Role of projective psychological tests in patients with Prader-Willi syndrome.

INTRODUCTION: The purpose of this study was to evaluate the usefulness and relevance of projective techniques such as house-tree-person (HTP) and family in individuals with Prader-Willi syndrome (PWS), who have a limited ability to identify and verbalize emotions and express them often using behaviors. METHODS: We included individuals with genetic confirmation of PWS immersed in a regular transdisciplinary treatment in an institution dedicated to rare diseases. All individuals were evaluated using the HTP and family projective techniques. These instruments are commonly administered to the general population and, in this case, to people with mild to moderate intellectual disabilities, including difficulties in their communication abilities. RESULTS: A total of 25 individuals with PWS between 10 and 41 years old (15 men and 10 women) were included. We identified the presence of graphic indicators corresponding to the behavioral phenotype of individuals with PWS, such as anxiety, stubbornness, emotional lability, difficulty in achieving adequate externalization and identification of emotions, impulsivity, aggressive traits, poor social skills, need for support and interaction, low self-concept, and compulsive behaviors. CONCLUSIONS: In the present study, we demonstrated the usefulness of graphic techniques to elucidate aspects of behavior, emotions, and thoughts that individuals with PWS cannot formulate due to expression and communication difficulties.

Prader-Willi Syndrome: The More We Know, the Less We Know.

Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder with multisystem impact and a unique behavior profile that evolves over the life span. Beyond the primary care needs of all children and adults, the unique medical concerns and management needs of those with PWS are best served in a multidisciplinary academic center. Our PWS center has provided care for individuals with PWS and their families since 1981. Our growth hormone studies contributed to growth hormone supplementation becoming standard of care in this country. Here, in collaboration with the primary care provider, early childhood intervention programs, schools and local parent organizations, solid, patient-centered care for affected individuals and their families can be provided across the life-span. The purpose of this article is to provide a brief overview of PWS and the attendant medical and behavior management challenges attendant to the disorder.

Psychiatric care for people with Prader-Willi syndrome-characteristics, needs and barriers.

BACKGROUND: Prader-Willi syndrome (PWS) is commonly associated with intellectual disability, but also with a specific behavioural phenotype and a high predisposition to psychiatric comorbidity. This study examines the psychiatric care situation of people with PWS. METHOD: A structured online questionnaire was administered to carers of people with PWS living in Germany, asking about demographic, diagnostic and treatment parameters as well as personal experiences. RESULTS: Of 77 people with PWS, 44.2% had at least one psychiatric comorbid diagnosis. The main reasons for seeking psychiatric care were emotional outbursts and aggressive behaviour. 34.9% reported that they were currently seeking psychiatric care without success. However, 32.5% of PWS had been treated with psychotropic medication, mainly antipsychotics. CONCLUSIONS: Psychiatric comorbidity appears to be undertreated in PWS, especially in the ambulatory setting. Uncertainty among mental health care providers may also lead to frequent off-label use of psychotropic medications.

Herlyn-Werner-Wunderlinch: An unusual presentation in a patient with Prader-Willi syndrome.

Herlyn-Werner-Wunderlich syndrome is an uncommon urogenital anomaly defined by uterus didelphys, obstructed hemi-vagina and unilateral renal anomalies. The most common clinical presentation is dysmenorrhoea following menarche, but it can also present as pain and an abdominal mass. Prader-Willi syndrome is a rare neuroendocrine genetic syndrome. Hypothalamic dysfunction is common and pituitary hormone deficiencies including hypogonadism are prevalent. We report the case of a 33-year-old female with Prader-Willi syndrome who was referred to the Gynaecology clinic due to vaginal bleeding and abdominal pain. Abdominal ultrasound revealed a haematometra and haematocolpos and computed tomography showed a uterus malformation and a right uterine cavity occupation (hematometra) as well as right kidney agenesis. Vaginoscopy and hysteroscopy were performed under general anaesthesia, finding a right bulging vaginal septum and a normal left cervix and hemiuterus. Septotomy was performed with complete haematometrocolpos drainage. The association of the two syndromes remains unclear.

Endocrine features of Prader-Willi syndrome: a narrative review focusing on genotype-phenotype correlation.

Prader-Willi syndrome (PWS) is a complex genetic disorder caused by three different types of molecular genetic abnormalities. The most common defect is a deletion on the paternal 15q11-q13 chromosome, which is seen in about 60% of individuals. The next most common abnormality is maternal disomy 15, found in around 35% of cases, and a defect in the imprinting center that controls the activity of certain genes on chromosome 15, seen in 1-3% of cases. Individuals with PWS typically experience issues with the hypothalamic-pituitary axis, leading to excessive hunger (hyperphagia), severe obesity, various endocrine disorders, and intellectual disability. Differences in physical and behavioral characteristics between patients with PWS due to deletion versus those with maternal disomy are discussed in literature. Patients with maternal disomy tend to have more frequent neurodevelopmental problems, such as autistic traits and behavioral issues, and generally have higher IQ levels compared to those with deletion of the critical PWS region. This has led us to review the pertinent literature to investigate the possibility of establishing connections between the genetic abnormalities and the endocrine disorders experienced by PWS patients, in order to develop more targeted diagnostic and treatment protocols. In this review, we will review the current state of clinical studies focusing on endocrine disorders in individuals with PWS patients, with a specific focus on the various genetic causes. We will look at topics such as neonatal anthropometry, thyroid issues, adrenal problems, hypogonadism, bone metabolism abnormalities, metabolic syndrome resulting from severe obesity caused by hyperphagia, deficiencies in the GH/IGF-1 axis, and the corresponding responses to treatment.

[The importance of early recognition of Prader-Willi syndrome]. / Het Prader-Willi-syndroom.

Due to its rare nature and subtle dysmorphisms, Prader-Willi syndrome can be challenging to recognize and diagnose in the neonatal period. Feeding difficulties and hypotonia ('floppy infant') are the most striking characteristics. Prader-Willi syndrome requires specific follow-up and treatment, emphasizing the importance of early recognition.We encountered an infant of three months old with severe hypotonia. The hypotonia ameliorated spontaneously over time, although feeding per nasogastric tube was necessary. There were no apparent dysmorphisms. Extensive genetic investigations showed a maternal uniparental disomy of chromosome 15, fitting with Prader-Willi syndrome explaining all symptoms. After excluding contraindications, treatment with growth hormone therapy was started. Parents were educated regarding medical emergencies specific for Prader-Willi syndrome ('medical alerts'). Although Prader-Willi syndrome is rare, it should always be considered in cases of neonatal hypotonia. Early recognition is paramount as specific recommendations and treatment are warranted.

Metabolomic profiling of Prader-Willi syndrome compared with essential obesity.

Introduction: Prader-Willi syndrome (PWS) is a rare disease, which shows a peculiar clinical phenotype, including obesity, which is different from essential obesity (EOB). Metabolomics might represent a valuable tool to reveal the biochemical mechanisms/pathways underlying clinical differences between PWS and EOB. The aim of the present (case-control, retrospective) study was to determine the metabolomic profile that characterizes PWS compared to EOB. Methods: A validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeted metabolomic approach was used to measure a total of 188 endogenous metabolites in plasma samples of 32 patients with PWS (F/M = 23/9; age: 31.6 ± 9.2 years; body mass index [BMI]: 42.1 ± 7.0 kg/m2), compared to a sex-, age- and BMI-matched group of patients with EOB (F/M = 23/9; age: 31.4 ± 6.9 years; BMI: 43.5 ± 3.5 kg/m2). Results: Body composition in PWS was different when compared to EOB, with increased fat mass and decreased fat-free mass. Glycemia and HDL cholesterol were higher in patients with PWS than in those with EOB, while insulinemia was lower, as well as heart rate. Resting energy expenditure was lower in the group with PWS than in the one with EOB, a difference that was missed after fat-free mass correction. Carrying out a series of Tobit multivariable linear regressions, adjusted for sex, diastolic blood pressure, and C reactive protein, a total of 28 metabolites was found to be associated with PWS (vs. non-PWS, i.e., EOB), including 9 phosphatidylcholines (PCs) ae, 5 PCs aa, all PCs aa, 7 lysoPCs a, all lysoPCs, 4 acetylcarnitines, and 1 sphingomyelin, all of which were higher in PWS than EOB. Conclusions: PWS exhibits a specific metabolomic profile when compared to EOB, suggesting a different regulation of some biochemical pathways, fundamentally related to lipid metabolism.

Establishing a Standardized DNA Extraction Method Using NaCl from Oral Mucosa Cells for Its Application in Imprinting Diseases Such as Prader-Willi and Angelman Syndromes: A Preliminary Investigation.

BACKGROUND: Diagnosing imprinting defects in neonates and young children presents challenges, often necessitating molecular analysis for a conclusive diagnosis. The isolation of genetic material from oral swabs becomes crucial, especially in settings where blood sample collection is impractical or for vulnerable populations like newborns, who possess limited blood volumes and are often too fragile for invasive procedures. Oral swab samples emerge as an excellent source of DNA, effectively overcoming obstacles associated with rare diseases. METHODS: In our study, we specifically addressed the determination of the quality and quantity of DNA extracted from oral swab samples using NaCl procedures. RESULTS: We compared these results with extractions performed using a commercial kit. Subsequently, the obtained material underwent MS-HRM analysis for loci associated with imprinting diseases such as Prader-Willi and Angelman syndromes. CONCLUSIONS: Our study emphasizes the significance of oral swab samples as a reliable source for obtaining DNA for MS-HRM analysis. NaCl extraction stands out as a practical and cost-effective method for genetic studies, contributing to a molecular diagnosis that proves particularly beneficial for patients facing delays in characterization, ultimately influencing their treatment.

Pathological analysis of Prader-Willi syndrome using adipocytes.

Prader-Willi syndrome (PWS) is a complex epigenetic disorder caused by the deficiency of paternally expressed genes in chromosome 15q11-q13. This syndrome also includes endocrine dysfunction, leading to short stature, hypogonadism, and obscure hyperphagia. Although recent progress has been made toward understanding the genetic basis for PWS, the molecular mechanisms underlying its pathology in obesity remain unclear. In this study, we examined the adipocytic characteristics of two PWS-induced pluripotent stem cell (iPSC) lines: those with the 15q11-q13 gene deletion (iPWS cells) and those with 15q11-q13 abnormal methylation (M-iPWS cells). The transcript levels of the lipid-binding protein aP2 were decreased in iPWS and M-iPWS adipocytes. Flow-cytometry analysis showed that PWS adipocytes accumulated more lipid droplets than did normal individual adipocytes. Furthermore, glucose uptake upon insulin stimulation was attenuated compared to that in normal adipocytes. Overall, our results suggest a significantly increased lipid content and defective in glucose metabolism in PWS adipocytes.

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.

Similar metabolic pathways are affected in both Congenital Myasthenic Syndrome-22 and Prader-Willi Syndrome.

Loss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic Syndrome-22 (CMS22). It is characterized by severe neonatal hypotonia, feeding problems, growth retardation, and hyperphagia leading to rapid weight gain later in childhood. The phenotypic similarities with Prader-Willi syndrome (PWS) are striking, suggesting that similar pathways are affected. The aim of this study was to identify changes in the hypothalamic-pituitary axis in mouse models for both disorders and to examine mitochondrial function in skin fibroblasts of patients and knockout cell lines. We have demonstrated that Prepl is downregulated in the brains of neonatal PWS-IC-p/+m mice. In addition, the hypothalamic-pituitary axis is similarly affected in both Prepl-/- and PWS-IC-p/+m mice resulting in defective orexigenic signaling and growth retardation. Furthermore, we demonstrated that mitochondrial function is altered in PREPL knockout HEK293T cells and can be rescued with the supplementation of coenzyme Q10. Finally, PREPL-deficient and PWS patient skin fibroblasts display defective mitochondrial bioenergetics. The mitochondrial dysfunction in PWS fibroblasts can be rescued by overexpression of PREPL. In conclusion, we provide the first molecular parallels between CMS22 and PWS, raising the possibility that PREPL substrates might become therapeutic targets for treating both disorders.

Examination of sensory reception and integration abilities in children with and without Prader-Willi syndrome.

BACKGROUND: Good postural stability control is dependent upon the complex integration of incoming sensory information (visual, somatosensory, vestibular) with neuromotor responses that are constructed in advance of a voluntary action or in response to an unexpected perturbation. AIMS: To examine whether differences exist in how sensory inputs are used to control standing balance in children with and without Prader-Willi syndrome (PWS). METHODS AND PROCEDURES: In this cross-sectional study, 18 children with PWS and 51 children categorized as obese but without PWS (without PWS) ages 8-11 completed the Sensory Organization Test®. This test measures the relative contributions of vision, somatosensory, and vestibular inputs to the control of standing balance. The composite equilibrium score (CES) derived from performance in all sensory conditions, in addition to equilibrium scores (EQs) and falls per condition were compared between groups. OUTCOMES AND RESULTS: The CES was lower for children with PWS compared to children without PWS (M=53.93, SD=14.56 vs. M=66.17, SD=9.89, p = .001) while EQs declined in both groups between conditions 1 and 4 (F (1.305, 66.577) = 71.381, p < .001). No group differences in the percent of falls were evident in condition 5 but more children with PWS fell in condition 6 (χ2 (1) = 7.468, p = .006). Group differences in frequency of repeated falls also approached significance in conditions 5 (χ2 (3) = 4.630, p = .099) and 6 (χ2 (3) = 5.167, p = .076). CONCLUSIONS AND IMPLICATIONS: Children with PWS demonstrated a lower overall level of postural control and increased sway when compared to children with obesity. Both the higher incidence and repeated nature of falls in children with PWS in conditions 5 and 6 suggest an inability to adapt to sensory conditions in which vestibular input must be prioritized. Postural control training programs in this population should include activities that improve their ability to appropriately weight sensory information in changing sensory environments, with a particular focus on the vestibular system. WHAT DOES THIS STUDY ADD?: This study shows that children with PWS demonstrate a lower level of postural stability. The results suggest that children with PWS show inability to adapt to sensory conditions that require prioritizing vestibular information to maintain postural control. This information can be used to help guide training programs in this population.

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).

Prevalence and genotypic associations of epilepsy in Prader-Willi Syndrome: A systematic review and meta-analysis.

OBJECTIVE: To estimate the prevalence of epilepsy and febrile seizures and their association with genotype, i.e., 15q11-q13 deletions, uniparental chromosome 15 disomy (UPD) and other mutations, in the population with Prader-Willi syndrome (PWS). METHODS: A systematic search of Medline, Scopus, Web of Science and the Cochrane Library was conducted. Studies estimating the prevalence of seizures, epilepsy and febrile seizures in the PWS population were included. Meta-analyses of the prevalence of epilepsy and febrile seizures and their association with genotype using the prevalence ratio (PR) were performed. RESULTS: Fifteen studies were included. The prevalence of epilepsy was 0.11 (0.07, 0.15), similar to the prevalence of febrile seizures, with a prevalence of 0.09 (0.05, 0.13). The comparison "deletion vs. UPD" had a PR of 2.03 (0.90, 4.57) and 3.76 (1.54, 9.18) for epilepsy and febrile seizures. CONCLUSIONS: The prevalence of seizure disorders in PWS is higher than in the general population. In addition, deletions in 15q11-q13 may be associated with a higher risk of seizure disorders. Therefore, active screening for seizure disorders in PWS should improve the lives of these people. In addition, genotype could be used to stratify risk, even for epilepsy, although more studies or larger sample sizes are needed.

Expanding deep phenotypic spectrum associated with atypical pathogenic structural variations overlapping 15q11-q13 imprinting region.

BACKGROUND: The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic phenomenon that causes differential gene expression based on the parent of origin. In most diploid organisms, gene expression typically involves an equal contribution from both maternal and paternal alleles, shaping the phenotype. Nevertheless, in mammals, including humans, mice, and marsupials, the functional equivalence of parental alleles is not universally maintained. Notably, during male and female gametogenesis, parental alleles may undergo differential marking or imprinting, thereby modifying gene expression without altering the underlying DNA sequence. Neurodevelopmental disorders, such as Prader-Willi syndrome (PWS) (resulting from the absence of paternally expressed genes in this region), Angelman syndrome (AS) (associated with the absence of the maternally expressed UBE3A gene), and 15q11-q13 duplication syndrome (resulting from the two common forms of duplications-either an extra isodicentric 15 chromosome or an interstitial 15 duplication), are the outcomes of genetic variations in this imprinting region. METHODS: Conducted a genomic study to identify the frequency of pathogenic variants impacting the 15q11-q13 region in an ethnically homogenous population from Bangladesh. Screened all known disorders from the DECIPHER database and identified variant enrichment within this cohort. Using the Horizon analysis platform, performed enrichment analysis, requiring at least >60% overlap between a copy number variation and a disorder breakpoint. Deep clinical phenotyping was carried out through multiple examination sessions to evaluate a range of clinical symptoms. RESULTS: This study included eight individuals with clinically suspected PWS/AS, all previously confirmed through chromosomal microarray analysis, which revealed chromosomal breakpoints within the 15q11-q13 region. Among this cohort, six cases (75%) exhibited variable lengths of deletions, whereas two cases (25%) showed duplications. These included one type 2 duplication, one larger atypical duplication, one shorter type 2 deletion, one larger type 1 deletion, and four cases with atypical deletions. Furthermore, thorough clinical assessments led to the diagnosis of four PWS patients, two AS patients, and two individuals with 15q11-q13 duplication syndrome. CONCLUSION: Our deep phenotypic observations identified a spectrum of clinical features that overlap and are unique to PWS, AS, and Dup15q syndromes. Our findings establish genotype-phenotype correlation for patients impacted by variable structural variations within the 15q11-q13 region.

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.

Neuromodulation for the treatment of Prader-Willi syndrome - A systematic review.

Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological derangements. Recent developments in advanced neuroimaging have led to a growing understanding of PWS as a neural circuit disorder, as well as subsequent interests in the application of neuromodulatory therapies. Various non-invasive and invasive device-based neuromodulation methods, including vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) have all been reported to be potentially promising treatments for addressing the major symptoms of PWS. In this systematic literature review, we summarize the recent literature that investigated these therapies, discuss the underlying circuits which may underpin symptom manifestations, and cover future directions of the field. Through our comprehensive search, there were a total of 47 patients who had undergone device-based neuromodulation therapy for PWS. Two articles described VNS, 4 tDCS, 1 rTMS and 2 DBS, targeting different symptoms of PWS, including aberrant behavior, hyperphagia and weight. Multi-center and multi-country efforts will be required to advance the field given the low prevalence of PWS. Finally, given the potentially vulnerable population, neuroethical considerations and dialogue should guide the field.

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of cases. Two distinct genetic subtypes of PWS deletions are characterized, where type I (PWS T1) carries four extra haploinsufficient genes compared to type II (PWS T2). PWS T1 individuals display more pronounced physiological and cognitive abnormalities than PWS T2, yet the exact neuropathological mechanisms behind these differences remain unclear. Our study employed postmortem hypothalamic tissues from PWS T1 and T2 individuals, conducting transcriptomic analyses and cell-specific protein profiling in white matter, neurons, and glial cells to unravel the cellular and molecular basis of phenotypic severity in PWS sub-genotypes. In PWS T1, key pathways for cell structure, integrity, and neuronal communication are notably diminished, while glymphatic system activity is heightened compared to PWS T2. The microglial defect in PWS T1 appears to stem from gene haploinsufficiency, as global and myeloid-specific Cyfip1 haploinsufficiency in murine models demonstrated. Our findings emphasize microglial phagolysosome dysfunction and altered neural communication as crucial contributors to the severity of PWS T1's phenotype.

Pharmacogenomics for Prader-Willi syndrome: caregiver interest and planned utilization.

Aim: The study aim was to determine caregiver interest and planned utilization of pharmacogenomic (PGx) results for their child with Prader-Willi syndrome. Methods: Caregivers consented to PGx testing for their child and completed a survey before receiving results. Results: Of all caregivers (n = 48), 93.8% were highly interested in their child's upcoming PGx results. Most (97.9%) planned to share results with their child's medical providers. However, only 47.9% of caregivers were confident providers would utilize the PGx results. Conclusion: Caregivers are interested in utilizing PGx but are uncertain providers will use these results in their child's care. More information about provider comfort with PGx utilization is needed to understand how PGx education would benefit providers and ultimately patients with PGx results.

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.