, and obsessive-compulsive tendencies. PWS males showed reduced oxytocin receptor (OTR) gene expression and density in the hypothalamic paraventricular nucleus that may play a role in PWS psychopathology. Oxytocin is an anorexigenic neuropeptide similar to vasopressin that is associated with social cognition and obsessive-compulsive behavior. To evaluate oxytocin biology in PWS, we examined overnight fasting plasma oxytocin levels in 23 children with PWS (mean ± SD age: 8.2 ± 2.0 year) having genetic confirmation and 18 age matched healthy unrelated siblings without PWS (mean ± SD age: 8.2 ± 2.3 year) and a similar gender ratio under the same clinical assessments, specimen processing and laboratory conditions. Multiplex immune assays were carried out using the Milliplex Human Neuropeptide Magnetic panel and the Luminex system. Natural log-transformed oxytocin levels were analyzed using general linear model adjusting for diagnosis, gender, age and body mass index (BMI). Oxytocin plasma levels were significantly elevated in children with PWS (168 ± 121 pg/ml) compared with unrelated and unaffected siblings without the diagnosis of PWS (64.8 ± 83.8 pg/ml, F = 8.8, P < 0.01) and the diagnosis of PWS predicted oxytocin level (F = 9.5, P < 0.003) in controlled regression analysis with an overall model fit R(2) = 0.33 (P < 0.01). The symptoms of hyperphagia, anxiety and repetitive behaviors classically seen in PWS may be related to the disruption of oxytocin responsivity or feedback in the hypothalamic paraventricular nucleus possibly influencing vasopressin signaling. Further study is needed to characterize oxytocin function in PWS.

Prader–Willi syndrome (PWS) is caused by loss of paternally expressed genes from the 15q11-q13 region and reportedly rearranged as a cause of autism. Additionally, increased inflammatory markers and features of autism are reported in PWS. Cytokines encoded by genes involved with inflammation, cell proliferation, migration, and adhesion play a role in neurodevelopment and could be disturbed in PWS as abnormal plasma cytokine levels are reported in autism. We analyzed 41 plasma cytokines in a cohort of well-characterized children with PWS between 5 and 11 years of age and unaffected unrelated siblings using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Data were analyzed using ANOVA testing for effects of diagnosis, gender, body mass index (BMI) and age on the 24 cytokines meeting laboratory criteria for inclusion. No significant effects were observed for age, gender or BMI. The log-transformed levels of the 24 analyzable cytokines were examined simultaneously using MANOVA adjusting for age and gender and a main effect of diagnosis was found (P-value

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.

Circulating total ghrelin levels are elevated in older children and adults with Prader-Willi syndrome (PWS). However, the presence or absence of hyperghrelinemia in young children with PWS remains controversial. We hypothesized that a more robust way to analyze appetite-regulating hormones in PWS would be by nutritional phases rather than age alone. Our objectives were to compare total serum ghrelin levels in children with PWS by nutritional phase as well as to compare total ghrelin levels in PWS (5 weeks to 21 years of age) to normal weight controls and individuals with early-onset morbid obesity (EMO) without PWS. Fasting serum total ghrelin levels were measured in 60 subjects with PWS, 39 subjects with EMO of unknown etiology, and in 95 normal non-obese sibling controls of PWS or EMO subjects (SibC) in this 12 year longitudinal study. Within PWS, total ghrelin levels were significantly (P

Objective Hyperphagia is a central feature of inherited disorders (e.g., Prader–Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. Design and Methods International conference with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates. Results The reviewed collective research and clinical experience provides a critical body of new and novel information on hyperphagia at levels ranging from molecular to population. Gaps in understanding and tools needed for additional research were identified. Conclusions This report documents the full scope of important topics reviewed at a comprehensive international meeting devoted to the topic of hyperphagia and identifies key areas for future funding and research.

Frequency of Prader–Willi syndrome in births conceived via assisted reproductive technology

The effect of vacuum exposure on latent fingerprint chemistry has been evaluated. Fingerprints were analysed using a quartz crystal microbalance to measure changes in mass, gas chromatography mass spectrometry to measure changes in lipid composition and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) to determine changes in the content of water, fatty acids and their esters after exposure to vacuum. The results are compared with samples aged under ambient conditions. It was found that fingerprints lose around 26% of their mass when exposed to vacuum conditions, equivalent to around 5 weeks ageing under ambient conditions. Further exposure to vacuum causes a significant reduction in the lipid composition of a fingerprint, in particular with the loss of tetradecanoic and pentadecanoic acid, that was not observed in ambient aged samples. There are therefore implications for sequence in which fingerprint development procedures (for example vacuum metal deposition) are carried out, as well as the use of vacuum based methods such as secondary ion mass spectrometry (SIMS) and matrix-assisted laser desorption ionisation (MALDI) in the study of fingerprint chemistry.

Sim1 haploinsufficiency in mice induces hyperphagic obesity and developmental abnormalities of the brain. In humans, abnormalities in chromosome 6q16, a region that includes SIM1, were reported in obese children with a Prader-Willi-like syndrome; however, SIM1 involvement in obesity has never been conclusively demonstrated. Here, SIM1 was sequenced in 44 children with Prader-Willi-like syndrome features, 198 children with severe early-onset obesity, 568 morbidly obese adults, and 383 controls. We identified 4 rare variants (p.I128T, p.Q152E, p.R581G, and p.T714A) in 4 children with Prader-Willi-like syndrome features (including severe obesity) and 4 other rare variants (p.T46R, p.E62K, p.H323Y, and p.D740H) in 7 morbidly obese adults. By assessing the carriers' relatives, we found a significant contribution of SIM1 rare variants to intra-family risk for obesity. We then assessed functional effects of the 8 substitutions on SIM1 transcriptional activities in stable cell lines using luciferase gene reporter assays. Three mutations showed strong loss-of-function effects (p.T46R, p.H323Y, and p.T714A) and were associated with high intra-family risk for obesity, while the variants with mild or no effects on SIM1 activity were not associated with obesity within families. Our genetic and functional studies demonstrate a firm link between SIM1 loss of function and severe obesity associated with, or independent of, Prader-Willi-like features.

Prader-Willi syndrome (PWS) is caused by the loss of RNA expression from an imprinted region on chromosome 15 that includes SNRPN, SNORD115, and SNORD116. Currently, there are no mouse models that faithfully reflect the human phenotype and investigations rely on human post-mortem material. During molecular characterization of tissue deposited in a public brain bank from a patient diagnosed with Prader-Willi syndrome, we found RNA expression from SNRPN, SNORD115, and SNORD116 which does not support a genetic diagnosis of Prader-Willi syndrome. The patient was a female, Caucasian nursing home resident with history of morbid obesity (BMI 56.3) and mental retardation. She died at age of 56 from pulmonary embolism. SNORD115 and SNORD116 are unexpectedly stable in post mortem tissue and can be used for post-mortem diagnosis. Molecular characterization of PWS tissue donors can confirm the diagnosis and identify those patients that have been misdiagnosed.

Prader-Willi syndrome (PWS) is a rare, complex multisystem genetic disorder which includes hypothalamic dysfunction, hyperphagia, cognitive and behavioral problems, increased anxiety, and compulsive behaviors. Individuals with PWS have a deficit of oxytocin producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin plays a role in regulation of feeding behaviors, social interactions, and emotional reactivity, which are all issues that significantly affect the quality of life for individuals with this syndrome. We performed a double-blind, placebo-controlled, crossover study in 24 children with PWS at three academic institutions using 5 days of intranasal oxytocin (IN-OT) or 5 days of intranasal placebo spray, followed by a 4 week washout period, and then patients returned for 5 days of treatment with the alternate source. Questionnaires, including the Aberrant Behavior Checklist, Social Responsiveness Scale, Repetitive Behavior Scale - Revised, and the Hyperphagia Questionnaire, as well as Clinical Global Impression scales were administered. Blood testing for sodium, potassium, and glucose levels on days 2, 4, and 6, and a 24 hr diet recall. All scales factor improvement from Day 3 to Day 6 favored oxytocin over placebo. No single factor showed a statistically significant difference (P

The purpose of the current study was to develop syndrome-specific standardized growth curves for growth hormone–treated Prader-Willi syndrome (PWS) individuals aged 0 to 18 years. Anthropometric growth-related measures were obtained on 171 subjects with PWS who were treated with growth hormone for at least 40% of their lifespan. They had no history of scoliosis. PWS standardized growth curves were developed for 7 percentile ranges using the LMS method for weight, height, head circumference, weight/length, and BMI along with normative 3rd, 50th, and 97th percentiles plotted using control data from the literature and growth databases. Percentiles were plotted on growth charts for comparison purposes. Growth hormone treatment appears to normalize stature and markedly improves weight in PWS compared with standardized curves for non–growth hormone–treated PWS individuals. Growth chart implications and recommended usage are discussed.

Background Children with Prader-Willi syndrome (PWS) have a predictable pattern of weight gain, with obesity beginning in early childhood and worsening as they get older and hyperphagia increases. Data on the most effective dietary modifications are scant and primarily anecdotal. As part of a longitudinal study investigating the natural history of PWS, we evaluated the effect of a well-balanced, energy-restricted diet on body composition and weight in young children with PWS.

Restricted and repetitive behavior (RRB) is a group of heterogeneous maladaptive behaviors. RRB is one of the key diagnostic features of autism spectrum disorders (ASDs) and also commonly observed in Prader–Willi syndrome (PWS). In this study, we assessed RRB using the Repetitive Behavior Scale-Revised (RBS-R) in two ASD samples (University of Illinois at Chicago [UIC] and University of Florida [UF]) and one PWS sample. We compared the RBS-R item endorsements across three ASD cohorts (UIC, UF and an ASD sample from Lam, The Repetitive Behavior Scale-Revised: independent validation and the effect of subject variables, PhD thesis, 2004), and a PWS sample. We also compared the mean RBS-R subscale/sum scores across the UIC, UF and PWS samples; across the combined ASD (UIC + UF), PWS-deletion and PWS-disomy groups; and across the combined ASD sample, PWS subgroup with a Social Communication Questionnaire (SCQ) score ≥15, and PWS subgroup with a SCQ score

Prader-Willi syndrome (PWS) is a complex neurobehavioral condition which has been classically described as having two nutritional stages: poor feeding, frequently with failure to thrive (FTT) in infancy (Stage 1), followed by hyperphagia leading to obesity in later childhood (Stage 2). We have longitudinally followed the feeding behaviors of individuals with PWS and found a much more gradual and complex progression of the nutritional phases than the traditional two stages described in the literature. Therefore, this study characterizes the growth, metabolic, and laboratory changes associated with the various nutritional phases of PWS in a large cohort of subjects. We have identified a total of seven different nutritional phases, with five main phases and sub-phases in phases 1 and 2. Phase 0 occurs in utero, with decreased fetal movements and growth restriction compared to unaffected siblings. In phase 1 the infant is hypotonic and not obese, with sub-phase 1a characterized by difficulty feeding with or without FTT (ages birth-15 months; median age at completion: 9 months). This phase is followed by sub-phase 1b when the infant grows steadily along a growth curve and weight is increasing at a normal rate (median age of onset: 9 months; age quartiles 5-15 months). Phase 2 is associated with weight gain-in sub-phase 2a the weight increases without a significant change in appetite or caloric intake (median age of onset 2.08 years; age quartiles 20-31 months;), while in sub-phase 2b the weight gain is associated with a concomitant increased interest in food (median age of onset: 4.5 years; quartiles 3-5.25 years). Phase 3 is characterized by hyperphagia, typically accompanied by food-seeking and lack of satiety (median age of onset: 8 years; quartiles 5-13 years). Some adults progress to phase 4 which is when an individual who was previously in phase 3 no longer has an insatiable appetite and is able to feel full. Therefore, the progression of the nutritional phases in PWS is much more complex than previously recognized. Awareness of the various phases will aid researchers in unraveling the pathophysiology of each phase and provide a foundation for developing rational therapies. Counseling parents of newly diagnosed infants with PWS as to what to expect with regard to these nutritional phases may help prevent or slow the early-onset of obesity in this syndrome.

Carnitine deficiency or coenzyme Q10 (CoQ10) deficiency may present with hypotonia, poor growth, easy fatigability, and apnea. This constellation of findings can also be seen in individuals with Prader–Willi syndrome (PWS). Animal studies indicate that increased fat mass due to obesity negatively correlates with both carnitine and CoQ10 levels in skeletal muscle. Increased body fat and obesity are characteristic of individuals with PWS. Currently, there is no documentation of serum carnitine levels, and only one study investigating plasma CoQ10 levels, in individuals with PWS. Fasting serum carnitine and plasma CoQ10 levels were measured in 40 individuals with molecularly confirmed PWS (ages 1–27 years; 19 F/21 M), 11 individuals with early-onset morbid obesity of unknown etiology (ages 3–13 years; 5 F/6 M), and 35 control siblings from both groups (ages 1–24 years; 19 F/16 M). There were no significant differences among the three groups in either total carnitine, free carnitine, or CoQ10 levels. However, individuals with PWS had higher serum levels of carnitine esters (P = 0.013) and higher ester-to-free carnitine ratios (P = 0.0096) than controls suggesting a possible underlying impairment of peripheral carnitine utilization and mitochondrial energy metabolism in some individuals with PWS. Serum sampling identified no significant differences in total and free carnitine or CoQ10 levels between individuals with PWS, obese individuals, and sibling control groups. Muscle biopsy or measurement in leukocytes or cultured skin fibroblasts could be a better method to identify abnormalities in carnitine and CoQ10 metabolism in individuals with PWS than peripheral blood sampling. © 2011 Wiley-Liss, Inc.

Prader–Willi syndrome (PWS) is a highly variable genetic disorder affecting multiple body systems whose most consistent major manifestations include hypotonia with poor suck and poor weight gain in infancy; mild mental retardation, hypogonadism, growth hormone insufficiency causing short stature for the family, early childhood-onset hyperphagia and obesity, characteristic appearance, and behavioral and sometimes psychiatric disturbance. Many more minor characteristics can be helpful in diagnosis and important in management. PWS is an example of a genetic condition involving genomic imprinting. It can occur by three main mechanisms, which lead to absence of expression of paternally inherited genes in the 15q11.2–q13 region: paternal microdeletion, maternal uniparental disomy, and imprinting defect.

Alkaline anion-exchange membranes (AAEMs) are being developed for metal-cation-free solid alkaline fuel cells. Reduced solvent uptakes were observed after immersion in methanol, ethanol and ethylene glycol relative to a Nafion®-115 proton-exchange membrane (PEM); this translated directly into lower alcohol permeabilities. Alkaline polymer electrolytes showed lowered degrees of swelling (membrane thickness), when immersed in methanol and ethanol, relative to Nafion-115. The open circuit voltages, VOCV, of the corresponding direct alcohol fuel cells were superior to acid equivalents with membranes of identical fully hydrated thicknessess; this is indicative of a combination of reduced alcohol permeabilities and changed electrokinetics on PtRu anode catalysts at high pH. VOCV values for the AAEM-DAFCs were higher with ethanol than with methanol (consequent on lower permeability to ethanol), but were lower with ethylene glycol. Promisingly, and contrary to Nafion equivalents, peak power densities were not reduced when C2 alcohols (C-C bond containing) replaced methanol.

Purpose: Prader-Willi syndrome is a well-defined genetic cause of childhood-onset obesity that can serve as a model for investigating early-onset childhood obesity. Individuals with Prader-Willi syndrome have speech and language impairments, suggesting possible involvement of the perisylvian region of the brain. Clinical observations suggest that many individuals with early-onset morbid obesity have similar speech/language deficits, indicating possible perisylvian involvement in these children as well. We hypothesized that similar perisylvian abnormalities may exist in both disorders. Methods: Participants included individuals with Prader-Willi syndrome (n = 27), their siblings (n = 16), individuals with early-onset morbid obesity (n = 13), and their siblings (n = 10). Quantitative and qualitative assessments of sylvian fissure conformation, insula closure, and planum temporale length were performed blind to hemisphere and diagnosis. Results: Quantitative measurements verified incomplete closure of the insula in individuals with Prader-Willi syndrome. Planar asymmetry showed its normal bias toward leftward asymmetry in all groups except those with Prader-Willi syndrome maternal uniparental disomy. Individuals with Prader-Willi syndrome and siblings had a normal distribution of sylvian fissure types in both hemispheres, while individuals with early-onset morbid obesity and their siblings had a high proportion of rare sylvian fissures in the right hemisphere. Conclusions: The contrast between the anatomic findings in individuals with Prader-Willi syndrome and early-onset morbid obesity suggests that the language problems displayed by children with these two conditions may be associated with different neurodevelopmental processes.

Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by loss of paternally expressed genes from the 15q11-q13 region generally due to a paternally-derived deletion of the 15q11-q13 region or maternal disomy 15 (UPD). Maternal disomy 15 is usually caused by maternal meiosis I non-disjunction associated with advanced maternal age and after fertilization with a normal sperm leading to trisomy 15, a lethal condition unless trisomy rescue occurs with loss of the paternal chromosome 15. To further characterize the pathogenesis of maternal disomy 15 process in PWS, the status of X-chromosome inactivation was calculated to determine whether non-random skewing of X-inactivation is present indicating a small pool of early embryonic cells. We studied X-chromosome inactivation in 25 females with PWS-UPD, 35 with PWS-deletion, and 50 controls (with similar means, medians, and age ranges) using the polymorphic androgen receptor (AR) gene assay. A significant positive correlation (r = 0.5, P = 0.01) was seen between X-chromosome inactivation and age for only the UPD group. Furthermore, a significantly increased level (P = 0.02) of extreme X-inactivation skewness (>90%) was detected in our PWS-UPD group (24%) compared to controls (4%). This observation could indicate that trisomy 15 occurred at conceptus with trisomy rescue in early pregnancy leading to extreme skewness in several PWS-UPD subjects. Extreme X-inactivation skewness may also lead to additional risks for X-linked recessive disorders in PWS females with UPD and extreme X-chromosome skewness.

Prader–Willi syndrome (PWS) is an obesity-related genetic condition, most commonly due to a paternal deletion of the chromosome 15q11-q13 region. PWS is characterized by growth hormone deficiency, infantile hypotonia and feeding problems, hypogenitalism/hypogonadism, increased pain threshold and thermal instability, decreased gastric motility, and hyperphagia in childhood leading to severe obesity. Neuro-endocrine peptides are known to influence gastric function and pain sensation which led us to measure a specific peptide that may be involved [i.e., neurotensin (NT)] in PWS and compared with unrelated control siblings. Overnight fasting plasma NT levels were obtained from 23 children with confirmed PWS (age: 8.2 ± 2.0 years; range: 5–11 years) and 18 unaffected, unrelated siblings (age: 8.2 ± 2.3 years; range: 5–11 years) and measured using Multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Plasma NT levels were natural log-transformed and analyzed by ANOVA with adjustments for age, gender, and body mass index (BMI). No difference was found in plasma NT levels for gender, age or BMI or significant correlations seen with age or BMI. Higher plasma NT levels (P

Objective Systemic lupus erythematosus (SLE) is associated with type I interferons (IFNs) and can be induced by IFNα treatment. This study looked for evidence of autoimmunity in a pedigree consisting of 4 family members with a balanced translocation 9;21 and 2 members with an unbalanced translocation resulting in trisomy of the short (p) arm and part of the long (q) arm of chromosome 9. These latter 2 subjects had 3 copies of the IFN gene cluster. Methods Subjects were evaluated clinically and serologically for autoimmune disease. Expression levels of IFNα4, IFNβ, the type I IFN–inducible gene Mx1, the type I IFN receptor, interleukin-6, and tumor necrosis factor α were determined by real-time polymerase chain reaction. Circulating plasmacytoid dendritic cells, the main IFN-producing cells, were quantified by flow cytometry. Results Both subjects with trisomy of chromosome 9p had a lupus-like syndrome with joint manifestations and antinuclear antibodies: one had anti-RNP and antiphospholipid autoantibodies, and the other had anti–Ro 60. The 3 family members with a balanced translocation 9;21 had no clinical or serologic evidence of autoimmunity, similar to that in relatives who were unaffected by the chromosomal translocation. In the 2 subjects with trisomy of 9p, high levels of IFNα/β (comparable with those found in patients with SLE), increased signaling through the IFN receptor (as indicated by high Mx1 expression), and low levels of circulating plasmacytoid dendritic cells (as observed in patients with SLE) were evident. These abnormalities were not seen in individuals with a balanced translocation. Conclusion Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFNα/β and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE.

Angelman syndrome (AS) is a neurodevelopmental disorder due to a functional deficit, usually a deletion, of the UBE3A gene located in the 15q11–q13 chromosome region. We report the first microarray analysis of gene expression in AS using a custom cDNA microarray to compare expression patterns from lymphoblastoid cell lines from control males and AS subjects with a 15q deletion or uniparental paternal disomy 15. Expression patterns of genes known to be biallelically expressed or paternally or maternally expressed were consistent with expectations. We detected paternal or maternal allelic bias in the expression of several genes and transcripts (e.g., GABRA5, GABRB3, WI14946). Additionally, mechanisms controlling paternal allele expression appear to be faithfully replicated in each paternal chromosome in individuals with paternal disomy. Our results indicate that interconnected mechanisms can produce subtle and unexpected changes in gene expression that may help explain the phenotypic differences observed among the genetic subtypes of AS. D 2004 Elsevier Inc. All rights reserved.

Based on the formation of the XY body at pachytene and expression studies of a few X-linked genes, the X and Y chromosomes seem to undergo transcriptional inactivation during mammalian spermatogenesis. However, the extent and the mechanism of X and Y inactivation are not known. Here, we show that both the X and Y chromosomes undergo sequential changes in their histone modifications beginning at the pachytene stage of meiosis. These changes usually are associated with transcriptional inactivation in somatic cells, and they coincide with the exclusion of the phosphorylated (active) form of RNA polymerase II from the XY body. Both sex chromosomes undergo extensive deacetylation at histones H3 and H4 and (di)methylation of lysine (K)9 on histone H3; however, there are no changes in H3–K4 methylation. These changes persist even when the XY body disappears in late pachytene, and the X and Y chromosomes segregate from one another after the first meiotic division. By the spermatid stage, histone modifications of the X and Y chromosomes revert to those of active chromatin and RNA polymerase II reengages with both chromosomes. Our observations indicate that X and Y inactivation is extensive and persists even when the X and Y chromosomes are separated in secondary spermatocytes. These findings provide insights into epigenetic programming and chromatin dynamics in the male germ line.

OBJECTIVE:The goal of this study was to generate and report standardized growth curves for weight, height, head circumference, and BMI for non–growth hormone–treated white male and female US subjects with Prader-Willi syndrome (PWS) between 3 and 18 years of age and develop standardized growth charts.METHODS:Anthropometric measures (N = 133) were obtained according to standard methods from 120 non–growth hormone–treated white subjects (63 males and 57 females) with PWS between 3 and 18 years of age. Standardized growth curves were developed for the third, 10th, 25th, 50th, 75th, 90th, and 97th percentiles by using the LMS method for weight, height, head circumference, and BMI for PWS subjects along with the normative third, 50th, and 97th percentiles from national and international growth data. The LMS smoothing procedure summarized the distribution of the anthropometric variables at each age using three parameters: power of the Box-Cox transformation λ (L), median μ (M) and coefficient of variation δ (S).RESULTS:Weight, height, head circumference, and BMI standardized growth charts representing 7 percentile ranges were developed from 120 non–growth hormone–treated white male and female US subjects with PWS (age range: 3–18 years) and normative third, 50th, and 97th percentiles from national and international data.CONCLUSIONS:We encourage the use of syndrome-specific growth standards to examine and evaluate subjects with PWS when monitoring growth patterns and determining nutritional and obesity status. These variables can be influenced by culture, individual medical care, diet intervention, and physical activity plans.

1.5 Mutational spectrum 75% Maternal deletion 15q11–q13. 1–2% Paternal uniparental disomy (upd(15)pat). 3% Imprinting defect. 5–10% Variants in the UBE3A gene. 10–15% Unknown (It is important to exclude differential diagnoses in these cases as there is phenotypic overlap with several other genetic disorders). Data on this disease (gene variants/phenotype) can be found in the public database Decipher (https://decipher.sanger.ac.uk).

About 1% of individuals with autism or types of pervasive developmental disorder have a duplication of the 15q11-q13 region. These abnormalities can be detected by routine G-banded chromosome study, showing an extra marker chromosome, or demonstrated by fluorescence in situ hybridization (FISH) analysis, revealing an interstitial duplication. We report here the molecular, cytogenetic, clinical and neuropsychiatric evaluations of a family in whom 3 of 4 siblings inherited an interstitial duplication of 15q11-q13. This duplication was inherited from their mother who also had a maternally derived duplication. Affected family members had apraxia of speech, phonological awareness deficits, developmental language disorder, dyslexia, as well as limb apraxia but did not have any dysmorphic clinical features. The observations in this family suggest that the phenotypic manifestations of proximal 15q duplications may also involve language-based learning disabilities.

BACKGROUND—Angelman syndrome (AS) is a severe neurobehavioural disorder caused by defects in the maternally derived imprinted domain located on 15q11-q13. Most patients acquire AS by one of five mechanisms: (1) a large interstitial deletion of 15q11-q13; (2) paternal uniparental disomy (UPD) of chromosome 15; (3) an imprinting defect (ID); (4) a mutation in the E3 ubiquitin protein ligase gene (UBE3A); or (5) unidentified mechanism(s). All classical patients from these classes exhibit four cardinal features, including severe developmental delay and/or mental retardation, profound speech impairment, a movement and balance disorder, and AS specific behaviour typified by an easily excitable personality with an inappropriately happy affect. In addition, patients can display other characteristics, including microcephaly, hypopigmentation, and seizures. METHODS—We restricted the present study to 104 patients (93 families) with a classical AS phenotype. All of our patients were evaluated for 22 clinical variables including growth parameters, acquisition of motor skills, and history of seizures. In addition, molecular and cytogenetic analyses were used to assign a molecular class (I-V) to each patient for genotype-phenotype correlations. RESULTS—In our patient repository, 22% of our families had normal DNA methylation analyses along 15q11-q13. Of these, 44% of sporadic patients had mutations within UBE3A, the largest percentage found to date. Our data indicate that the five molecular classes can be divided into four phenotypic groups: deletions, UPD and ID patients, UBE3A mutation patients, and subjects with unknown aetiology. Deletion patients are the most severely affected, while UPD and ID patients are the least. Differences in body mass index, head circumference, and seizure activity are the most pronounced among the classes. CONCLUSIONS—Clinically, we were unable to distinguish between UPD and ID patients, suggesting that 15q11-q13 contains the only significant maternally expressed imprinted genes on chromosome 15. Keywords: Angelman syndrome; genotype-phenotype correlations; DNA methylation; 15q11-q13

Purpose: To determine: 1) If a 15q11–13 deletion was transmitted from a female with Angelman syndrome to her fetus, and 2) If the UBE3A gene was functionally imprinted in fetal eye. Methods: Individuals were genotyped by microsatellite analysis. DNA methylation imprints were assessed by Southern blot analysis and methylationspecific PCR. Expression was analyzed by RT-PCR. Results: The mother and fetus inherited large deletions of maternal 15q11–13 and demonstrated paternal-only DNA methylation imprints along 15q11–13. UBE3A was paternally expressed in eye tissue from the fetus with Angelman syndrome. Conclusions: We show that females with Angelman syndrome are fully capable of reproduction and that UBE3A is not imprinted in fetal eye.

Summary Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively. At a de novo frequency of ∼.67–1/10,000 births, these deletions represent a common structural chromosome change in the human genome. To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster. Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions. Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints. The END -repeat units are derived from large genomic duplications of a novel gene ( HERC2 ), many copies of which are transcriptionally active in germline tissues. One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event. We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion. Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.

Loss of imprinting at IGF2 , generally through an H19 -independent mechanism, is associated with a large percentage of patients with the overgrowth and cancer predisposition condition Beckwith–Wiedemann syndrome (BWS). Imprinting control elements are proposed to exist within the KvLQT1 locus, because multiple BWS-associated chromosome rearrangements disrupt this gene. We have identified an evolutionarily conserved, maternally methylated CpG island ( KvDMR1 ) in an intron of the KvLQT1 gene. Among 12 cases of BWS with normal H19 methylation, 5 showed demethylation of KvDMR1 in fibroblast or lymphocyte DNA; whereas, in 4 cases of BWS with H19 hypermethylation, methylation at KvDMRl was normal. Thus, inactivation of H19 and hypomethylation at KvDMR1 (or an associated phenomenon) represent distinct epigenetic anomalies associated with biallelic expression of IGF2 . Reverse transcription–PCR analysis of the human and syntenic mouse loci identified the presence of a KvDMR1 -associated RNA transcribed exclusively from the paternal allele and in the opposite orientation with respect to the maternally expressed KvLQT1 gene. We propose that KvDMR1 and/or its associated antisense RNA ( KvLQT1-AS ) represents an additional imprinting control element or center in the human 11p15.5 and mouse distal 7 imprinted domains.

SummaryMicrodeletions of a region termed the “imprinting center” (IC) in chromosome 15q11-q13 have been identified in several families with Prader-Willi syndrome (PWS) or Angelman syndrome who show epigenetic inheritance for this region that is consistent with a mutation in the imprinting process. The IC controls resetting of parental imprints in 15q11-q13 during gametogenesis. We have identified a larger series of cases of familial PWS, including one case with a deletion of only 7.5 kb, that narrows the PWS critical region to

The Prader-Willi (PWS) and Angelman (AS) syndromes are two clinically distinct syndromes which result from lack of expression of imprinted genes within chromosome 15q11-q13. These two syndromes result from 15q11-q13 deletions, chromosome 15 uniparental disomy (UPD), imprinting centre mutations and, for AS, probable mutations in a single gene. The differential phenotype results from a paternal genetic deficiency in PWS patients and a maternal genetic deficiency in AS patients. Within 15q11-q13, four genes (SNRPN, IPW, ZNF127, FNZ127) and two expressed sequence tags (PAR1 and PAR5) have been found to be expressed only from the paternally inherited chromosome, and therefore all must be considered candidate genes involved in the pathogenesis of PWS. A candidate AS gene (UBE3A) has very recently been identified. The mechanisms of imprinted gene expression are not yet understood, but it is clear that DNA methylation is involved in both somatic cell expression and inheritance of the imprint. The presence of DNA methylation imprints that distinguish the paternally and maternally inherited alleles is a common characteristic of all known imprinted genes which have been studied extensively, including SNRPN and ZNF127. Recently, several PWS and AS patients have been found that have microdeletions in a region upstream of the SNRPN gene referred to as the imprinting centre, or IC. Paternal IC deletions in PWS patients and maternal IC deletions in AS patients result in uniparental DNA methylation and uniparental gene expression at biparentally inherited loci. The IC is a novel genetic element which controls initial resetting of the parental imprint in the germline for all imprinted gene expression over a 1.5-2.5 Mb region within chromosome 15q11-q13.

Recent studies have identified a new class of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients who have biparental inheritance, but neither the typical deletion nor uniparental disomy (UPD) or translocation. However, these patients have uniparental DNA methylation throughout 15q11-q13, and thus appear to have a mutation in the imprinting process for this region. Here we describe detailed clinical findings of five AS imprinting mutation patients (three families) and two PWS imprinting mutation patients (one new family). All these patients have essentially the classical clinical phenotype for the respective syndrome, except that the incidence of microcephaly is lower in imprinting mutation AS patients than in deletion AS patients. Furthermore, imprinting mutation AS and PWS patients do not typically have hypopigmentation, which is commonly found in patients with the usual large deletion. Molecular diagnosis of these cases is initially achieved by DNA methylation analyses of the DN34/ZNF127, PW71 (D15S63), and SNRPN loci. The latter two probes have clear advantages in the simple molecular diagnostic analysis of PWS and AS patients with an imprinting mutation, as has been found for typical deletion or UPD PWS and AS cases. With the recent finding of inherited microdeletions in PWS and AS imprinting mutation families, our studies define a new class of these two syndromes. The clinical and molecular identification of these PWS and AS patients has important genetic counseling consequences.

The neurobiology relating to the insatiable appetite observed in Prader-Willi syndrome (PWS) has not been fully characterised. Two functional magnetic resonance imaging (fMRI) scans were performed on each of three adults with PWS. The scans were carried out pre- and post-treatment with the antiepileptic topiramate, which had little effect on body weight and appetite in these subjects. Subjects fasted overnight and drank a 75 g dextrose solution prior to fMRI scans for measurement of brain activation levels during/after glucose ingestion. Following glucose administration, there was a significant delay in activation at the hypothalamus and other brain regions associated with satiety compared with previous data on obese volunteers. These regions include the insula, ventromedial prefrontal cortex, and nucleus accumbens. Individuals with PWS showed a mean latency of 24 min while in a previous study obese volunteers had shown a latency of 15 min and lean volunteers a latency of 10 min in the hypothalamus. Our results provide evidence towards a satiety dysfunction in the central nervous system of PWS patients.