Specificity of Early Childhood Hyperphagia Profiles in Neurogenetic Conditions.

Hyperphagia is highly penetrant in Prader-Willi syndrome (PWS) and has increasingly been reported in other neurogenetic conditions (NGC). The Hyperphagia Questionnaire (HQ) was completed by caregivers of 4-8-year-olds with PWS (n = 17), Angelman syndrome (AS; n = 22), Williams syndrome (WS; n = 25), or low-risk controls (LRC; n = 35). All NGC groups were significantly elevated in HQ Total and Behavior scores compared to LRC. Only AS and WS were significantly elevated in the Drive domain, and only PWS in the Severity domain. After controlling for externalizing behavior, HQ Total scores were higher for PWS relative to other groups. Hyperphagic symptoms may not differentiate PWS from other NGCs in early childhood. However, hyperphagic phenotypes may be most severe in PWS. Further investigation of these profiles may inform etiology and syndrome-specific treatments.

Behavioral changes in patients with Prader-Willi syndrome receiving diazoxide choline extended-release tablets compared to the PATH for PWS natural history study.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension study, C602. METHODS: To better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0-36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP). RESULTS: Relative to the PATH for PWS natural history study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p < 0.001) and 52 weeks (LSmean [SE] -9.2 [0.77] vs. -3.4 [0.47], p < 0.001). The comparison between the cohorts remained significant in the worst-case imputation sensitivity analysis. There were also significant improvements in all domains of the PWSP at 26 weeks (all p < 0.001) and 52 weeks (all p ≤ 0.003) for C601/C602 participants compared to the PATH for PWS participants. CONCLUSION: Long-term administration of DCCR to people with PWS resulted in changes in hyperphagia and other behavioral complications of PWS that are distinct from the natural history of the syndrome as exemplified by the cohort from PATH for PWS. The combined effects of administration of DCCR should reduce the burden of the syndrome on the patient, caregivers and their families, and thereby may benefit people with PWS and their families. TRIAL REGISTRATION: Clinical study C601 was originally registered on ClinicalTrials.gov on February 22, 2018 (NCT03440814). Clinical study C602 was originally registered on ClinicalTrials.gov on October 22, 2018 (NCT03714373). PATH for PWS was originally registered on ClinicalTrials.gov on October 24, 2018 (NCT03718416).

Effect of semaglutide on weight loss and glycaemic control in patients with Prader-Willi Syndrome and type 2 diabetes.

Prader-Willi Syndrome (PWS) is the most common genetic cause of obesity, occurring in approximately 1 in 15,000 newborns. It results from the lack of expression of genes on the paternal allele of the chromosomal region 15q-11q13 (65-75% due to type 1 or type 2 deletion). Individuals with PWS experience associated symptoms such as hypotonia, hyperphagia, and early-onset obesity (before 5 years of age). Around 20% of adults with PWS also develop type 2 diabetes. Previous studies have shown the beneficial effects of GLP1-RA medications, such as exenatide and liraglutide, in treating type 2 diabetes in PWS. However, there is limited information available on the use of semaglutide in PWS. This study aimed to evaluate the effects of semaglutide on weight loss and glycaemic control in four patients with PWS and type 2 diabetes associated with obesity. The patients were started on weekly subcutaneous progressive doses of semaglutide.

The Pivotal Role of Oxytocin's Mechanism of Thermoregulation in Prader-Willi Syndrome, Schaaf-Yang Syndrome, and Autism Spectrum Disorder.

Oxytocin (Oxt) regulates thermogenesis, and altered thermoregulation results in Prader-Willi syndrome (PWS), Schaaf-Yang syndrome (SYS), and Autism spectrum disorder (ASD). PWS is a genetic disorder caused by the deletion of the paternal allele of 15q11-q13, the maternal uniparental disomy of chromosome 15, or defects in the imprinting center of chromosome 15. PWS is characterized by hyperphagia, obesity, low skeletal muscle tone, and autism spectrum disorder (ASD). Oxt also increases muscle tonicity and decreases proteolysis while PWS infants are hypotonic and require assisted feeding in early infancy. This evidence inspired us to merge the results of almost 20 years of studies and formulate a new hypothesis according to which the disruption of Oxt's mechanism of thermoregulation manifests in PWS, SYS, and ASD through thermosensory abnormalities and skeletal muscle tone. This review will integrate the current literature with new updates on PWS, SYS, and ASD and the recent discoveries on Oxt's regulation of thermogenesis to advance the knowledge on these diseases.

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

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

Feeding tube use and complications in Prader-Willi syndrome: Data from the Global Prader-Willi Syndrome Registry.

Guidance on indications for, and types of, feeding tubes recommended in Prader-Willi syndrome (PWS) is needed. A Global PWS Registry survey was developed to investigate nasogastric (NG) and gastrostomy (G) tube use and associated complications. Of 346 participants, 242 (69.9%) had NG-tubes, 17 (4.9%) had G-tubes, and 87 (25.1%) had both NG- and G-tubes. Primary indication for placement was "feeding difficulties and/or poor weight gain" for both NG- (90.2%) and G-tubes (71.2%), while "aspiration/breathing difficulties" was the procedural indication for 6.4% of NG-tubes and 23.1% of G-tubes. NG-tubes were generally removed by age 6 months (NG Only: 82.9%; NG/G: 98.8%), while G-tubes were often removed by age 2 years (G Only: 85.7%; NG/G: 70.5%). The severe complication rate from G-tubes was 31.7% and from NG-tubes was 1.2%. Overall, caregivers indicated the presence of an NG- or G-tube had a positive effect on quality of life. Feeding difficulties in PWS are largely managed by NG-tube alone. The severe complication rate from G-tubes was about 25 times higher than from NG-tubes; yet, G-tube placement rates have generally increased. G-tube placement puts individuals with PWS at risk for anesthesia and surgery-related complications and should be considered judiciously by a multidisciplinary team.

m6A-Mediated Upregulation of Imprinted in Prader-Willi Syndrome Induces Aberrant Apical-Basal Polarization and Oxidative Damage in RPE Cells.

Purpose: To reveal the clinical significance, pathological involvement and molecular mechanism of imprinted in Prader-Willi syndrome (IPW) in RPE anomalies that contribute to AMD. Methods: IPW expression under pathological conditions were detected by microarrays and qPCR assays. In vitro cultured fetal RPE cells were used to study the pathogenicity induced by IPW overexpression and to analyze its upstream and downstream regulatory networks. Results: We showed that IPW is upregulated in the macular RPE-choroid tissue of dry AMD patients and in fetal RPE cells under oxidative stress, inflammation and dedifferentiation. IPW overexpression in fetal RPE cells induced aberrant apical-basal polarization as shown by dysregulated polarized markers, disrupted tight and adherens junctions, and inhibited phagocytosis. IPW upregulation was also associated with RPE oxidative damages, as demonstrated by intracellular accumulation of reactive oxygen species, reduced cell proliferation, and accelerated cell apoptosis. Mechanically, N6-methyladenosine level of the IPW transcript regulated its stability with YTHDC1 as the reader. IPW mediated RPE features by suppressing MEG3 expression to sequester its inhibition on the AKT serine-threonine kinase (AKT)/mammalian target of rapamycin (mTOR) pathway. We also noticed that the mTOR inhibitor rapamycin suppresses the AKT/mTOR pathway to alleviate the IPW-induced RPE anomalies. Conclusions: We revealed that IPW overexpression in RPE induces aberrant apical-basal polarization and oxidative damages, thus contributing to AMD progression. We also annotated the upstream and downstream regulatory networks of IPW in RPE. Our findings shed new light on the molecular mechanisms of RPE dysfunctions, and indicate that IPW blockers may be a promising option to treat RPE abnormalities in AMD.

Orthopedic manifestations in children with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic disease often associated with bone problems, mainly scoliosis and hip dysplasia (HD). This study aimed to analyze the clinical characteristics of orthopedic deformities in patients with PWS. METHODS: A retrospective study was conducted on 175 patients up to March 2023. The Cobb angle(CA) of the spine, the alpha angle of the hip joint, and the acetabular index (AI) were measured. This study aimed to evaluate the relationship between demographic parameters and bone deformities. RESULTS: Scoliosis was found in 66 patients (43.7%), including 52 (78.8%) with mild scoliosis, 10 (15.2%) with moderate scoliosis, and 4 (6.1%) with severe scoliosis. Only seven patients received orthopedic treatment (10.6%). The median age of scoliosis was 4.5 years old, and the prevalence of scoliosis increased rapidly at the age of 5 years and adolescence. The mean CA in this study increased gradually with age. HD was found in 47 patients (38.2%), and 6 patients received orthopedic treatment (12.7%). The median age at HD was 1.8 years old. The mean AI of the study population decreased with age. The prevalence of HD treated with recombinant human growth hormone (rhGH) was low. No significant differences were observed in sex, genotype, body mass index (BMI), obesity rate, or onset of scoliosis and HD. CONCLUSION: The prevalence of scoliosis and HD was higher in patients with PWS. The onset age and developmental trends of the different skeletal malformations were different. Early diagnosis and treatment are important for the prognosis and treatment of orthopedic diseases in patients with PWS.

Genotype-phenotype correlation in Prader-Willi syndrome: A large-sample analysis in China.

The genotype-phenotype relationship in PWS patients is important for a better understanding of the clinical phenotype and clinical characteristics of different genotypes of PWS in children. We aimed to explore the influence of specific gene changes on the clinical symptoms of PWS and the value of early screening and early intervention of the condition. All data in this study were extracted from the database of the XiaoPang Weili Rare Disease Care Center. The collected information included basic demographics, maternal pregnancy information, endocrine abnormalities, growth and development abnormalities, and other clinical phenotypes. The relationships between genotypes and phenotypes in the major categories of PWS were analyzed. A total of 586 PWS cases with confirmed molecular diagnosis and genotyping were included in this study. Among them, 83.8% belonged to the deletion type, 10.9% the uniparental disomy (UPD) type, and 5.3% the imprinting defect (ID) type. Age-wide comparison among the three groups: The rate of hypopigmentation in the deletion group was higher than that in the UPD group (88.8% vs. 60.9%; p < 0.05); A total of 62 patients (14.2%) had epilepsy; and no statistical significance was found among the three groups (p = 0.110). Age-wide comparison between the deletion and non-deletion types: the rate of skin hypopigmentation and epilepsy in the deletion group was significantly higher than that in the non-deletion group (88.8% vs. 68.4%, p < 0.001; 15.9% vs. 7.6%, p = 0.040). The intergroup comparison for the >2-year age group: there were significant intergroup differences in the language development delay among the three groups (p < 0.001). The incidence of delayed language development was the highest in the deletion group, followed by the UPD group, and the lowest in the ID group. The rates of obesity and hyperphagia in the deletion group were also higher than those in the non-deletion group (71.1% vs. 58.9%, p = 0.041; 75.7% vs. 62.0%, p = 0.016). There are significant differences in the rates of skin hypopigmentation and language developmental delay among the deletion, UPD, and ID genotypes. The patients with deletion type had significantly higher rates of lighter skin color, obesity, hyperphagia, language developmental delay, and epilepsy. The results of this study will help clinicians better understand the impact of different PWS molecular etiologies on specific phenotypes.

Schaaf-Yang Syndrome: Clinical Phenotype and Effects of 4 years of Growth Hormone Treatment.

INTRODUCTION: Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder caused by truncating mutations of the MAGEL2 gene, located in the Prader-Willi syndrome (PWS) region. PWS and SYS have phenotypic overlap. Patients with SYS are often treated with growth hormone (GH), but evidence for the effectiveness of the treatment in patients with SYS is limited. METHODS: This study describes 7 children with SYS. We studied their phenotype, genotype, and the effect of GH treatment on height and body mass index (BMI) during 4 years and on body composition during 1 year. RESULTS: All patients had a normal birth weight. Most patients had hypotonia and feeding difficulties after birth (86%). Full-scale IQ ranged from <50 to 92. All patients above the age of 2 years had psycho-behavioral problems. There were no apparent correlations between the phenotype and the location of the defect in the MAGEL2 gene. Mean (95% CI) height SDS increased significantly from -1.74 (-3.55; 0.07) at start to -0.05 (-1.87; 1.77) after 4 years of GH treatment. Mean (95% CI) BMI SDS decreased significantly from 2.01 (1.02; 3.00) to 1.22 (0.18; 2.26) after 6 months and remained the same during the rest of the follow-up. Fat mass percentage SDS decreased and lean body mass did not change during 1 year of treatment in 3 patients. CONCLUSION: Patients presented with a phenotype of hypotonia, respiratory insufficiency, and feeding difficulties after birth, endocrine disorders, intellectual disability, and behavioral problems. Treatment with GH significantly improved height SDS and BMI over the course of 4 years.

Diazoxide choline extended-release tablet in people with Prader-Willi syndrome: results from long-term open-label study.

OBJECTIVE: This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi syndrome (PWS). METHODS: The authors studied 125 participants with PWS, age ≥ 4 years, who were enrolled in the DESTINY PWS Phase 3 study and who received DCCR for up to 52 weeks in DESTINY PWS and/or its open-label extension. The primary efficacy endpoint was Hyperphagia Questionnaire for Clinical Trials (HQ-CT) score. Other endpoints included behavioral assessments, body composition, hormonal measures, and safety. RESULTS: DCCR administration resulted in significant improvements in HQ-CT (mean [SE] -9.9 [0.77], p < 0.0001) and greater improvements in those with more severe baseline hyperphagia (HQ-CT > 22). Improvements were seen in aggression, anxiety, and compulsivity (all p < 0.0001). There were reductions in leptin, insulin, and insulin resistance, as well as a significant increase in adiponectin (all p < 0.004). Lean body mass was increased (p < 0.0001). Disease severity was reduced as assessed by clinician and caregiver (both p < 0.0001). Common treatment-emergent adverse events included hypertrichosis, peripheral edema, and hyperglycemia. Adverse events infrequently resulted in discontinuation (7.2%). CONCLUSIONS: DCCR administration to people with PWS was well tolerated and associated with broad-ranging improvements in the syndrome. Sustained administration of DCCR has the potential to reduce disease severity and the burden of care for families.

The outcomes of growth hormone therapy in the obstructive sleep apnea parameters of Prader-Willi syndrome patients: a systematic review.

PURPOSE: Prader-Willi syndrome is a serious genetic condition, capable of causing endocrinological imbalance, which has as one of its main treatments the growth hormone therapy. However, this therapy still causes some uncertainty concerning its effects on the respiratory parameters of those patients, especially in cases of obstructive sleep apnea, therefore, presenting a need for the analysis of the relationship between the therapy and the otolaryngologic condition. METHODS: A systematic review following the PRISMA model was developed, with searches for keywords made in the databases PubMed (MEDLINE), Scopus, and Web of Science and registration in the PROSPERO platform (CRD42023404250). RESULTS: Three randomized controlled trials were considered eligible for inclusion in the review. None of the studies demonstrated statistically significant modifications in the obstructive sleep apnea parameters of Prader-Willi patients related to the growth hormone administration. CONCLUSIONS: Growth hormone therapy is safe for Prader-Willi syndrome patients when analyzing their obstructive sleep apnea parameters.

Analysis of Hyperphagia Questionnaire for Clinical Trials (HQ-CT) scores in typically developing individuals and those with Prader-Willi syndrome.

The Hyperphagia Questionnaire for Clinical Trials (HQ-CT) is an observer-reported outcome measure that has been widely used in interventional studies to assess changes in hyperphagic behaviors in individuals with Prader-Willi syndrome (PWS). However, HQ-CT scores in the wider PWS population and the general population have not been reported. Here we report HQ-CT scores from more than 400 individuals with PWS and 600 typical individuals, aged 5-26. Overall, HQ-CT scores were significantly higher in those with PWS compared to typically developing individuals at all ages evaluated. In addition, while HQ-CT scores in the typically developing population decreased with age, scores increased with age in PWS. To further understand the variability of HQ-CT scores in the PWS population, semi-structured interviews were conducted with caregivers of a small subset of adults with PWS who had unexpectedly low HQ-CT scores. These caregivers reported that strict adherence to a food routine, food security measures and supervised food preparation reduced the frequency and intensity of hyperphagic behaviors measured by HQ-CT. Thus, hyperphagic behaviors are captured by the HQ-CT for most individuals with PWS, but for some individuals residing in settings with highly structured food routines, HQ-CT scores may not fully reflect the extent of PWS-associated hyperphagia.

Food cue reward salience does not explain Hyperphagia in adolescents with Prader-Willi syndrome.

Prader-Willi Syndrome (PWS) is characterized by hyperphagia, an extreme and persistent hunger that emerges in early childhood. We used event-related potentials (ERPs) to objectively investigate brain responses to low- and high-calorie foods, animals, and household objects in 20 satiated adolescents with PWS. Late Positive Potential (LPP) responses to food images did not differ from non-food images. Rather, we observed larger ERPs to high-calorie foods relative to animal images (p=.001) in an earlier time window. These responses correlated with greater severity of hyperphagia (p = .01). Thus, hyperphagia associated with PWS may be due to altered satiety regulation rather than increased motivational salience.

Ovarian cyst torsion in Prader-Willi Syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a genetic disorder involving multiple systems, with an incidence of about 1/10000-25000. Ovarian torsion (OT) is not commonly found in children. Ovarian cyst acts as one of the primary factors resulting in OT. While ovarian cyst torsion with Prader-Willi Syndrome has not been reported before. CASE PRESENTATION: A 12-years old female was admitted to Emergency Department of our hospital with the chief complaint of abdominal pain. The outcomes of physical examination revealed the height of 150 cm, weight of 103 kg, BMI of 45.77 kg/m2. The patient manifested the special facial features, an obese body, with the abdomen distended into a spherical shape. The fat accumulation in the abdomen significantly embarrassed the palpation. The abdominal CT scan indicated a huge cystic mass in the abdominal cavity, sized about 138 mm × 118 mm. According to medical history, the patient was born with low crying and hypotonia, who has developed the uncontrollable eating behavior since 3-years old. These abnormalities led to a speculation of PWS syndrome, so a genetic test was performed and finally confirmed it, concluding a torsion of ovarian cyst with PWS. With the multidisciplinary consultation, a careful treatment strategy containing the control of blood pressure and blood sugar, coenzyme Q10 was administrated to nourish the myocardium and the application of Growth Hormone was developed. All the above preoperative treatments have brought great benefits to patients. Thus promising the successful completion of operation. The postoperative follow-up till now indicated that the abdominal incision was well healed, without operative complications. CONCLUSIONS: This may be the first case report. In the treatment of ovarian cyst torsion, PWS syndrome requires fully consideration, as the latter can lead to multisystem abnormalities, especially the relation to perioperative management, and even fatalities. Genetic testing should be conducted early when PWS was suspected, accompanied with adequate preparation for the perioperative period, the follow-ups of patients should be maintained for a long time after surgery.

The importance of gynecological examination in adolescent girls and adult women with Prader-Willi syndrome.

Current published guidelines for routine care of women with Prader-Willi syndrome (PWS) do not include recommendations for gynecologic examinations. We describe our experience with gynecological examinations in women with PWS and offer recommendations for routine health care for these patients. Data were collected on all 41 PWS females ages ≥12 year, followed in our national Israeli multidisciplinary clinic between the years 2011 and 2022. Menstrual data and findings on external gynecological examination, including evaluation of the vulva and hymen were recorded at yearly visits. During the gynecological evaluation the topic of sexual education was discussed. Pelvic ultrasound, specifically for antral follicular count, was performed for those visiting the clinic during 2020-2022. Blood samples for luteinizing hormone (LH), follicular stimulating hormone (FSH), and estradiol were obtained routinely and DEXA scans for bone density were done when indicated. Of the 41 women, (median age at start of follow-up 17 years, range [12.3-39], BMI 30.4 kg/m2 [IQR 23.5-37.1]), 39 women agreed to external gynecological examination. Eleven women (27%) had spontaneous menses, with menarche at the age of 14 to as late as 31 years. The hymen was intact in all except one. Poor hygiene was observed in eight women, three women with vulvovaginitis, and five with irritated vulva related to poor hygiene. Gynecological ultrasound was performed in 27 women. In 22, endometrial thickness was less than 5 mm. The median antral follicular count (AFC) was 6 (<10th percentile for age). No correlation between AFC and menstruation or BMI was found. Mean FSH level was 5.7 ± 3.6 IU, LH was 2.29 ± 2.23, and estradiol was 128 ± 76 pmol/L. Data on DEXA measurements were available in 25 women aged 16-39. Median spine T score was -1.3 (range between 0.5 and -3.7), and hip T score was -1.2 (range between 0.8 and -3.3). A negative correlation was found between endometrial thickness and the presence of osteopenia or osteoporosis (r = -0.5, p = 0.013). Despite our recommendations, only eight of 14 women agreed to hormonal treatment or contraception. One woman who received treatment had a thromboembolic event. Routine health care for women with PWS should include gynecological examinations. The gynecological evaluation should include external genital examination, assessment of hygiene, obtaining a blood sample for hormone levels, and documenting a history of sexual experience or sexual abuse. Hormonal treatment or contraception should be offered when appropriate.

N-Acetylglucosamine Kinase-Small Nuclear Ribonucleoprotein Polypeptide N Interaction Promotes Axodendritic Branching in Neurons via Dynein-Mediated Microtubule Transport.

N-acetylglucosamine kinase (NAGK) has been identified as an anchor protein that facilitates neurodevelopment with its non-canonical structural role. Similarly, small nuclear ribonucleoprotein polypeptide N (SNRPN) regulates neurodevelopment and cognitive ability. In our previous study, we revealed the interaction between NAGK and SNRPN in the neuron. However, the precise role in neurodevelopment is elusive. In this study, we investigate the role of NAGK and SNRPN in the axodendritic development of neurons. NAGK and SNRPN interaction is significantly increased in neurons at the crucial stages of neurodevelopment. Furthermore, overexpression of the NAGK and SNRPN proteins increases axodendritic branching and neuronal complexity, whereas the knockdown inhibits neurodevelopment. We also observe the interaction of NAGK and SNRPN with the dynein light-chain roadblock type 1 (DYNLRB1) protein variably during neurodevelopment, revealing the microtubule-associated delivery of the complex. Interestingly, NAGK and SNRPN proteins rescued impaired axodendritic development in an SNRPN depletion model of Prader-Willi syndrome (PWS) patient-derived induced pluripotent stem cell neurons. Taken together, these findings are crucial in developing therapeutic approaches for neurodegenerative diseases.

Systemic immune profile in Prader-Willi syndrome: elevated matrix metalloproteinase and myeloperoxidase and reduced macrophage inhibitory factor.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental syndrome with highly increased risk of obesity and cardiovascular disease (CVD). Recent evidence suggests that inflammation is implicated in the pathogenesis. Here we investigated CVD related immune markers to shed light on pathogenetic mechanisms. METHODS: We performed a cross-sectional study with 22 participants with PWS and 22 healthy controls (HC), and compared levels of 21 inflammatory markers that reflect activity in different aspects of CVD related immune pathways and analyzed their association with clinical CVD risk factors. RESULTS: Serum levels of matrix metalloproteinase 9 (MMP-9) was (median (range)) 121 (182) ng/ml in PWS versus 44 (51) ng/ml in HC, p = 1 × 10-9), myeloperoxidase (MPO) was 183 (696) ng/ml versus 65 (180) ng/ml, p = 1 × 10-5) and macrophage inhibitory factor (MIF) was 46 (150) ng/ml versus 121 (163) ng/ml (p = 1 × 10-3), after adjusting for age and sex. Also other markers tended to be elevated (OPG, sIL2RA, CHI3L1, VEGF) but not significantly after Bonferroni correction (p > 0.002). As expected PWS had higher body mass index, waist circumference, leptin, C-reactive protein, glycosylated hemoglobin (HbA1c), VAI and cholesterol, but MMP-9, MPO and MIF remained significantly different in PWS after adjustment for these clinical CVD risk factors. CONCLUSION: PWS had elevated levels of MMP-9 and MPO and of reduced levels of MIF, which were not secondary to comorbid CVD risk factors. This immune profile suggests enhanced monocyte/neutrophil activation, impaired macrophage inhibition with enhanced extracellular matrix remodeling. These findings warrant further studies targeting these immune pathways in PWS.

Effectiveness of a transdisciplinary approach on hyperphagia management among patients with Prader Willi syndrome.

BACKGROUND: One of the main characteristics of Prader Willi syndrome (PWS) is hyperphagia and obesity. This study sought to evaluate behaviours related to hyperphagia in individuals with PWS under a non-pharmacological transdisciplinary approach. METHODS: This observational study included PWS patients under a traditional non-pharmacological nutritional approach immersed within a regular transdisciplinary treatment (RTT) and a control group of PWS individuals without RTT. All individuals were evaluated using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). RESULTS: Forty-three individuals were evaluated. The mean age at baseline (treatment onset) was 18.4±8.3 years in the RTT group and 19.1±6.9 years in the control group (p=0.74). Hyperphagia-related behaviours were significantly lower among those under RTT (RTT 5.7±3.7 vs control 13.1±7.5, p<0.0001). This was also identified within the three categories: arguing or manipulating to obtain food (2.71±2.1 vs 5.41±3.2, p=0.003), sneaking food (1.33±1.5 vs 3.55±3.3, p=0.007), and anger or tantrums related to food (1.67±1.8 vs 4.09±2.7, p=0.001). After a mean treatment duration of 41.0 months, the RTT group had a reduction in body mass index (baseline 38.7±17.1kg/m2 vs follow-up 29.2±9.2kg/m2; p<0.0001). A significant association between RTT duration and BMI reduction (p=0.037) was identified. CONCLUSION: We observed a positive impact on behaviours related to hyperphagia and a BMI reduction in PWS individuals in a context of a non-pharmacological nutritional approach as part of an RTT.