Codesigning a Neurocognitive Assessment Protocol for Hyperphagia: Perspectives From Stakeholders in Prader-Willi Syndrome.

Background: Hyperphagia, an overwhelming feeling of hunger and a strong drive to consume food, often leads to overeating. It is a hallmark feature of Prader-Willi Syndrome (PWS), significantly impacting quality of life. There is an urgent need for rigorous research to develop objective measures of hyperphagia to advance therapeutic innovation and improve clinical outcomes for individuals with PWS and other conditions linked to hyperphagia. Eye-tracking is a powerful tool for measuring cognitive processes in neurodevelopmental research and holds promise as an objective measure of hyperphagia.Methods: This study aimed to evaluate and adapt an eye-tracking study protocol—designed to measure fluctuations in hunger and satiety—for use with the PWS community. A co-design approach was employed, involving focus groups with professionals and individuals with lived experience. Key barriers to participation, such as food-related anxiety, sensory sensitivities, and the need for predictable routines, were identified and addressed. Protocol adaptations included flexible scheduling, individualized meal options, and the integration of "food certainty" to reduce participant stress and enhance adherence.Results: The implementation phase demonstrated the feasibility and acceptability of the adapted protocol, with high completion rates (92.6%) and full adherence to fasting and standardized meal requirements in the PWS cohort. Participants and stakeholders reported improved comfort and engagement with the adapted protocol.Conclusion: These findings highlight the value of stakeholder co-design in research protocols for individuals with complex neurodevelopmental conditions. Incorporating stakeholder input can enhance research engagement, improve data quality, and increase participant satisfaction. The successful adaptation of this eye-tracking protocol supports its potential as a scalable, objective tool for measuring hyperphagia in clinical and research settings.

American College of Medical Genetics Statement on Diagnostic Testing for Uniparental Disomy

Reply

Prader-Willi Syndrome has an estimated birth incidence of 1 in 10,000-30,000 people and affects male and females equally. The rare genetic disorder is caused by absent expression of the paternally-inherited genes on chromosome 15q11.2-q13 and presents implications on the endocrine system from early life as a result of associated hypothalamic dysfunction. Patients with Prader-Willi Syndrome experience endocrine disorders such as hypogonadism, hypothyroidism, adrenal insufficiency, and poor bone mineral density. The features of Prader-Willi Syndrome are also consistent with those of growth hormone deficiency; patients also present with short stature and growth deceleration. Those with Prader-Willi Syndrome are also at a higher risk of obesity, owing to their lower resting energy expenditure and lack of satiety, as well as 2 diabetes mellitus and metabolic syndrome. Accordingly, individuals with Prader-Willi Syndrome should be advised and monitored by an endocrinologist throughout their lifespan. This collection aims to present up-to-date research relating to the presentation, diagnosis, treatment, and risk-factors of endocrine disorders in patients with Prader-Willi Syndrome. Submissions may include, but are not limited to, reviews, original research , or other accepted articles relating to: - Presentation of endocrine dysfunction in patients with Prader-Willi Syndrome; - Specific risk-factors of endocrine dysfunction in patients with Prader-Willi Syndrome; - Management or treatment of endocrine disorders in patients with Prader-Willi Syndrome - Tools for the diagnosis of endocrine disorders in patients with Prader-Willi Syndrome - Endocrine dysfunction in patients with Prader-Willi Syndrome and comorbidities.

An insatiable appetite is a cardinal feature of Prader-Willi syndrome (PWS) with stomach rupturing as a reported consequence. Peptide YY, secreted by the intestine and released post-prandially, inhibits appetite, while ghrelin, secreted by the stomach during mealtime hunger, stimulates appetite. Both peptide YY and ghrelin act at the brain level, particularly the hypothalamus. Recently, plasma ghrelin levels were reported to be elevated in children and adults with PWS but peptide YY levels have not been studied in this syndrome or ghrelin in infants with PWS. To further address the abnormal eating behavior in PWS, we obtained fasting plasma peptide YY and ghrelin levels in 12 infants and children with PWS ranging in age from 2.5 months to 13.3 years and compared them with values from normal populations reported in the literature. Plasma ghrelin levels in our patients with PWS were similar to those of other children with PWS and were significantly higher than those reported in obese children without PWS. Our infants with PWS had similar plasma ghrelin levels compared with our children with PWS but peptide YY levels in our children and infants with PWS were lower than reported in similarly aged individuals without PWS. In addition, we performed preliminary gene expression analysis of ghrelin and peptide YY and their receptors in patients with PWS using established lymphoblastoid cell lines but gene expression did not correlate with plasma ghrelin or peptide YY levels.

This study examined sensitivity of eye tracking measures to hyperphagia severity in Prader-Willi syndrome (PWS). Gaze data were collected in 57 children with PWS, age 3-11 years, and 47 typically developing peers at two study sites during free visual exploration of complex stimulus arrays that included images of food, animals, and household objects. Analysis of the number and duration of fixations as well as gaze perseverations revealed that food items are not exceptionally salient for children with PWS. Instead, increased attention to food in the context of other high-interest items (e.g., animals) was associated with caregiver reports of more severe hyperphagia and more advanced nutritional phase. The study also provided preliminary evidence of possible genetic subtype and sex differences as well as demonstrated that multiple investigators in a wide range of settings can effectively implement the eye tracking protocol. The results indicate that gaze characteristics derived from eye tracking may be a promising objective marker of hyperphagia in PWS for use in research and clinical trials.

Background: Elevated plasma ghrelin levels have recently been reported in adults and children with Prader-Willi syndrome (PWS). The aim of the study is to investigate the relationship between obesity, growth hormone (GH) deficiency (GHD) and ghrelinemia in PWS and to examine whether hyperghrelinemia is specific to PWS. Methods: We measured fasting ghrelinemia in children with PWS, idiopathic GHD (iGHD), obese children, controls and in 6 children presenting another congenital syndrome associated with GHD: pituitary stalk interruption (PSI). Results: Children with PWS exhibited significantly higher ghrelin levels (995 pg/ml (801/1,099, median 1st/3rd quartile)) than iGHD (517 pg/ml (392/775)), obese (396 pg/ml (145/610)) and control (605 ng/ml (413/753)) children. Similar to PWS hyperghrelinemia was found in PSI children (1,029 pg/ml (705/1,151)), and was not modified by GH treatment. Conclusion: We conclude that hyperghrelinemia in PWS and PSI is not related to GH secretion. We hypothesize that a major site of ghrelin action is at the hypothalamic level and that a ‘ghrelin resistance’ syndrome may be present in these patients, primarily due to a hypothalamic defect. Combined alterations such as impaired serotonin receptor regulation associated with abnormal ghrelin responsiveness are probably responsible for obesity in PWS.

Chronic diazoxide treatment decreases fat mass and improves endurance capacity in an obese mouse model of Prader-Willi syndrome

Objective To study the clinical features of the Prader-Willi syndrome (PWS) in neonatal period, and to explore intervention methods to improve their intelligence development. Method From September 2012 to September 2017, clinical data of infants with PWS in our hospital were retrospectively analyzed. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) were used for genetic testing. The patients received rehabilitation training and drug treatment, and followed-up every 6 months after the diagnosis. Result A total of 11 infants with PWS (6/11 male) were included. 8 cases had fetal bradycardia before delivery, 11 cases had hypomyotonia, lethargy, feeding difficulty, no or weak crying and nasogastric tube feeding. Among them, 9 cases had facial anomalies, 8 cases whitish skin and 7 cases genital dysplasia. 2 infants died shortly after discharge, 2 infants received no intervention, 3 infants were regularly trained in our rehabilitation division with oral treatment of docosahexaenoic acid (DHA), and 4 infants were trained at home with intermittent oral DHA treatment. Among 11 cases, 3 cases received growth hormone treatment at the age of 6 months and 1 case received at the age of 59 months. The survivors received intelligence test every 6 months using children′s mental behavior scale (0-6 years old). They had severe mental retardation with the scores between 20 and 70 points. 5 cases had gene deletion of q11 related area in chromosome 15, 4 cases had gene deletion of q11-13 related area in chromosome 15. 1 case had abnormal demethylation of q11-13 in chromosome 15, and 1 case had loss of heterozygosity with methylation abnormality in chromosome 15 q11-13 areas. Conclusion Children with PWS can exhibit certain characteristics during both fetal and neonatal periods. Deletion of related genes are more frequently seen than abnormal methylation in these patients. During infantile period with rapid development of nervous system, the growth and development of infants with PWS can not be obviously improved using conventional rehabilitation training and drug treatment. Key words: Prader-Willi syndrome; Genotype; Disease attributes; Infant, newborn

Introduction Prader-Willi syndrome (PWS) is the most common genetic disease causing childhood morbid obesity. Early diagnosis and treatment are utmost important for improving prognosis and bettering outcome in PWS patients. However, the early diagnosis rate is still relatively low. One of the main reasons for delayed diagnosis is not sufficient recognition of perinatal and neonatal features of PWS in clinicians. Recognizing the perinatal features of PWS for early diagnosis is now becoming a hot research interest. Areas covered This review covers perinatal and neonatal features recognition which are valuable for obstetricians and neonatologists. We also provide a detailed genetic testing flow diagram for reference. A comprehensive search was undertaken using the databases including PubMed, Web of Science, Scopus, Cochrane databases. Expert opinion For obstetricians, if the pregnant women had combined prenatal features including polyhydramnios, decreased fetal movement, and or abnormal intrauterine fetal growth, amniocentesis can be considered, and PWS should be included as a differential diagnosis. For excluding diagnosis of PWS, methylation test should be done, and MS-MLPA is the optimal choice. If amniocentesis is not possible, molecular testing should be appointed after birth as soon as possible particularly for the neonates with presentations of hypotonia or sucking problem/feeding difficulty.

Objective To know more about the features of Prader-Willi syndrome(PWS) in neonates and to promote early interventions for PWS patients. Methods The clinical data from 7 PWS patients being definitely diagnosed by array comparative genomic hybridization(array-CGH)from Jan. 2007 to Dec. 2012 in Department of Neonato-logy, Guangzhou Women and Children's Medical Center were collected retrospectively. The data were analyzed with lite-rature being reviewed. Results There were 7 cases described in this study, of which 6 cases were male and 1 case was female. All patients had the features of hypotonia, poor responses, feeding difficulties, less crying or weak crying. Seven cases had 5 or more of the following distinctive facial appearances: prominent forehead, narrow face, almond eyes, small mouth, downturned mouth corners, thin upper lip, and micromandible. Six cases of male children were small scrotum, among them 3 cases were cryptorchidism. Seven cases were diagnosed as PWS by array-CGH. Seven children were fed by using gastric tube, in which 4 cases accepted swallow training after admission, and their gastric tube lasted from 8 to 20 days [(13.0±5.1) d], 3 cases did not receive continuous tube feeding but swallow training them of from 15 to 35 days [(18.0±4.3) d]. Other comprehensive therapy measures included offering the parents a detailed health education, informing and their gastric tube lasted the basic information about the disease, teaching the parents how to facilitate feeding and prevent asphyxia and other aspects of skills. This might increase the baby's passive activities and promote normal development of the baby's nutritional management measures to prevent excessive or inadequate nutritional intake. Multidisciplinary consultation was necessary including the intervention of mass language training, nutrition, neuro-logy, psychiatry, psychology and osteology. Conclusions PWS newborns have the characteristics of hypotonia, poor responses, feeding difficulties, less crying or weak crying, genital hypoplasia and typical facial features. Genetic testing should be necessary for early diagnosis, as early diagnosis is benefitial for early intervention including comprehensive treatment measures such as swallowing training, which may improve the life quality of PWS patients, and improve the prognosis, and prevent growth retardation, obesity and other problems. Key words: Prader-Willi syndrome; Intervention; Diagnosis; Infant, newborn

Two patients with classical features of Angel-man syndrome (AS) and one with Prader-Willi syndrome (PWS) had unbalanced reciprocal translocations involving the chromosome 15 proximal long arm and the telomeric region of chromosomes 7, 8 and 10. Fluorescence in situ hybridization (FISH) was used for the detection of chromosome 15(q11-13) deletions (with probes from the PWS/AS region) and to define the involvement of the telomere in the derivative chromosomes (with library probes and telomere-specific probes). The 15(q11-13) region was not deleted in one patient but was deleted in the other two. The telomere on the derivative chromosomes 7, 8 and 10 was deleted in all three cases. Thus, these are true reciprocal translocations in which there has been loss of the small satellited reciprocal chromosome (15) fragment.

BackgroundRapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a very rare and potentially fatal pediatric disorder, the cause of which is presently unknown. ROHHAD is often compared to Prader-Willi syndrome (PWS) because both share childhood obesity as one of their most prominent and recognizable signs, and because other symptoms such as hypoventilation and autonomic dysfunction are seen in both. These phenotypic similarities suggest they might be etiologically related conditions. We performed an in-depth clinical comparison of the phenotypes of ROHHAD and PWS and used NGS and Sanger sequencing to analyze the coding regions of genes in the PWS region among seven ROHHAD probands.ResultsDetailed clinical comparison of ROHHAD and PWS patients revealed many important differences between the phenotypes. In particular, we highlight the fact that the areas of apparent overlap (childhood-onset obesity, hypoventilation, autonomic dysfunction) actually differ in fundamental ways, including different forms and severity of hypoventilation, different rates of obesity onset, and different manifestations of autonomic dysfunction. We did not detect any disease-causing mutations within PWS candidate genes in ROHHAD probands.ConclusionsROHHAD and PWS are clinically distinct conditions, and do not share a genetic etiology. Our detailed clinical comparison and genetic analyses should assist physicians in timely distinction between the two disorders in obese children. Of particular importance, ROHHAD patients will have had a normal and healthy first year of life; something that is never seen in infants with PWS.

Prader-Willi syndrome (PWS) is a genetic disorder characterized by hypotonia and poor feeding in infancy which progresses to hyperphagia in early-mid childhood, as well as developmental delays, a spectrum of behavioral and psychiatric concerns, endocrinopathies, orthopedic issues, and less commonly, seizures, sleep apnea, and narcolepsy with or without cataplexy. This study used data in the Global PWS Registry (N=893) to explore the onset and severity over time of the neuropsychiatric features reported in individuals with PWS and explored its associations with sleep disorders, seizures, and psychiatric symptoms. Results demonstrate that seizures are more common in the deletion subtype and that narcolepsy and cataplexy are more common in individuals who have sleep-related seizures. Finally, this work shows that anxiety and compulsive behaviors are persistent features of PWS that may arise early in childhood, and that anxiety is associated with higher frequency of other comorbid psychiatric diagnoses. In conclusion, this study is one of the largest to date characterizing sleep disorders and neuropsychiatric characteristics of individuals with PWS and reports on the novel association between sleep disorders and seizures. This study is also one of the first to offer details on the nature of the progression of these features in individuals with PWS.

Visual food cue processing in children with Prader-Willi Syndrome