Oxytocin may be useful to increase trust in others and decrease disruptive behaviours in patients with Prader-Willi syndrome: a randomised placebo-controlled trial in 24 patients

<p>Abstract</p> <p>Background</p> <p>Prader-Willi syndrome (PWS) is a complex neurodevelopmental genetic disorder with hypothalamic dysfunction, early morbid obesity with hyperphagia, and specific psychiatric phenotypes including cognitive and behavioural problems, particularly disruptive behaviours and frequent temper outbursts that preclude socialization. A deficit in oxytocin (OT)-producing neurons of the hypothalamic paraventricular nucleus has been reported in these patients.</p> <p>Methods</p> <p>In a double-blind, randomised, placebo-controlled study, 24 adult patients with PWS received a single intranasal administration of 24 IU of OT or placebo and were tested 45 min later on social skills. Behaviours were carefully monitored and scored using an in-house grid as follows: over the two days before drug administration, on the half-day following administration, and over the subsequent two days. All patients were in a dedicated PWS centre with more than ten years of experience. Patients are regularly admitted to this controlled environment.</p> <p>Results</p> <p>Patients with PWS who received a single intranasal administration of OT displayed significantly increased trust in others (P = 0.02) and decreased sadness tendencies (P = 0.02) with less disruptive behaviour (P = 0.03) in the two days following administration than did patients who received placebo. In the half-day following administration, we observed a trend towards less conflict with others (p = 0.07) in the OT group compared with the placebo group. Scores in tests assessing social skills were not significantly different between the two groups.</p> <p>Conclusions</p> <p>This study needs to be reproduced and adapted. It nevertheless opens new perspectives for patients with PWS and perhaps other syndromes with behavioural disturbances and obesity.</p> <p>Trial registration number</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01038570">NCT01038570</a></p

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Anomalies hypophysaires associées à un syndrome polymalformatif (hypothèses physiopathologiques et génétiques)

ROUEN-BU Médecine-Pharmacie (765402102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Apprendre les émotions aux enfants porteurs d’un syndrome de Prader-Willi : le programme EMOT

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Impact of Deprivation on Obesity in Children with PWS

International audienceOur study aimed to evaluate the social deprivation score in families with a child with Prader-Willi syndrome (PWS) and analyze its impact on the occurrence of obesity in the affected child. We included 147 children with PWS followed in our reference center with Evaluation of the Deprivation and Inequalities of Health in Healthcare Centres by the EPICES score. Deprivation (EPICES ≥ 30) was found in 25.9% of the population. Compared with the non-obese children, children with obesity had more deprived families, 50.0 vs. 18.0% (p = 0.0001); were older, with a median of 10.1 vs. 6.0 years (p = 0.0006); were less frequently treated with growth hormone (GH), 80.6 vs. 91.9% (p = 0.07). The mothers of obese children were more frequently obese, 46.9 vs. 13.3% (p < 0.0001), and achieved high study levels less frequently (≥Bac+2), 40.9 vs. 70.1% (p = 0.012). The multivariate logistic regression indicated that age, living in a deprived family, and having a mother with overweight/obesity were significantly associated with an increased risk of obesity (respectively, OR = 3.31 (1.26–8.73) and OR = 6.76 (2.36–19.37)). The same risk factors of obesity observed in the general population were found in children with PWS. Families at risk, including social deprivation, will require early identification and a reinforced approach to prevent obesity

Equivocal expression of emotions in children with Prader-Willi syndrome: what are the consequences for emotional abilities and social adjustment?

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Necdin plays a role in the serotonergic modulation of the mouse respiratory network: implication for Prader-Willi syndrome.

International audiencePrader-Willi syndrome is a neurogenetic disease resulting from the absence of paternal expression of several imprinted genes, including NECDIN. Prader-Willi children and adults have severe breathing defects with irregular rhythm, frequent sleep apneas, and blunted respiratory regulations. For the first time, we show that Prader-Willi infants have sleep apneas already present at birth. In parallel, in wild-type and Necdin-deficient mice, we studied the respiratory system with in vivo plethysmography, in vitro electrophysiology, and pharmacology. Because serotonin is known to contribute to CNS development and to affect maturation and function of the brainstem respiratory network, we also investigated the serotonergic system with HPLC, immunohistochemistry, Rabies virus tracing approaches, and primary culture experiments. We report first that Necdin-deficiency in mice induces central respiratory deficits reminiscent of Prader-Willi syndrome (irregular rhythm, frequent apneas, and blunted respiratory regulations), second that Necdin is expressed by medullary serotonergic neurons, and third that Necdin deficiency alters the serotonergic metabolism, the morphology of serotonin vesicles in medullary serotonergic neurons but not the number of these cells. We also show that Necdin deficiency in neonatal mice alters the serotonergic modulation of the respiratory rhythm generator. Thus, we propose that the lack of Necdin expression induces perinatal serotonergic alterations that affect the maturation and function of the respiratory network, inducing breathing deficits in mice and probably in Prader-Willi patients

Diabetes Mellitus in Prader-Willi Syndrome: Natural History during the Transition from Childhood to Adulthood in a Cohort of 39 Patients

International audienceType 2 diabetes mellitus (T2DM) affects 20% of patients with Prader-Willi syndrome (PWS), with many cases diagnosed during the transition period. Our aim was to describe the natural history of T2DM in patients with PWS before the age of 25 years and to develop screening and preventive strategies. Thirty-nine patients followed in the French PWS Reference Center were included (median age 25.6 years [23.7; 31.7]). Twenty-one had been treated with growth hormone (GH), fifteen had not, and three had an unknown status. The median age at T2DM diagnosis was 16.8 years (11–24) and the median BMI was 39 kg/m2 [34.6; 45], with 34/35 patients living with obesity. The patients displayed frequent psychiatric (48.3% hospitalization,) and metabolic (56.4% hypertriglyceridemia,) comorbidities and a parental history of T2DM (35.7%) or overweight (53.6%) compared to the PWS general population. There was no difference in BMI and metabolic complications between the GH-treated and non-GH-treated groups at T2DM diagnosis. Patients with PWS who develop early T2DM have severe obesity, a high frequency of psychiatric and metabolic disorders, and a family history of T2DM and overweight. These results underline the need for early identification of patients at risk, prevention of obesity, and repeated blood glucose monitoring during the transition period

Liraglutide for Weight Management in Children and Adolescents With Prader-Willi Syndrome and Obesity

CONTEXT: Prader-Willi syndrome (PWS) is characterized by lack of appetite control and hyperphagia, leading to obesity. Pharmacological options for weight management are needed. OBJECTIVE: To determine whether liraglutide treatment for weight management is superior to placebo/no treatment in pediatric individuals with PWS. METHODS: This was a multicenter, 52-week, placebo-controlled trial with a 16-week double-blinded period. Adolescents (n = 31, aged 12-17 years; Tanner stage 2-5) and children (n = 24, aged 6-11 years; Tanner stage <2) with PWS and obesity were included. Patients were randomized 2:1 to liraglutide 3.0 mg (or maximum-tolerated dose) or placebo for 16 weeks, after which placebo was stopped. Liraglutide was continued for 52 weeks. All patients followed a structured diet and exercise program throughout the trial. The coprimary endpoints were change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 and 52 weeks. Secondary endpoints included other weight-related parameters, hyperphagia, and safety. RESULTS: Change in BMI SDS from baseline to weeks 16 and 52 was not significantly different between treatments in adolescents (estimated treatment difference: -0.07 at week 16 and -0.14 at week 52) and children (-0.06 and -0.07, respectively). Changes in other weight-related parameters between treatments were not significant. At week 52, hyperphagia total and drive scores were lower in adolescents treated with liraglutide vs no treatment. The most common adverse events with liraglutide were gastrointestinal disorders. CONCLUSION: Although the coprimary endpoints were not met, changes in hyperphagia total and drive scores in adolescents warrant further studies on liraglutide in this population