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Prader-Willi syndrome (PWS) is a complex, genetic, neurodevelopmental disorder. PWS has three molecular genetic classes. The most common defect is due to a paternal 15q11-q13 deletion observed in about 60% of individuals. This is followed by maternal disomy 15 (both 15 s from the mother), found in approximately 35% of cases. the remaining individuals have a defect of the imprinting center that controls the activity of imprinted genes on chromosome 15. Mild cognitive impairment and behavior problems in PWS include self-injury, anxiety, compulsions, and outbursts in childhood, impacted by genetic subtypes. Food seeking and hyperphagia can lead to morbid obesity and contribute to diabetes and cardiovascular or orthopedic problems. The control of hyperphagia and improving food-related behaviors are the most important unmet needs in PWS and could be addressed with the development of a new therapeutic agent, as currently no approved therapeutics exist for PWS treatment. The status of clinical trials with existing results for the management of obesity and hyperphagia in PWS will be discussed in this review, including treatments such as beloranib, setmelanotide, a diazoxide choline controlled-release tablet (DCCR), an unacylated ghrelin analogue, oxytocin and related compounds, glucagon-like peptide 1 receptor agonists, surgical intervention, and transcranial direct-current stimulation.

BackgroundPrader-Willi syndrome (PWS) is an imprinting disorder caused by the absence of paternal expressed genes in the Prader-Willi critical region (PWCR) on chromosome 15q11.2-q13. Three molecular mechanisms have been known to cause PWS, including a deletion in the PWCR, uniparental disomy 15 and imprinting defects.ResultsWe report the first case of PWS associated with a single-nucleotide SNRPN variant in a 10-year-old girl presenting with clinical features consistent with PWS, including infantile hypotonia and feeding difficulty, developmental delay with cognitive impairment, excessive eating with central obesity, sleep disturbances, skin picking and related behaviour issues. Whole-exome sequencing revealed a de novo mosaic nonsense variant of the SNRPN gene (c.73C>T, p.R25X) in 10% of DNA isolated from buccal cells and 19% of DNA from patient-derived lymphoblast cells. DNA methylation study did not detect an abnormal methylation pattern in the SNRPN locus. Parental origin studies showed a paternal source of an intronic single-nucleotide polymorphism within the locus in proximity to the SNRPN variant.ConclusionsThis is the first report that provides evidence of a de novo point mutation of paternal origin in SNRPN as a new disease-causing mechanism for PWS. This finding suggests that gene sequencing should be considered as part of the diagnostic workup in patients with clinical suspicion of PWS.

Congenital anomalies of the kidney and urinary tract (CAKUT) and congenital heart disease (CHD) are the most common congenital defects and constitute a major cause of morbidity in children. Anomalies of both systems may be isolated or associated with congenital anomalies of other organ systems. Various reports support the co‐occurrence of CAKUT and CHD, although the prevalence can vary. Cardiovascular anomalies occur in 11.2% to 34% of patients with CAKUT, and CAKUT occur in 5.3% to 35.8% of those with CHD. The co‐occurrence of genetic factors in both CAKUT and CHD would raise common etiologies including genetics, genetic‐environmental interactions, or shared molecular mechanisms and pathways such as NODAL, NOTCH, BMP, WNT, and VEGF. Studies in animal models and humans have indicated a genetic etiology for CHD and CAKUT with hundreds of genes recognized and thousands of entries, found in a catalog of human genetic disorders. There are over 80 CAKUT genes and over 100 CHD genes available for clinical testing. For example, the HNFIB gene accounts for 5% to 31% of reported cases of CAKUT. In view of the association between CAKUT and CHD, a thorough cardiac examination should be performed in patients with CAKUT, and a similar evaluation for CAKUT in the presence of CHD. This will allow early diagnosis and therapeutic intervention to improve the long‐ term outcome of patients affected, and test for at‐risk family members. We present here evidence for an association of anomalies involving the two organ systems, and discuss possible etiologies of targeted genes, their functions, biological processes and interactions on embryogenesis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Context: 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 not controlled. Objective: The primary end point was change from baseline in hyperphagia using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT). Other end points included Global Impression Scores, and changes in body composition, behaviors, and hormones. Methods: In DESTINY PWS, a 13-week, randomized, double-blind, placebo-controlled, phase 3 trial, 127 participants with PWS aged 4 years and older with hyperphagia were randomly assigned 2:1 to diazoxide choline extended-release tablet (DCCR) or placebo. Results: DCCR did not significantly improve hyperphagia (HQ-CT least-square mean (LSmean) [SE] -5.94 [0.879] vs -4.27 [1.145]; P=.198), but did so in participants with severe hyperphagia (LSmean [SE] -9.67 [1.429] vs -4.26 [1.896]; P=.012). Two of 3 secondary end points were improved (Clinical Global Impression of Improvement [CGI-I]; P=.029; fat mass; P=.023). In an analysis of results generated pre-COVID, the primary (HQ-CT; P=.037) and secondary end points were all improved (CGI-I; P=.015; Caregiver Global Impression of Change; P=.031; fat mass; P=.003). In general, DCCR was well tolerated with 83.3% in the DCCR group experiencing a treatment-emergent adverse event and 73.8% in the placebo group (not significant). Conclusion: DCCR did not significantly improve hyperphagia in the primary analysis but did in participants with severe baseline hyperphagia and in the pre-COVID analysis. DCCR treatment was associated with significant improvements in body composition and clinician-reported outcomes. [ABSTRACT FROM AUTHOR]

Background Prader-Willi syndrome (PWS) is an imprinting disorder caused by the absence of paternal expressed genes in the Prader-Willi critical region (PWCR) on chromosome 15q11.2-q13. Three molecular mechanisms have been known to cause PWS, including a deletion in the PWCR, uniparental disomy 15 and imprinting defects. Results We report the first case of PWS associated with a single-nucleotide SNRPN variant in a 10-year-old girl presenting with clinical features consistent with PWS, including infantile hypotonia and feeding difficulty, developmental delay with cognitive impairment, excessive eating with central obesity, sleep disturbances, skin picking and related behaviour issues. Whole-exome sequencing revealed a de novo mosaic nonsense variant of the SNRPN gene (c.73C>T, p.R25X) in 10% of DNA isolated from buccal cells and 19% of DNA from patient-derived lymphoblast cells. DNA methylation study did not detect an abnormal methylation pattern in the SNRPN locus. Parental origin studies showed a paternal source of an intronic single-nucleotide polymorphism within the locus in proximity to the SNRPN variant. Conclusions This is the first report that provides evidence of a de novo point mutation of paternal origin in SNRPN as a new disease-causing mechanism for PWS. This finding suggests that gene sequencing should be considered as part of the diagnostic workup in patients with clinical suspicion of PWS. [ABSTRACT FROM AUTHOR]

Variants in the pleckstrin homology domain‐interacting protein (PHIP) gene are implicated in the clinical phenotype of Chung–Jansen syndrome, which includes dysmorphic features, cognitive dysfunction, aberrant behavior, and childhood onset obesity. Following a systematic literature review, 35 patients are reported to have unique PHIP variants impacting the encoded protein product. We summarize the status and frequency of these variants and relationship to clinical presentation. We also describe an additional patient with a rare, pathogenic variant due to a five base pair deletion leading to an altered codon at I307 but with a stop codon at 22 codons downstream; notably, a variant was identified at the same location as seen previously at protein position I307 in one other subject and a frameshift change at that protein position. We compare the clinical characteristics between the two patients and analyze whether certain types of gene defects impact clinical presentation in previously reported individuals. In addition, we predict structural protein models, which yielded unique differences between the wild‐type and I307P‐related mutant truncated proteins. Protein–protein interactions indicate involvement of POMC and related proteins with potential contribution to obesity, congenital, neuromuscular, and lipid disorders with heart, gastrointestinal, and rheumatoid diseases. With its surrounding proline‐rich region, the I307P point mutation increases susceptibility to conformational rigidity and thermodynamic stability, ultimately impacting function as well as a stop codon downstream. Furthermore, the frameshift mutation seen in our patient may result in a truncated protein with a short abnormal region prior to the stop codon due to a five base pair deletion at I307 or target the protein for nonsense‐mediated mRNA decay. [ABSTRACT FROM AUTHOR]

Competing Interests: Competing interests: None declared.

Purpose of Review: Prader-Willi (PWS) and Angelman (AS) syndromes arise from errors in 15q11-q13 imprinting. This review describes recent advances in genomics and how these expand our understanding of these rare disorders, guiding treatment strategies to improve patient outcomes., Recent Findings: PWS features include severe infantile hypotonia, failure to thrive, hypogonadism, developmental delay, behavioral and psychiatric features, hyperphagia, and morbid obesity, if unmanaged. AS presents severe intellectual disability, motor dysfunction, seizures, absent speech, and a characteristic happy demeanor. Standard-of-care testing involves SNRPN promoter methylation, chromosomal microarrays and genomic studies for individuals presenting these features. These tests identify syndromic-specific DNA methylation patterns and molecular genetic classes responsible for disease etiology. This review provides an update on studies of genotype-phenotype relationships and novel genomic technologies used for diagnostic purposes., Summary: We give an overview and update on the genetics and underlying mechanisms associated with symptoms and potential treatments with focus on features reported to be different between specific molecular genetic classes. The review also describes laboratory testing methods for screening and diagnosis of these imprinting disorders with implications for clinical practice., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)