Symptoms Of Prader-Willi Syndrome Research Articles

The relationship between endogenous oxytocin and vasopressin levels and the Prader-Willi syndrome behaviour phenotype.

Oxytocin and vasopressin systems are altered in Prader Willi syndrome (PWS). However, investigations into endogenous oxytocin and vasopressin levels as well as clinical trials evaluating the effect of exogenous oxytocin on PWS symptoms have had mixed results. It is also unknown whether endogenous oxytocin and vasopressin levels are associated with certain PWS behaviours. We compared plasma oxytocin and vasopressin and saliva oxytocin levels in 30 adolescents and adults with PWS to 30 typically developing age-matched controls. We also compared neuropeptide levels between gender and genetic subtypes within the PWS cohort and examined the relationship between neuropeptide levels and PWS behaviours. While we did not measure a group difference in plasma or saliva oxytocin levels, plasma vasopressin was significantly lower in individuals with PWS compared to controls. Within the PWS cohort, saliva oxytocin levels were higher in females compared to males and individuals with the mUPD compared to the deletion genetic subtype. We also found the neuropeptides correlated with different PWS behaviours for males and females and for genetic subtypes. For the deletion group, higher plasma and saliva oxytocin levels were related to fewer behaviour problems. For the mUPD group, higher plasma vasopressin levels were related to more behaviour problems. These findings support existing evidence of a vasopressin system defect in PWS and for the first time identify potential differences in the oxytocin and vasopressin systems across PWS genetic subtypes.

Deleting Snord115 genes in mice remodels monoaminergic systems activity in the brain toward cortico-subcortical imbalances.

The neuronal-specific SNORD115 has gathered interest because its deficiency may contribute to the pathophysiology of Prader-Willi syndrome (PWS), possibly by altering post-transcriptional regulation of the gene encoding the serotonin (HTR2C) receptor. Yet, Snord115-KO mice do not resume the main symptoms of PWS, and only subtle-altered A-to-I RNA editing of Htr2c mRNAs was uncovered. Because HTR2C signaling fine-tunes the activity of monoaminergic neurons, we addressed the hypothesis that lack of Snord115 alters monoaminergic systems. We first showed that Snord115 was expressed in both monoaminergic and non-monoaminergic cells of the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN) harboring cell bodies of dopaminergic and serotonergic neurons, respectively. Measuring the tissue level of monoamines and metabolites, we found very few differences except that the content of homovanillic acid-a metabolite of dopamine-was decreased in the orbitofrontal and prefrontal cortex of Snord115-KO mice. The latter effects were, however, associated with a few changes in monoamine tissue content connectivity across the 12 sampled brain regions. Using in vivo single-cell extracellular recordings, we reported that the firing rate of VTA dopaminergic neurons and DRN serotonergic neurons was significantly increased in Snord115-KO mice. These neural circuit dysfunctions were not, however, associated with apparent defects in binge eating, conditioned place preference to cocaine, cocaine-induced hyperlocomotion or compulsive behavior. Altogether, our multiscale study shows that the absence of Snord115 impacts central monoaminergic circuits to an extent that does not elicit gross behavioral abnormalities.

Reference Genes across Nine Brain Areas of Wild Type and Prader-Willi Syndrome Mice: Assessing Differences in Igfbp7, Pcsk1, Nhlh2 and Nlgn3 Expression.

Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by the deletion or inactivation of paternally expressed imprinted genes at the chromosomal region 15q11–q13. The PWS-critical region (PWScr) harbors tandemly repeated non-protein coding IPW-A exons hosting the intronic SNORD116 snoRNA gene array that is predominantly expressed in brain. Paternal deletion of PWScr is associated with key PWS symptoms in humans and growth retardation in mice (PWScr model). Dysregulation of the hypothalamic–pituitary axis (HPA) is thought to be causally involved in the PWS phenotype. Here we performed a comprehensive reverse transcription quantitative PCR (RT-qPCR) analysis across nine different brain regions of wild-type (WT) and PWScr mice to identify stably expressed reference genes. Four methods (Delta Ct, BestKeeper, Normfinder and Genorm) were applied to rank 11 selected reference gene candidates according to their expression stability. The resulting panel consists of the top three most stably expressed genes suitable for gene-expression profiling and comparative transcriptome analysis of WT and/or PWScr mouse brain regions. Using these reference genes, we revealed significant differences in the expression patterns of Igfbp7, Nlgn3 and three HPA associated genes: Pcsk1, Pcsk2 and Nhlh2 across investigated brain regions of wild-type and PWScr mice. Our results raise a reasonable doubt on the involvement of the Snord116 in posttranscriptional regulation of Nlgn3 and Nhlh2 genes. We provide a valuable tool for expression analysis of specific genes across different areas of the mouse brain and for comparative investigation of PWScr mouse models to discover and verify different regulatory pathways affecting this complex disorder.

Intranasal Carbetocin Reduces Hyperphagia and Anxiety and Distress Behaviors in Prader-Willi Syndrome: Results From the CARE-PWS Randomized, Double-Blind, Placebo-Controlled Study

Prader-Willi syndrome (PWS) is a complex genetic disorder associated with multiple neuroendocrine abnormalities, including significantly decreased hypothalamic oxytocin levels, resulting in symptoms of severe hyperphagia (an unrelenting false sense of starvation) and multiple severe neuropsychiatric and behavioral issues. CARE-PWS, a multi-center, randomized, double-blind, placebo-controlled phase 3 study, has evaluated the efficacy, safety and tolerability of intranasal carbetocin, a selective oxytocin receptor agonist, in participants with PWS. Eligible participants aged 7 through 18 with genetically confirmed PWS were randomized in equal proportions to three treatment arms for the 8-week placebo-controlled period of the study: carbetocin 9.6 mg, carbetocin 3.2 mg, or a matching placebo, administered by nasal spray three times a day with meals. The primary endpoint assessed changes from baseline to week 8 in Hyperphagia Questionnaire for Clinical Trials (HQ-CT) or Children’s Yale-Brown Obsessive Compulsive Scale (CY-BOCS) scores for the carbetocin 9.6 mg arm vs placebo, and the first secondary endpoint assessed changes from baseline to week 8 in HQ-CT or CY-BOCS scores for the carbetocin 3.2 mg arm vs placebo. Additional secondary endpoints included changes from baseline to week 8 in PWS Anxiety and Distress Questionnaire (PADQ) scores, and Clinical Global Impression of Change (CGI-C) scores evaluating the overall change in severity of PWS symptoms at week 8. Due to COVID-19, enrollment was closed early with 119 evaluable participants for the primary analysis. In the carbetocin 9.6 mg arm, trends toward numerically greater improvements in HQ-CT and CGI-C scores relative to placebo were observed but did not reach statistical significance; however, the carbetocin 3.2 mg arm demonstrated a significant improvement in HQ-CT scores (LS mean improvement vs placebo -3.14 points, p=0.016). In the 3.2 mg arm, additional consistent evidence of improvements versus placebo was seen in multiple secondary endpoints, including CGI-C (p=0.027) and PADQ (p=0.027). Numeric trends toward improvement in CY-BOCS scores were observed in each dose arm, but did not reach statistical significance versus placebo. During the subsequent long-term follow-up period of the study, both carbetocin arms have experienced continued numeric improvements from baseline across multiple endpoints. Intranasal carbetocin was generally well-tolerated; the most frequently reported adverse event was flushing, which was generally mild and transient. In conclusion, results of the CARE-PWS study support that intranasal carbetocin appears to be safe and well tolerated, and reduces hyperphagia and anxiety and distress behaviors in PWS.

Chapter 29 - Animal models for Prader–Willi syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia, hypotonia, learning disability, as well as a range of psychiatric conditions. The conservation of the PWS genetic interval on chromosome 15q11-q13 in human, and a cluster of genes on mouse chromosome 7, has facilitated the use of mice as animal models for PWS. Some models faithfully mimic the loss of all gene expression from the paternally inherited PWS genetic interval, whereas others target smaller regions or individual genes. Collectively, these models have provided insight into the mechanisms, many of which lead to alterations in hypothalamic function, underlying the core symptoms of PWS, including growth retardation, hyperphagia and metabolism, reproductive maturation and endophenotypes of relevance to behavioral and psychiatric problems. Here we review and summarize these studies.

Transcranial Direct Current Stimulation for Prader-Willi Syndrome.

Given the limited therapeutic options for Prader-Willi syndrome (PWS), we conducted an open-label clinical trial to evaluate the effects of transcranial direct current stimulation (tDCS) for hyperphagia, food craving, and aberrant behaviors on this population. Twelve subjects with PWS (11-35 years old) were included. The subjects underwent 10 daily 20-minute sessions of tDCS in 2 weeks. The anode was positioned over the left dorsolateral prefrontal cortex, and the cathode over the contralateral region. We observed amelioration of hyperphagic and food craving symptoms (P < 0.05), as well as amelioration of behavioral symptoms measured with the Aberrant Behavior Checklist (P < 0.05). To our knowledge, this is the first proof-of-concept trial to report the positive effects of increasing excitability of the left dorsolateral prefrontal cortex, using tDCS, for the behavioral, hyperphagia, and food craving symptoms in PWS, which is a low-cost, well-studied, safe alternative for brain stimulation.

Genotype-Phenotype Relationships and Endocrine Findings in Prader-Willi Syndrome.

Prader-Willi syndrome (PWS) is a complex imprinting disorder related to genomic errors that inactivate paternally-inherited genes on chromosome 15q11-q13 with severe implications on endocrine, cognitive and neurologic systems, metabolism, and behavior. The absence of expression of one or more genes at the PWS critical region contributes to different phenotypes. There are three molecular mechanisms of occurrence: paternal deletion of the 15q11-q13 region; maternal uniparental disomy 15; or imprinting defects. Although there is a clinical diagnostic consensus criteria, DNA methylation status must be confirmed through genetic testing. The endocrine system can be the most affected in PWS, and growth hormone replacement therapy provides improvement in growth, body composition, and behavioral and physical attributes. A key feature of the syndrome is the hypothalamic dysfunction that may be the basis of several endocrine symptoms. Clinical and molecular complexity in PWS enhances the importance of genetic diagnosis in therapeutic definition and genetic counseling. So far, no single gene mutation has been described to contribute to this genetic disorder or related to any exclusive symptoms. Here we proposed to review individually disrupted genes within the PWS critical region and their reported clinical phenotypes related to the syndrome. While genes such as MKRN3, MAGEL2, NDN, or SNORD115 do not address the full spectrum of PWS symptoms and are less likely to have causal implications in PWS major clinical signs, SNORD116 has emerged as a critical, and possibly, a determinant candidate in PWS, in the recent years. Besides that, the understanding of the biology of the PWS SNORD genes is fairly low at the present. These non-coding RNAs exhibit all the hallmarks of RNA methylation guides and can be incorporated into ribonucleoprotein complexes with possible hypothalamic and endocrine functions. Also, DNA conservation between SNORD sequences across placental mammals strongly suggests that they have a functional role as RNA entities on an evolutionary basis. The broad clinical spectrum observed in PWS and the absence of a clear genotype-phenotype specific correlation imply that the numerous genes involved in the syndrome have an additive deleterious effect on different phenotypes when deficiently expressed.

Cyfip1 Haploinsufficiency Increases Compulsive-Like Behavior and Modulates Palatable Food Intake in Mice: Dependence on Cyfip2 Genetic Background, Parent-of Origin, and Sex

Binge eating (BE) is a heritable trait associated with eating disorders and involves episodes of rapid, large amounts of food consumption. We previously identified cytoplasmic FMR1-interacting protein 2 (Cyfip2) as a genetic factor underlying compulsive-like BE in mice. CYFIP2 is a homolog of CYFIP1 which is one of four paternally-deleted genes in patients with Type I Prader-Willi Syndrome (PWS), a neurodevelopmental disorder whereby 70% of cases involve paternal 15q11-q13 deletion. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/−) would enhance compulsive-like behavior and palatable food (PF) intake in a parental origin- and sex-dependent manner on two Cyfip2 genetic backgrounds, including the BE-prone C57BL/6N (Cyfip2N/N) background and the BE-resistant C57BL/6J (Cyfip2J/J) background. Cyfip1+/− mice showed increased compulsive-like behavior on both backgrounds and increased PF intake on the Cyfip2N/N background. In contrast, maternal Cyfip1 haploinsufficiency on the BE-resistant Cyfip2J/J background induced a robust escalation in PF intake in wild-type Cyfip1J/J males while having no effect in Cyfip1J/- males. Notably, induction of behavioral phenotypes in wild-type males following maternal Fmr1+/− has previously been reported. In the hypothalamus, there was a paternally-enhanced reduction in CYFIP1 protein whereas in the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Nochange in FMR1 protein (FMRP) was observed in Cyfip1+/− mice, regardless of parental origin. To summarize, Cyfip1 haploinsufficiency increased compulsive-like behavior and induced genetic background-dependent, sex-dependent, and parent-of-origin-dependent effects on PF consumption and CYFIP1 expression that could have relevance for neurodevelopmental and neuropsychiatric disorders.

Cognitive deficits in the Snord116 deletion mouse model for Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is an imprinted neurodevelopmental disease caused by a loss of paternal genes on chromosome 15q11-q13. It is characterized by cognitive impairments, developmental delay, sleep abnormalities, and hyperphagia often leading to obesity. Clinical research has shown that a lack of expression of SNORD116, a paternally expressed imprinted gene cluster that encodes multiple copies of a small nucleolar RNA (snoRNA) in both humans and mice, is most likely responsible for many PWS symptoms seen in humans. The majority of previous research using PWS preclinical models focused on characterization of the hyperphagic and metabolic phenotypes. However, a crucial understudied clinical phenotype is cognitive impairments and thus we investigated the learning and memory abilities using a model of PWS, with a heterozygous deletion in Snord116. We utilized the novel object recognition task, which doesn't require external motivation, or exhaustive swim training. Automated findings were further confirmed with manual scoring by a highly trained blinded investigator. We discovered deficits in Snord116+/- mutant mice in the novel object recognition, location memory and tone cue fear conditioning assays when compared to age-, sex- matched, littermate control Snord116+/+ mice. Further, we confirmed that despite physical neo-natal developmental delays, Snord116+/- mice had normal exploratory and motor abilities. These results show that the Snord116+/- deletion murine model is a valuable preclinical model for investigating learning and memory impairments in individuals with PWS without common confounding phenotypes.

Hypothalamic loss of Snord116 and Prader-Willi syndrome hyperphagia: the buck stops here?

Hyperphagia and obesity are the best-known manifestations of Prader-Willi syndrome (PWS) and are responsible for most of the overall morbidity and mortality associated with the disease. Yet these PWS symptoms remain poorly understood and without effective pharmacologic therapies. Mouse models attempting to recapitulate both the genetic alterations and marked hyperphagia plus obesity of PWS have been enigmatic, leading to skepticism about the use of mouse models to investigate PWS. In this issue of the JCI, Polex-Wolf and colleagues challenge the skeptics by successfully inducing hyperphagia following bilateral mediobasal hypothalamic deletion of the Snord116 gene from adult mice. Obesity also resulted, although only in a subset of mice. While this approach represents an exciting advance, highlighting a pathologic effect of loss of mediobasal hypothalamic Snord116 expression on the development of PWS's hallmark symptoms, the variability in the body-weight and body composition responses to this site-selective gene deletion raises several questions.

Aberrant, autistic, and food-related behaviors in adults with Prader-Willi syndrome. The comparison between young adults and adults

This study aims to explore the differences of age as well as genotype in regards to the severity of behavioral symptoms in Prader-Willi syndrome (PWS), with emphasis on the comparison between youngadults and adults.The Food Related Problem Questionnaire (FRPQ), the Aberrant Behavior Checklist Japanese Version (ABC-J), and the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS) were administered to 46 PWS patients, including 33 young adults (ages 18–28) and 13 adults(ages 30–45). To examine the differences between young adults and adults, Mann-Whitney U tests were conducted. Statistically significant differences were found in ABC-J (p = .027) and PARS (p = .046), with higher scores in young adults than adults. Such differences between the two age groups were still true for the subgroups having a paternal chromosome 15q deletion (DEL) for ABC-J (p = .050) and part of PARS (“Problematic behavior”; p = .007). By contrast, there was no significant differences between young adults and adults regarding FRPQ (p = .65).These results suggest that aberrant behaviors decline from around the ages of thirty, in PWS patients in general and in DEL subgroups in particular, while food-related behaviors give no indication of diminishing in spite of developmental growth

Hypothalamus Specific Re-Introduction of SNORD116 into Otherwise Snord116 Deficient Mice Increased Energy Expenditure.

The Snord116 gene cluster has been recognised as a critical contributor to the Prader-Willi syndrome (PWS), with mice lacking Snord116 displaying many classical PWS phenotypes, including low postnatal body weight, reduced bone mass and increased food intake. However, these mice do not develop obesity as a result of increased energy expenditure. To understand the physiological function of SNORD116 better and potentially rescue the altered metabolism of Snord116-/- mice, we used an adeno-associated viral (AAV) approach to reintroduce the product of the Snord116 gene into the hypothalamus in Snord116-/- mice at different ages. The results obtained show that mid-hypothalamic re-introduction of SNORD116 in 6-week-old Snord116-/- mice leads to significantly reduced body weight and weight gain, which is associated with elevated energy expenditure. Importantly, when the intervention targets other areas such as the anterior region of the hypothalamus or the reintroduction occurs in older mice, the positive effects on energy expenditure are diminished. These data indicate that the metabolic symptoms of PWS develop gradually and the Snord116 gene plays a critical role during this process. Furthermore, when we investigated the consequences of SNORD116 re-introduction under conditions of thermoneutrality where the mild cold stress influences are avoided, we also observed a significant increase in energy expenditure. In conclusion, the rescue of mid-hypothalamic Snord116 deficiency in young Snord116 germline deletion mice increases energy expenditure, providing fundamental information contributing to potential virus-mediated genetic therapy in PWS.

Metabolic Parameters and Orexigenic/Anorexigenic Factors of Obesity in Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder that arises from lack of expression of paternally inherited imprinted genes on chromosome 15 [1]. PWS is the most frequent cause of syndromic obesity occurring in 1 out of 10000–30 000 live births [2]. It is a neurodevelopmental disorder, characterized by neonatal hypotonia and failure to thrive, followed by a rapid weight gain between the ages of 1 and 6 years, leading most PWS subjects to develop morbid obesity and therefore premature mortality from its complications. The PWS phenotype includes multiple characteristics, most of which are central of origin (temperature dysregulation, high pain threshold, behavioral abnormalities, hypothalamic hypogonadism, growth hormone deficiency, central hypothyroidism, central adrenal insufficiency). Obesity, mostly due to an insatiable appetite, represents one of the most serious symptoms of PWS, leading to develop premature mortality from its complications. Therefore, we tried to investigate more deeply distinctive features of obesity and appetite regulation in PWS patients.

Prader-Willi Critical Region, a Non-Translated, Imprinted Central Regulator of Bone Mass: Possible Role in Skeletal Abnormalities in Prader-Willi Syndrome.

Prader-Willi Syndrome (PWS), a maternally imprinted disorder and leading cause of obesity, is characterised by insatiable appetite, poor muscle development, cognitive impairment, endocrine disturbance, short stature and osteoporosis. A number of causative loci have been located within the imprinted Prader-Willi Critical Region (PWCR), including a set of small non-translated nucleolar RNA’s (snoRNA). Recently, micro-deletions in humans identified the snoRNA Snord116 as a critical contributor to the development of PWS exhibiting many of the classical symptoms of PWS. Here we show that loss of the PWCR which includes Snord116 in mice leads to a reduced bone mass phenotype, similar to that observed in humans. Consistent with reduced stature in PWS, PWCR KO mice showed delayed skeletal development, with shorter femurs and vertebrae, reduced bone size and mass in both sexes. The reduction in bone mass in PWCR KO mice was associated with deficiencies in cortical bone volume and cortical mineral apposition rate, with no change in cancellous bone. Importantly, while the length difference was corrected in aged mice, consistent with continued growth in rodents, reduced cortical bone formation was still evident, indicating continued osteoblastic suppression by loss of PWCR expression in skeletally mature mice. Interestingly, deletion of this region included deletion of the exclusively brain expressed Snord116 cluster and resulted in an upregulation in expression of both NPY and POMC mRNA in the arcuate nucleus. Importantly, the selective deletion of the PWCR only in NPY expressing neurons replicated the bone phenotype of PWCR KO mice. Taken together, PWCR deletion in mice, and specifically in NPY neurons, recapitulates the short stature and low BMD and aspects of the hormonal imbalance of PWS individuals. Moreover, it demonstrates for the first time, that a region encoding non-translated RNAs, expressed solely within the brain, can regulate bone mass in health and disease.

Genetics of Prader-Willi syndrome and Prader-Will-Like syndrome

The Prader-Willi syndrome (PWS) is a human imprinting disorder resulting from genomic alterations that inactivate imprinted, paternally expressed genes in human chromosome region 15q11-q13. This genetic condition appears to be a contiguous gene syndrome caused by the loss of at least 2 of a number of genes expressed exclusively from the paternal allele, including SNRPN, MKRN3, MAGEL2, NDN and several snoRNAs, but it is not yet well known which specific genes in this region are associated with this syndrome. Prader-Will-Like syndrome (PWLS) share features of the PWS phenotype and the gene functions disrupted in PWLS are likely to lie in genetic pathways that are important for the development of PWS phenotype. However, the genetic basis of these rare disorders differs and the absence of a correct diagnosis may worsen the prognosis of these individuals due to the endocrine-metabolic malfunctioning associated with the PWS. Therefore, clinicians face a challenge in determining when to request the specific molecular test used to identify patients with classical PWS because the signs and symptoms of PWS are common to other syndromes such as PWLS. This review aims to provide an overview of current knowledge relating to the genetics of PWS and PWLS, with an emphasis on identification of patients that may benefit from further investigation and genetic screening.

Autism spectrum disorder in Prader-Willi syndrome: A systematic review.

Prader-Willi syndrome (PWS) is a rare genetic disorder that results from lack of expression of paternally-derived genes on chromosome 15q11-13; caused by a deletion (DEL), uniparental disomy (UPD), or a rare imprinting center defect. PWS is associated with a distinct behavioral phenotype that in some respects overlaps with autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by restricted or repetitive behaviors (RRBs) and social-communication impairment. The goal of this review was to (i) review published literature investigating core ASD symptoms in PWS and (ii) provide a prevalence estimate of ASD in PWS. Two independent reviewers searched Medline, CINAHL, PsychINFO, Embase, and Web of Science to find studies that answered the research questions. Individuals with PWS demonstrate significant levels of RRBs and social-communication impairment, in some reports reaching similar levels to those of non-PWS ASD comparison groups. Individuals with UPD had more social-communication impairment than those with DEL. Of 786 PWS participants, 210 (26.7%) were reported as meeting criteria for ASD, either based on clinical diagnosis or by exceeding clinical cut-points on relevant ASD symptom measures. In studies that distinguished genetic subtypes, rates of ASD were higher in individuals with PWS with UPD (67 of 190; 35.3%) than those with DEL (47 of 254; 18.5%). Published data on the association of PWS and ASD to date are limited to sample means of 8 years of age and older. Further research is needed to identify early markers of ASD in PWS children, to support earlier diagnosis and intervention for this important comorbidity.

A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome.

Individuals with Prader-Willi syndrome (PWS) have a significant reduction in the number of oxytocin-producing neurons (42%) in the hypothalamic paraventricular nucleus. A number of animal studies and observations of humans show that lesions in this region can produce PWS-like symptoms. Given the evidence for potential oxytocin deficiency, we tested the effects of a course of intranasal oxytocin on PWS symptoms. Thirty individuals with PWS aged 12-30 years participated in an 18-week randomized double-blind placebo-controlled crossover trial. Participants received 8 weeks of oxytocin and 8 weeks of placebo with a minimum 2-week washout period. The first 11 participants received the following oxytocin doses: 24 IU (twice daily) B.I.D for participants 16 years and over and 18 IU B.I.D for participants 13-15 years. The dose was increased for the remaining 18 participants to 40 IU B.I.D for participants 16 years and over and 32 IU B.I.D for 13-15 years. Measures used to assess changes were standardized well-accepted measures, including the Developmental Behavior Checklist-Monitor, Parent, Teacher, and Adult; The Yale-Brown Obsessive Compulsive Scale; The Dykens Hyperphagia questionnaire; Reading The Mind in the Eyes Test; Epworth Sleepiness Scale and the Movie Stills. Oxytocin had little impact on any measure. The only significant difference found between the baseline, oxytocin, and placebo measures was an increase in temper outbursts (P = 0.023) with higher dose oxytocin. The lack of effect of oxytocin nasal spray may reflect the importance of endogenous release of oxytocin in response to exogenous oxytocin.

Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms including hyperphagia and hyperghrelinemia. In this study, male Snord116del mice were characterized and tested for their acute and chronic responses to anorexic substances related to the ghrelin pathway. In comparison with their wild-type littermates, the food intake rate of Snord116del mice was 14% higher when fed ad libitum, and 32% to 49% higher within 12 hours after fasting. Fasted Snord116del mice were less sensitive to the acute anorexic effect of competitive antagonist [d-Lys(3)]-GHRP6, YIL-781, and reverse agonist [d-Arg(1),d-Phe(5),d-Trp(7,9),Leu(11)]-substance P (SPA) of ghrelin receptor GHS-R. All 3 GHS-R inhibitors failed to inhibit chronic food intake of either Snord116del or wild-type mice due to rapid adaptation. Although fasted Snord116del mice had normal sensitivity to the acute anorexic effect of glucagon-like peptide 1 receptor agonist exenatide, those fed ad libitum required a higher dose and more frequent delivery to achieve ∼15% suppression of long-term food intake in comparison with wild-type mice. Ghrelin, however, is unlikely to be essential for the anorexic effect of exenatide in fed mice, as shown by the fact that exenatide did not reduce ghrelin levels in fed mice and food intake of ghrelin(-/-) mice fed ad libitum could be suppressed by exenatide. In conclusion, this study suggests that GHS-R may not be an effective therapeutic target, and in contrast, exenatide may produce anorexic effect in PWS individuals.

Polisomnographic phenotype is linked with genetic findings in Prader–Willi syndrome

Prader-Willi syndrome (PWS) is a rare genetic disorder, usually sporadic, affecting 1/25,000 births, in which a critical region of chromosome 15 (15q11-q13) is affected. At birth, PWS infants exhibit characteristic facial features, small hands and feet, severe hypotonia with suckling and swallowing troubles, delay in psychomotor development and lethargy. After this initial phase, hyperphagia and absence of satiety (severe obesity and sleep apneas), growth hormone deficiency (short stature) and incomplete pubertal development are striking signs. Diagnosis is based on clinical criteria confirmed by genetic study, showing a deletion (DEL) or, less frequent and less severe, uniparental disomy (UPD). Eight newborn with dysmorphic features, weak reactivity to stimuli and hypotonia were evaluated. Genetic findings confirmed or excluded PWS diagnosis. Patients underwent a daily polysomnographic study (EEG, EOG, EMG, ECG, nasal airflow, respiratory movements and oxymetry); sleep and associated events were scored based on international rules for newborns (Anders et al., 1971). In 5 cases, CSF Hcrt-1 was measured. Genetic study confirmed PWS in 6 cases (DEL, n = 5 ; UPD, n = 1). Mean value of CSF Hcrt-1 in PWS-patients was 106.7 ± 16.9 pg/ml (>220 in non-PWS infants). EEG tracing was normal in 7 infants according to postconceptional age (one with slightly generalized slowing). The most relevant finding was a dramatic reduction of arousals and reactivity to stimuli, more severe in DEL-PWS, moderate in UPD-PWS and absent in non-PWS hypotonic infants (mean arousal index 4.1 /h, 5.4 /h and 14 /h; mean fragmentation index 4.1 /h, 18.3 /h and 21 /h). No significant respiratory events were recorded and other sleep parameters were similar to those seen in healthy neonates evaluated in our hospital. Sleep disturbances are already found in newborns, even before respiratory events appear. This data suggests that lack of reactivity to stimuli in newborns may be related to difficulty in regulation of sensory stimuli, leading to further symptoms of PWS (poor satiety recognition, decreased sensitivity to pain and sleep disorders). This generalized hypoarousal-state could be the primary mechanism underlying the sleep abnormalities in PWS patients. We thank Dr. J. Santamaría (H. Clinic, Barcelona, Spain) for his cooperation in typing and measurement of cerebrospinal fluid hypocretin-1 level.

The impact ofPrader–Willi syndrome on the family's quality of life and caregiving, and the unaffected siblings’ psychosocial adjustment

Prader-Willi syndrome (PWS), a complex multisystem genetic disorder, is characterised by developmental abnormalities leading to somatic and psychological symptoms. Symptoms of PWS include infantile hypotonia and failure-to-thrive, followed by life-long hyperphagia, developmental delays and moderate-to-severe behavioural problems and several physical problems that impact health. This study examined the effects of caring for a child diagnosed with PWS on the mothers and unaffected siblings. We assessed overall family functioning, the mothers' psychological health, the psychosocial and behavioural functioning of siblings, and the quality of life of siblings. Participants included 12 mothers and 13 siblings of a child with genetically confirmed PWS. Self-report measures administered to the mothers evaluated overall family functioning (PedsQL - Family Impact Module), the mothers' psychological health (Brief Symptom Inventory), and the mothers' perception of the sibling's quality of life (PedsQL - Parent Proxy). Self-report measures administered to the siblings evaluated their perceived quality of life (PedsQL) and symptoms of post-traumatic stress disorder (PTSD) (UCLA PTSD Index). Families/mothers/siblings with children with PWS showed poorer perceived quality of life compared with general inpatient and outpatient samples of children with complex health conditions. Families/mothers/siblings with children with PWS reported difficulties in family functioning, communication problems, and an increased number of conflicts. They appeared to be experiencing significant behavioural distress symptoms, with higher than average levels of depression and feelings of isolation, anger and worry. Ninety-two per cent of the siblings indicated moderate-to-severe symptoms of PTSD. Compared with normative populations, siblings demonstrated poorer quality of life, with mothers perceiving more significant deficits in the sibling. This study reaffirms that PWS affects the entire family system. Mothers and siblings would benefit from psychosocial support due to the multiple challenges of living with and caring for a child/young adult with PWS.