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Frontiers in Psychiatry 2024Children with neurogenetic syndromes commonly experience significant and pervasive sleep disturbances, however, associations with caregiver mental health remains...
When they just don't sleep: differential impacts of reduced child sleep on depression, anxiety, and stress among caregivers of children with and without neurogenetic syndromes.
INTRODUCTION
Children with neurogenetic syndromes commonly experience significant and pervasive sleep disturbances, however, associations with caregiver mental health remains unclear. Previous studies have linked sleep disturbances with increased caregiver depression in typically developing populations, and heightened caregiver stress among neurogenetic populations. The present study expands on findings by exploring the longitudinal association between child sleep duration and caregiver mental health (depression, anxiety, stress) throughout development (infancy to school-aged children) in dyads with and without a child affected by a neurogenetic syndrome.
METHODS
Participants were drawn from the Purdue Early Phenotype Study, including 193 caregivers (Age: = 34.40 years, = 4.53) of children with neurogenetic syndromes (Age: = 40.91 months, =20.72) and typically developing children (n = 55; Age: = 36.71 months, = 20.68). Children in the neurogenetic group were diagnosed with Angelman (n = 49), Prader Willi (n = 30), Williams (n = 51), and Fragile X (n = 8) syndromes. Caregivers completed assessments every six months up to child age three, and annual assessments thereafter. Child sleep duration was measured using the Brief Infant Sleep Questionnaire, and caregiver internalizing symptoms were assessed using the Depression, Anxiety, Stress Scale. Multilevel models were conducted to examine caregiver depression, anxiety, and stress in relation to child sleep duration at both between- and within-person levels, with child age as a moderator.
RESULTS
Results indicated a between-person effect of child sleep duration on caregiver depression (i.e., differences between families) and a within-person effect on caregiver stress (i.e., change over time) in the full, combined sample. These effects were not maintained when examined separately in neurogenetic and typically developing groups, except for a between-person effect on caregiver stress in the typically developing cohort. Moderating effects of child age were significant for depression and stress only in the typically developing cohort.
DISCUSSION
In summary, persistent child sleep disruptions were linked to exacerbated caregiver depression across the sample, while acute child sleep disruptions exacerbate caregiver stress within dyads over time. These findings emphasize the importance of addressing child sleep to enhance caregiver wellbeing and has potential relevance for a wide range of neurogenetic syndromes.
PubMed: 38707621
DOI: 10.3389/fpsyt.2024.1352881 -
Cureus Apr 2024Prader-Willi syndrome (PWS) is an exceedingly rare congenital syndrome of chromosome 15 that presents multiple comorbidities in said individuals. The associated quality...
Prader-Willi syndrome (PWS) is an exceedingly rare congenital syndrome of chromosome 15 that presents multiple comorbidities in said individuals. The associated quality of life for those with the disease is often severely diminished; more tragically, mortality associated with the disease is also increased. Pulmonary embolism (PE) is highly associated with mortality and has been shown to be more prevalent in patients with PWS. This case report details a patient with PWS who survived an acute saddle PE and looks to bring more clinical knowledge that can be applied when dealing with individuals with PWS.
PubMed: 38699101
DOI: 10.7759/cureus.57466 -
Journal of Neurodevelopmental Disorders Apr 2024Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region,...
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).
Topics: Humans; Prader-Willi Syndrome; Female; Male; Hyperphagia; Child; Adult; Adolescent; Diazoxide; Young Adult; Delayed-Action Preparations; Child, Preschool; Cohort Studies
PubMed: 38671361
DOI: 10.1186/s11689-024-09536-x -
Growth Hormone & IGF Research :... Jun 2024Prader-Willi syndrome (PWS) is a rare genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioral challenges, cognitive...
UNLABELLED
Prader-Willi syndrome (PWS) is a rare genetic disorder typically characterized by body composition abnormalities, hyperphagia, behavioral challenges, cognitive dysfunction, and hormone deficiencies. Hypogonadism is common but knowledge on potential side effects of testosterone replacement is limited, in particular, the long-term effects on behavior and PSA.
PATIENTS AND METHODS
Retrospective case studies of seven men, median age 46 years, with genetically verified PWS, testosterone treated hypogonadism and available PSA values were included. Long-term follow-up of PSA was accessible in four patients. Medical records were reviewed for adverse effects.
RESULTS
Five men were treated with intramuscular testosterone undecanoate, two had no hypogonadism. Median PSA was 0.68 μg/L (0.23-1.3), median testosterone 15 nmol/L. After a median time of 17 years of testosterone replacement median PSA was 0.75 μg/L (range 0.46-1.4). Testosterone replacement was well tolerated, and no major behavioral changes were reported. Five were treated with growth hormone for >20 years.
CONCLUSION
Levels of PSA were low. Long-term treatment with testosterone was working well and did not result in any clinically meaningful increase in PSA. Our results indicate that testosterone replacement is neither associated with serious adverse events regarding changes in behavior or effect on PSA. However, larger studies are needed to confirm our results.
Topics: Humans; Male; Prader-Willi Syndrome; Prostate-Specific Antigen; Testosterone; Retrospective Studies; Middle Aged; Adult; Hypogonadism; Hormone Replacement Therapy; Follow-Up Studies
PubMed: 38669801
DOI: 10.1016/j.ghir.2024.101593 -
European Journal of Translational... Apr 2024Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by hypothalamic dysfunction, hypotonia, cognitive deficits, and hyperphagia, primarily resulting...
Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by hypothalamic dysfunction, hypotonia, cognitive deficits, and hyperphagia, primarily resulting from genetic abnormalities on chromosome 15. Among its varied manifestations, musculoskeletal issues, notably scoliosis, pose important challenges in management. This study aims to investigate differences in postural-motor development and spinal range of movement between preadolescents and adolescents with PWS, with and without scoliosis, while also exploring the potential impact of scoliosis on caregiving burden, an aspect yet to be thoroughly explored in existing literature. This observational study evaluated 13 individuals diagnosed with PWS, including 5 with scoliosis (PWS-Sc) and 7 without (PWS-NSc). Inclusion criteria comprised ages 8 to 18 years, confirmed PWS diagnosis through genetic testing, and scoliosis diagnosis. Anamnestic data, physical examinations, and surface measurements were collected, along with parental burden assessments using the Zarit Burden Interview (ZBI). Both groups displayed delays in achieving postural-motor milestones, with the PWS-Sc group exhibiting a more pronounced delay, although statistical significance was not achieved. The main curve magnitude in the PWS-Sc group averaged 31.5° Cobb, with 60% of cases presenting an S-shaped curve. Surface measurements of physiological curves did not differ significantly between groups, but the scoliosis-affected group exhibited lower lumbar extension values (p=0.04). The overall ZBI revealed higher scores in the PWS-Sc group, although statistical significance was not reached. However, significant differences were observed in single questions score evaluating aspects such as social life and caregiver uncertainty (p=0.04 and p=0.03, respectively). Despite the small sample size, delays in achieving postural-motor milestones, particularly in individuals with scoliosis, were observed. The differences recorded in lumbo-pelvic movement suggest that tailored interventions may be beneficial. The heightened caregiving burden in the scoliosis group underscores the need for targeted support. Early intervention and ongoing monitoring should be important for accurate diagnosis and appropriate care, potentially with psychological support for caregivers.
PubMed: 38651535
DOI: 10.4081/ejtm.2024.12533 -
Cureus Mar 2024This case emphasizes the complexity of Prader-Willi syndrome (PWS), the need for a collaborative approach from specialists, and a closer look at the various...
This case emphasizes the complexity of Prader-Willi syndrome (PWS), the need for a collaborative approach from specialists, and a closer look at the various cardiovascular complexities associated with this syndrome. While current treatments focus on managing symptoms, ongoing genetic research offers hope for more favorable outcomes. Further studies are crucial to gauge the effectiveness of these treatments for PWS patients. We detail a patient with a complex medical history of PWS, further complicated by congenital heart disease with Eisenmenger's syndrome, diabetes mellitus, pulmonary hypertension, venous insufficiency, hypothyroidism, and hyperlipidemia. Reported in this study is a compilation of clinical data as well as suggestions from several medical specialists in applying a multifaceted approach to treatment, significantly emphasizing the need for interdisciplinary care and management of patients experiencing a combination of various medical issues with an emphasis on cardiovascular complications.
PubMed: 38646247
DOI: 10.7759/cureus.56591 -
Biochimica Et Biophysica Acta.... Jun 2024Loss of prolyl endopeptidase-like (PREPL) encoding a serine hydrolase with (thio)esterase activity leads to the recessive metabolic disorder Congenital Myasthenic...
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 mice. In addition, the hypothalamic-pituitary axis is similarly affected in both Prepl and PWS-IC 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.
Topics: Animals; Humans; Prader-Willi Syndrome; Mice; Myasthenic Syndromes, Congenital; Mice, Knockout; HEK293 Cells; Prolyl Oligopeptidases; Fibroblasts; Mitochondria; Metabolic Networks and Pathways; Disease Models, Animal; Ubiquinone; Serine Endopeptidases; Male; Female
PubMed: 38626828
DOI: 10.1016/j.bbadis.2024.167175 -
Brain and Behavior Apr 2024The 15q11-q13 region is a genetic locus with genes subject to genomic imprinting, significantly influencing neurodevelopment. Genomic imprinting is an epigenetic...
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.
Topics: Humans; Female; Male; Animals; Mice; DNA Copy Number Variations; Alleles; Angelman Syndrome; Prader-Willi Syndrome; Bangladesh; Mammals
PubMed: 38616334
DOI: 10.1002/brb3.3437 -
Research in Developmental Disabilities Jun 2024Good postural stability control is dependent upon the complex integration of incoming sensory information (visual, somatosensory, vestibular) with neuromotor responses...
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 (χ (1) = 7.468, p = .006). Group differences in frequency of repeated falls also approached significance in conditions 5 (χ (3) = 4.630, p = .099) and 6 (χ (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.
Topics: Humans; Prader-Willi Syndrome; Child; Female; Male; Postural Balance; Cross-Sectional Studies; Accidental Falls; Case-Control Studies; Visual Perception; Pediatric Obesity
PubMed: 38615631
DOI: 10.1016/j.ridd.2024.104730