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Bone Reports Dec 2023The incidence of osteopenia and osteoporosis is of concern in adults with Prader-Willi syndrome (PWS). Walking generates reaction forces that could stimulate bone...
INTRODUCTION
The incidence of osteopenia and osteoporosis is of concern in adults with Prader-Willi syndrome (PWS). Walking generates reaction forces that could stimulate bone mineralization and is popular in people with PWS. This study compared bone parameters and ground reaction forces (GRF) during gait between young adults with PWS and without PWS and explored associations between bone and GRFs during gait.
METHODS
10 adults with PWS, 10 controls with obesity (OB) and 10 with normal weight (NW) matched on sex participated. Segmental and full body dual-energy x-ray absorptiometry scans provided femoral neck, spine, total body minus the head bone mineral density (BMD), bone mineral content (BMC). Vertical GRF, vertical impulse, posterior force and negative impulse were measured during 5 walking trials at a self-selected speed along a 10 m runway.
RESULTS
Multivariate analyses of variance showed that adults with PWS ( = 7-8) had hip and body BMD and BMC comparable ( > .050) to NW and lower ( < .050) than OB. Adults with PWS showed slower speed than NW (p < .050) but similar to OB ( > .050). Adults with PWS presented lower absolute vertical GRF, vertical impulse and negative impulse than OB ( < .050). Pearson r correlations ( < .050) in those with PWS (n = 7-8) indicated that femoral neck BMC was associated with vertical GRF ( = 0.716), vertical impulse ( = 0.780), posterior force ( = -0.805), and negative impulse ( = -0.748). Spine BMC was associated with speed ( = 0.829) and body BMD was associated with speed ( = 0.893), and posterior force ( = -0.780).
CONCLUSIONS
Increased BMC in the femoral neck and body were associated with larger breaking forces during walking, a phenomenon normally observed at greater gait speeds. Faster walking speed was associated with greater BMC in the spine and body. Our preliminary results suggest that young adults with PWS could potentially benefit from faster walking for bone health; however, larger prospective studies are needed to confirm this.
PubMed: 37520935
DOI: 10.1016/j.bonr.2023.101700 -
Frontiers in Neuroscience 2024
PubMed: 38476870
DOI: 10.3389/fnins.2024.1370030 -
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 -
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 -
Orphanet Journal of Rare Diseases Jun 2024Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in...
BACKGROUND
Prader-Willi syndrome (PWS) is a genetic disorder characterized by abnormalities in the 15q11-q13 region. Understanding the correlation between genotype and phenotype in PWS is crucial for improved genetic counseling and prognosis. In this study, we aimed to investigate the correlation between genotype and phenotype in 45 PWS patients who previously underwent methylation-sensitive high-resolution melting (MS-HRM) for diagnosis.
RESULTS
We employed methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and Sanger sequencing, along with collecting phenotypic data from the patients for comparison. Among the 45 patients, 29 (64%) exhibited a deletion of 15q11-q13, while the remaining 16 (36%) had uniparental disomy. No statistically significant differences were found in the main signs and symptoms of PWS. However, three clinical features showed significant differences between the groups. Deletion patients had a higher prevalence of myopia than those with uniparental disomy, as well as obstructive sleep apnea and an unusual skill with puzzles.
CONCLUSIONS
The diagnostic tests (MS-HRM, MS-MLPA, and Sanger sequencing) yielded positive results, supporting their applicability in PWS diagnosis. The study's findings indicate a general similarity in the genotype-phenotype correlation across genetic subtypes of PWS.
Topics: Humans; Prader-Willi Syndrome; Female; Male; Genotype; Phenotype; Brazil; Child, Preschool; Child; Adolescent; Adult; Uniparental Disomy; Chromosomes, Human, Pair 15; Infant; Young Adult
PubMed: 38902749
DOI: 10.1186/s13023-024-03157-2 -
International Journal of Molecular... Sep 2023Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the... (Review)
Review
Growth hormone (GH) is a peptide hormone that plays a crucial role in controlling growth, development, and lifespan. Molecular regulation of GH is accomplished via the (), which is the main factor influencing human development and is essential to optimal functioning of the GH/IGF-I axis. Two GHR isoforms have been studied, according to the presence (flGHR) or absence (d3GHR) of exon 3. The d3GHR isoform, which lacks exon 3 has recently been related to longevity; individuals carrying this isoform have higher receptor activity, improved signal transduction, and alterations in the treatment response and efficacy compared with those carrying the wild type (WT) isoform (flGHR). Further, studies performed in patients with acromegaly, Prader-Willi syndrome, Turner syndrome, small for gestational age (SGA), and growth hormone deficiency (GHD) suggested that the d3GHR isoform may have an impact on the relationship between GH and IGF-I levels, height, weight, BMI, and other variables. Other research, however, revealed inconsistent results, which might have been caused by confounding factors, including limited sample sizes and different experimental methods. In this review, we lay out the complexity of the GHR isoforms and provide an overview of the major pharmacogenetic research conducted on this ongoing and unresolved subject.
PubMed: 37762211
DOI: 10.3390/ijms241813908 -
American Journal of Medical Genetics.... Jun 2024Prader-Willi syndrome (PWS) is the most common genetic syndrome with obesity and results from loss of expression of paternally inherited genes on chromosome 15q11-q13 by...
Prader-Willi syndrome (PWS) is the most common genetic syndrome with obesity and results from loss of expression of paternally inherited genes on chromosome 15q11-q13 by a variety of mechanisms which include large deletions (70%-75%), maternal uniparental disomy (UPD) (20%-30%), and imprinting defects (2%-5%) or balanced translocations. Individuals often have a characteristic behavior disorder with mild intellectual disability, infantile hypotonia associated with poor sucking, short stature, and obesity. PWS is characterized by hypothalamic-pituitary axis dysfunction with growth hormone (GH) deficiency, hypogonadism, and several other hormonal deficiencies resulting in short stature, centrally driven excessive appetite (hyperphagia), central obesity, cryptorchidism, and decreased lean body mass. In this study, we determined and sought differences in the incidence of thyroid abnormalities among the common genetic subtypes in a cohort of 52 subjects with PWS because there was limited literature available. We also sought the effects of growth hormone (GH) treatment on the thyroid profile. Fifty-two subjects with a genetically confirmed diagnosis of PWS were included in this study at the University of California, Irvine. Blood samples for baseline thyroxine stimulating hormone (TSH) and free thyroxine (fT4) levels were obtained in the morning after an overnight fast for 8-12 h. Statistical analyses were performed with SPSS (SPSS Inc., 21.0). Mean values were analyzed by one-way ANOVA, and student's t-test and statistical significance were set at p < 0.05. The subjects included 26 males and 26 females with an age range of 3-38 years. There were 29 subjects with chromosome 15q11-q13 deletions and 23 with UPD; 28 were GH treated currently or in the past, and 24 never received GH. There was no significant difference in age or body mass index (BMI) (kg/m2) between GH-treated versus non-GH-treated groups. BMI was higher in the deletion group compared to the UPD group (p = 0.05). We identified two individuals who were clinically diagnosed and treated for hypothyroidism, one of whom was on GH supplements. We identified two additional individuals with subclinical hypothyroidism who were not on GH treatment, giving a frequency of 7.6% (4/52) in this cohort of patients. We did not find significant differences in thyroid function (TSH) in the deletion versus UPD groups. We found significant differences in thyroid function, however, between GH-treated and non-GH-treated groups. The mean TSH was lower (2.25 ± 1.17 uIU/M, range 0.03-4.92 uIU/M versus 2.80 ± 1.44 uIU/M, range 0.55-5.33 uIU/M respectively, p = 0.046), and the free T4 levels were significantly higher (1.13 ± 0.70 and 1.03 ± 0.11 ng/dL, respectively, p = 0.05) in the GH-treated individuals compared to non-GH-treated individuals. In this cohort of subjects with PWS, we identified two previously diagnosed individuals with hypothyroidism and two individuals with subclinical hypothyroidism (4/52, 7.6%), three of whom were not receiving GH treatment. We did not find any significant differences in thyroid function between molecular subtypes; however, we found that euthyroid status (lower TSH levels and higher free T4 levels) was significantly higher in individuals who were treated with GH compared to the untreated group. We recommend that individuals with PWS should be screened regularly for thyroid deficiency and start treatment early with GH in view of the potentially lower incidence of thyroid deficiency.
PubMed: 38837660
DOI: 10.1002/ajmg.a.63724 -
Child: Care, Health and Development Jul 2024The 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...
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.
Topics: Humans; Prader-Willi Syndrome; Male; Female; Adult; Adolescent; Child; Young Adult; Projective Techniques; Emotions
PubMed: 38829287
DOI: 10.1111/cch.13289 -
BMC Bioinformatics Feb 2024DNA methylation is one of the most stable and well-characterized epigenetic alterations in humans. Accordingly, it has already found clinical utility as a molecular...
BACKGROUND
DNA methylation is one of the most stable and well-characterized epigenetic alterations in humans. Accordingly, it has already found clinical utility as a molecular biomarker in a variety of disease contexts. Existing methods for clinical diagnosis of methylation-related disorders focus on outlier detection in a small number of CpG sites using standardized cutoffs which differentiate healthy from abnormal methylation levels. The standardized cutoff values used in these methods do not take into account methylation patterns which are known to differ between the sexes and with age.
RESULTS
Here we profile genome-wide DNA methylation from blood samples drawn from within a cohort composed of healthy controls of different age and sex alongside patients with Prader-Willi syndrome (PWS), Beckwith-Wiedemann syndrome, Fragile-X syndrome, Angelman syndrome, and Silver-Russell syndrome. We propose a Generalized Additive Model to perform age and sex adjusted outlier analysis of around 700,000 CpG sites throughout the human genome. Utilizing z-scores among the cohort for each site, we deployed an ensemble based machine learning pipeline and achieved a combined prediction accuracy of 0.96 (Binomial 95% Confidence Interval 0.868[Formula: see text]0.995).
CONCLUSION
We demonstrate a method for age and sex adjusted outlier detection of differentially methylated loci based on a large cohort of healthy individuals. We present a custom machine learning pipeline utilizing this outlier analysis to classify samples for potential methylation associated congenital disorders. These methods are able to achieve high accuracy when used with machine learning methods to classify abnormal methylation patterns.
Topics: Humans; Genomic Imprinting; DNA Methylation; Beckwith-Wiedemann Syndrome; Silver-Russell Syndrome; Supervised Machine Learning
PubMed: 38347515
DOI: 10.1186/s12859-024-05673-1 -
JAMA Psychiatry Jun 2024Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is...
IMPORTANCE
Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies, but their population-level impact is unknown.
OBJECTIVE
To provide unbiased population-based estimates of prevalence and risk associated with psychiatric disorders for rCNVs and to compare risks across outcomes, rCNV dosage type (deletions or duplications), and locus features.
DESIGN, SETTING, AND PARTICIPANTS
This genetic association study is an analysis of data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) case-cohort sample of individuals born in Denmark in 1981-2008 and followed up until 2015, including (1) all individuals (n = 92 531) with a hospital discharge diagnosis of attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder, major depressive disorder (MDD), or schizophrenia spectrum disorder (SSD) and (2) a subcohort (n = 50 625) randomly drawn from the source population. Data were analyzed from January 2021 to August 2023.
EXPOSURES
Carrier status of deletions and duplications at 27 autosomal rCNV loci was determined from neonatal blood samples genotyped on single-nucleotide variant microarrays.
MAIN OUTCOMES AND MEASURES
Population-based rCNV prevalence was estimated with a survey model using finite population correction to account for oversampling of cases. Hazard ratio (HR) estimates and 95% CIs for psychiatric disorders were derived using weighted Cox proportional hazard models. Risks were compared across outcomes, dosage type, and locus features using generalized estimating equation models.
RESULTS
A total of 3547 rCNVs were identified in 64 735 individuals assigned male at birth (53.8%) and 55 512 individuals assigned female at birth (46.2%) whose age at the end of follow-up ranged from 7.0 to 34.7 years (mean, 21.8 years). Most observed increases in rCNV-associated risk for ADHD, ASD, or SSD were moderate, and risk estimates were highly correlated across these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and community-based studies revealed a higher prevalence of deletions and lower associated increase in risk for several rCNVs in iPSYCH2015.
CONCLUSIONS AND RELEVANCE
This study found that several rCNVs were more prevalent and conferred less risk of psychiatric disorders than estimated previously. Most case-control studies overestimate rCNV-associated risk of psychiatric disorders, likely because of selection bias. In an era where genetics is increasingly being clinically applied, these results highlight the importance of population-based risk estimates for genetics-based predictions.
PubMed: 38922630
DOI: 10.1001/jamapsychiatry.2024.1453