-
Obesity Science & Practice Aug 2023Prader-Willi syndrome (PWS) is the most frequently diagnosed genetic cause of early childhood obesity. Individuals with PWS typically progress through 7 different...
OBJECTIVE
Prader-Willi syndrome (PWS) is the most frequently diagnosed genetic cause of early childhood obesity. Individuals with PWS typically progress through 7 different nutritional phases during their lifetime. The main objective of this study was to assess potential factors, particularly insulin, that may be responsible for the weight gains in sub-phase 2a and their role in the subsequent increase in fat mass and obesity in sub-phase 2b and insatiable appetite in phase 3.
METHODS
Fasting plasma insulin levels were measured in children with PWS between the ages of 0-12 years and in age-matched non-PWS participants with early-onset major (clinically severe) obesity (EMO) and in healthy-weight sibling controls (SC).
RESULTS
Participants with PWS in nutritional phases 1a and 1b had plasma insulin levels comparable to SC. However, the transition from phase 1b up to phase 3 in the PWS group was accompanied by significant increases in insulin, coinciding in weight gains, obesity, and hyperphagia. Only individuals with PWS in phase 3 had comparable insulin levels to the EMO group who were higher than the SC group at any age.
CONCLUSIONS
Elevated insulin signaling is a probable trigger for weight gain and onset of hyperphagia in children with Prader-Willi syndrome. Regulating insulin levels early in childhood before the onset of the early weight gain may be key in modulating the onset and severity of obesity and hyperphagia in individuals with PWS, as well as in other young children with non-PWS early-onset obesity. Preventing or reversing elevated insulin levels in PWS with pharmacological agents and/or through diet restrictions such as a combined low carbohydrate, low glycemic-load diet may be a viable therapeutic strategy in combating obesity in children with PWS and others with early childhood obesity.
PubMed: 37546289
DOI: 10.1002/osp4.663 -
Journal of Applied Research in... Jul 2024Prader-Willi syndrome (PWS) is commonly associated with intellectual disability, but also with a specific behavioural phenotype and a high predisposition to psychiatric...
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.
Topics: Humans; Prader-Willi Syndrome; Male; Female; Adult; Mental Disorders; Middle Aged; Young Adult; Germany; Comorbidity; Adolescent; Psychotropic Drugs; Mental Health Services; Patient Acceptance of Health Care
PubMed: 38863266
DOI: 10.1111/jar.13266 -
Frontiers in Endocrinology 2023Spinal kinematics/motion are reported to be altered in adolescents and adults with essential obesity, while no information is available in patients with Prader-Willi...
INTRODUCTION
Spinal kinematics/motion are reported to be altered in adolescents and adults with essential obesity, while no information is available in patients with Prader-Willi syndrome so far. The aim of this study was to examine cross-sectionally the characteristics of spinal postures and mobility in 34 patients with PWS, in 35 age- and sex-matched adults with essential obesity, and in 37 normal-weight individuals.
METHODS
Spinal posture and mobility were assessed using a radiation-free back scan, the Idiag M360 (Idiag, Fehraltorf, Switzerland). Differences in spinal posture and mobility between the three groups were determined using a two-way analysis of variance.
RESULTS
Adults with Prader-Willi syndrome had greater thoracic kyphosis [difference between groups (Δ) = 9.6, 95% CI 3.3 to 15.6, p = 0.001], less lumbar lordosis (Δ = -6.5, 95% CI -12.7 to -0.3, p = 0.03) as well as smaller lumbar and hip mobility than those with normal weight.
DISCUSSION
Although the characteristics of the spine in patients with Prader-Will syndrome appear to be similar to that found in subjects with essential obesity, Prader-Willi syndrome was found to influence lumbar movements more than thoracic mobility. These results provide relevant information about the characteristics of the spine in adults with Prader-Willi syndrome to be taken into careful consideration in the management of spinal conditions. These findings also highlight the importance of considering the musculoskeletal assessment of spinal postures and approaches targeting spinal and hip flexibility in adults with Prader-Willi syndrome.
Topics: Adolescent; Humans; Adult; Prader-Willi Syndrome; Obesity; Posture; Switzerland
PubMed: 37800136
DOI: 10.3389/fendo.2023.1235030 -
Child: Care, Health and Development Jan 2024Caring for individuals with rare diseases can be challenging and represent a burden. Nevertheless, this has been scarcely explored in Prader-Willi syndrome (PWS)....
INTRODUCTION
Caring for individuals with rare diseases can be challenging and represent a burden. Nevertheless, this has been scarcely explored in Prader-Willi syndrome (PWS). Therefore, we sought to explore the psychological impact of caregiving, as well as the differences between main caregivers and other family members.
METHODS
Different evaluation tools and scales were used taking into consideration the impact on caregivers. The scales were administered to those relatives who are immersed in the usual dynamics of the patient, differentiating between the main caregiver and other relatives living in the family home.
RESULTS
A total of 33 families of patients with genetic confirmation of PWS were included. In this survey, 32% of primary caregivers reported a high probability of anxiety, compared with 19% of non-primary caregivers (p = 0.27). Concerning depression, 40% of primary caregivers related possible or probable cases of depression compared with non-primary caregivers 13% (p = 0.04). Regarding caregiver burden evaluated using the Zarit scale, 61% of the main caregivers presented high levels of overload, compared with 29% of the other relatives (p = 0.005). Family functioning evaluated using the APGAR scale showed a total lower response from primary caregivers, but no statistically relevant results were found [25.4 ± 6.7 vs. 26.0 ± 8.2 (p = 0.72)].
CONCLUSION
In this study, we observed that caring for people with PWS can have a significant effect on the mental health, burden and quality of life of caregivers, with a greater impact among primary caregivers compared with the other living relatives.
Topics: Humans; Prader-Willi Syndrome; Mental Health; Quality of Life; Caregivers; Anxiety
PubMed: 37614065
DOI: 10.1111/cch.13162 -
European Journal of Endocrinology Jul 2023Most patients with Prader-Willi syndrome (PWS) have mild to moderate cognitive impairment. Growth hormone (GH) treatment has positive short- and long-term effects on...
CONTEXT
Most patients with Prader-Willi syndrome (PWS) have mild to moderate cognitive impairment. Growth hormone (GH) treatment has positive short- and long-term effects on cognition in children with PWS. Few studies, however, have investigated the effects of GH on cognitive functioning in adults with PWS.
OBJECTIVE
To investigate the effects of 3 years of GH treatment on cognitive functioning and behavior in young adults with PWS who were treated with GH during childhood.
DESIGN
Open-label, prospective study.
SETTING
Dutch PWS Reference Center.
METHODS
Patients were treated with 0.33 mg GH/m²/day (∼0.012 mg/kg/day; 33% of childhood dose). Cognitive functioning was measured by Wechsler Adult Intelligence (WAIS) tests. Behavior was studied by a developmental behavior checklist-parents/caregivers (DBC-P).
RESULTS
Forty-six young adults with PWS with a median age of 19 (IQR 17-21) years were investigated. Estimated mean (95% CI) total, verbal, and performance IQ remained stable during 3 years of GH-treatment. Total IQ being 66 (63-69) at the start and 67 (64-71) after 3 years (P = .30); Verbal IQ being 65 (62-68) and 66 (62-70), respectively (P = .31) and performance IQ being 67 (63-70) and 67 (63-72) resp. (P = .42). Estimated mean Total DBC score did not significantly change during 3 years of GH-treatment, being 36.3 at start and 36.5 after 3 years (P = .94) (P50).
CONCLUSIONS
Three years of GH-treatment in young adults with PWS with 33% of the pediatric dose, maintains total, verbal, and performance IQ. The emotional and behavioral disturbances remained stable and were similar compared to peers with other intellectual disabilities.
Topics: Humans; Child; Young Adult; Adolescent; Adult; Growth Hormone; Prader-Willi Syndrome; Prospective Studies; Human Growth Hormone; Cognition
PubMed: 37440711
DOI: 10.1093/ejendo/lvad084 -
Frontiers in Medicine 2023Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on...
Register-based and genetic studies of Prader-Willi syndrome show a high frequency of gonadal tumors and a possible mechanism for tumorigenesis through imprinting relaxation.
Prader-Willi syndrome (PWS) is a rare disease caused by a lack of expression of inherited imprinted genes in the paternally derived Prader-Willi critical region on chromosome 15q11.2-q13. It is characterized by poor feeding and hypotonia in infancy, intellectual disability, behavioral abnormalities, dysmorphic features, short stature, obesity, and hypogonadism. PWS is not a known cancer predisposition syndrome, but previous investigations regarding the prevalence of cancer in these patients suggest an increased risk of developing specific cancer types such as myeloid leukemia and testicular cancer. We present the results from a Swedish national population-based cohort study of 360 individuals with PWS and 18,000 matched comparisons. The overall frequency of cancer was not increased in our PWS cohort, but we found a high frequency of pediatric cancers. We also performed whole-genome sequencing of blood- and tumor-derived DNAs from a unilateral dysgerminoma in a 13-year-old girl with PWS who also developed bilateral ovarian sex cord tumors with annular tubules. In germline analysis, there were no additional findings apart from the 15q11.2-q13 deletion of the paternal allele, while a pathogenic activating mutation was identified in the tumor. Additionally, methylation-specific multiplex ligation-dependent probe amplification revealed reduced methylation at the PWS locus in the dysgerminoma but not in the blood. In conclusion, our register-based study suggests an increased risk of cancer at a young age, especially testicular and ovarian tumors. We found no evidence of a general increase in cancer risk in patients with PWS. However, given our limited observational time, further studies with longer follow-up times are needed to clarify the lifetime cancer risk in PWS. We have also described the second case of locus-specific loss-of-imprinting in a germ cell tumor in PWS, suggesting a possible mechanism of carcinogenesis.
PubMed: 37575996
DOI: 10.3389/fmed.2023.1172565 -
Acta Neuropathologica Mar 2024Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder of genetic etiology, characterized by paternal deletion of genes located at chromosome 15 in 70% of...
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.
Topics: Humans; Mice; Animals; Prader-Willi Syndrome; Microglia; Carrier Proteins; Phenotype; Phagosomes; Adaptor Proteins, Signal Transducing
PubMed: 38556574
DOI: 10.1007/s00401-024-02714-0 -
Clinical Genetics Apr 2024The genotype-phenotype relationship in PWS patients is important for a better understanding of the clinical phenotype and clinical characteristics of different genotypes...
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.
Topics: Child; Pregnancy; Female; Humans; Prader-Willi Syndrome; Uniparental Disomy; Phenotype; Hyperphagia; Hypopigmentation; Genetic Association Studies; China; Epilepsy; Chromosomes, Human, Pair 15
PubMed: 38258470
DOI: 10.1111/cge.14477 -
Obesity (Silver Spring, Md.) Feb 2024This study assessed the effect of 1-year administration of diazoxide choline extended-release tablet (DCCR) on hyperphagia and other complications of Prader-Willi...
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.
Topics: Humans; Child, Preschool; Prader-Willi Syndrome; Diazoxide; Hyperphagia; Body Composition; Insulin
PubMed: 37919617
DOI: 10.1002/oby.23928 -
Neuroradiology Jan 2024Prader-Willi syndrome (PWS) suffers from brain functional reorganization and developmental delays during childhood, but the underlying neurodevelopmental mechanism is...
PURPOSE
Prader-Willi syndrome (PWS) suffers from brain functional reorganization and developmental delays during childhood, but the underlying neurodevelopmental mechanism is unclear. This paper aims to investigate the intra- and internetwork functional connectivity (FC) changes, and their relationships with developmental delays in PWS children.
METHODS
Resting-state functional magnetic resonance imaging datasets of PWS children and healthy controls (HCs) were acquired. Independent component analysis was used to acquire core resting-state networks (RSNs). The intra- and internetwork FC patterns were then investigated.
RESULTS
In terms of intranetwork FC, children with PWS had lower FC in the dorsal attention network, the auditory network, the medial visual network (VN) and the sensorimotor network (SMN) than HCs (FWE-corrected, p < 0.05). In terms of internetwork FC, PWS children had decreased FC between the following pairs of regions: posterior default mode network (DMN) and anterior DMN; posterior DMN and SMN; SMN and posterior VN and salience network and medial VN (FDR-corrected, p < 0.05). Partial correlation analyses revealed that the intranetwork FC patterns were positively correlated with developmental quotients in PWS children, while the internetwork FC patterns were completely opposite (p < 0.05). Intranetwork FC patterns showed an area under the receiver operating characteristic curve of 0.947, with a sensitivity of 96.15% and a specificity of 81.25% for differentiating between PWS and HCs.
CONCLUSION
Impaired intra- and internetwork FC patterns in PWS children are associated with developmental delays, which may result from neural pathway dysfunctions. Intranetwork FC reorganization patterns can discriminate PWS children from HCs.
REGISTRATION NUMBER ON THE CHINESE CLINICAL TRAIL REGISTRY
ChiCTR2100046551.
Topics: Child; Humans; Prader-Willi Syndrome; Brain Mapping; Magnetic Resonance Imaging; Nerve Net; Brain
PubMed: 38001311
DOI: 10.1007/s00234-023-03259-x