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Canadian Respiratory Journal 2023Sleep-disordered breathing (SDB) is common in patients with Prader-Willi Syndrome (PWS). However, the prevalence of SDB varies widely between studies. Early...
INTRODUCTION
Sleep-disordered breathing (SDB) is common in patients with Prader-Willi Syndrome (PWS). However, the prevalence of SDB varies widely between studies. Early identification of SDB and factors contributing to its incidence is essential, particularly when considering growth hormone (GH) therapy.
OBJECTIVES
The aims of the study were to describe the prevalence and phenotypes of sleep-disordered breathing (SDB) in patients with Prader-Willi syndrome (PWS) and to determine the effects of age, gender, symptoms, GH therapy and body mass index on SDB severity.
METHODS
This study was a retrospective chart review of all patients with genetically confirmed Prader-Willi syndrome who underwent diagnostic overnight polysomnography (PSG) in the sleep laboratory at Sidra Medicine. Clinical and PSG data of enrolled patients were collected.
RESULTS
We identified 20 patients (nine males, eleven females) with PWS who had overnight sleep polysomnography (PSG) at a median age (IQR) of 5.83 (2.7-12) years. The median apnea-hypopnea index (AHI) was 8.55 (IQR 5.8-16.9) events/hour. The median REM-AHI was 27.8 (IQR 15-50.6) events/hour. The median obstructive apnea-hypopnea index (OAHI) was 7.29 (IQR 1.8-13.5) events/hour. The median central apnea-hypopnea index (CAHI) was 1.77 (IQR 0.6-4.1) events/hour. Nineteen patients (95%) demonstrated SDB by polysomnography (PSG) based on AHI ≥1.5 events/hour. Nine patients (45%) were diagnosed with obstructive sleep apnea (OSA). Three patients (15%) were diagnosed with central sleep apnea (CSA). Seven patients (35%) were diagnosed with mixed sleep apnea. No correlations were observed between AHI and age, gender, BMI, symptoms, or GH therapy. However, REM-AHI was significantly correlated with BMI (=0.031).
CONCLUSION
This study shows a high prevalence of SDB among our patients with PWS. Obstructive sleep apnea was the predominant phenotype. BMI was the only predictor for high REM-AHI. Further studies of large cohorts are warranted to define SDB in PWS and design the appropriate treatment.
Topics: Male; Female; Humans; Child, Preschool; Prader-Willi Syndrome; Retrospective Studies; Prevalence; Sleep Apnea Syndromes; Sleep Apnea, Obstructive
PubMed: 37927914
DOI: 10.1155/2023/9992668 -
Children (Basel, Switzerland) Oct 2023The goal of this manuscript is to present and summarize several rare pediatric syndromes (Zellweger syndrome, Kartagener syndrome, Prader-Willi syndrome,... (Review)
Review
The goal of this manuscript is to present and summarize several rare pediatric syndromes (Zellweger syndrome, Kartagener syndrome, Prader-Willi syndrome, Schinzel-Giedion syndrome, Fanconi anemia, Joubert-Boltshauser syndrome, Poretti-Boltshauser syndrome, and Langer-Giedion syndrome) who have been named after luminary "Swiss" physicians (pediatricians, pediatric neurologists, or pediatric radiologists) who recognized, studied, and published these syndromes. In this manuscript, a brief historical summary of the physicians is combined with the key clinical symptoms at presentation and the typical imaging findings. This manuscript is not aiming to give a complete comprehensive summary of the syndromes, nor does it ignore the valuable contributions of many "Swiss" scientists who are not included here, but focuses on several rare syndromes that benefit from imaging data.
PubMed: 37892331
DOI: 10.3390/children10101668 -
MedRxiv : the Preprint Server For... Sep 2023Recurrent copy number variants (rCNVs) are associated with increased risk of neuropsychiatric disorders but their pathogenic population-level impact is unknown. We...
Recurrent copy number variants (rCNVs) are associated with increased risk of neuropsychiatric disorders but their pathogenic population-level impact is unknown. We provide population-based estimates of rCNV-associated risk of neuropsychiatric disorders for 34 rCNVs in the iPSYCH2015 case-cohort sample (n=120,247). Most observed significant increases in rCNV-associated risk for ADHD, autism or schizophrenia were moderate (HR:1.42-5.00), and risk estimates were highly correlated across these disorders, the most notable exception being high autism-associated risk with Prader-Willi/Angelman Syndrome duplications (HR=20.8). No rCNV was associated with significant increase in depression risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint. Comparison with published rCNV studies suggests that prevalence of some rCNVs is higher, and risk of psychiatric disorders lower, than previously estimated. In an era where genetics is increasingly being clinically applied, our results highlight the importance of population-based risk estimates for genetics-based predictions.
PubMed: 37886536
DOI: 10.1101/2023.09.04.23294975 -
BioRxiv : the Preprint Server For... Oct 2023Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder characterized principally by initial symptoms of neonatal hypotonia and failure-to-thrive in infancy,...
Prader-Willi syndrome (PWS) is a rare neurodevelopmental disorder characterized principally by initial symptoms of neonatal hypotonia and failure-to-thrive in infancy, followed by hyperphagia and obesity. It is well established that PWS is caused by loss of paternal expression of the imprinted region on chromosome 15q11-q13. While most PWS cases exhibit megabase-scale deletions of the paternal chromosome 15q11-q13 allele, several PWS patients have been identified harboring a much smaller deletion encompassing primarily . This finding suggests is a direct driver of PWS phenotypes. The gene cluster is composed of 30 copies of individual C/D box small nucleolar RNAs (snoRNAs). Many C/D box snoRNAs have been shown to guide chemical modifications of other RNA molecules, often ribosomal RNA (rRNA). However, snoRNAs are termed 'orphans' because no verified targets have been identified and their sequences show no significant complementarity to rRNA. It is crucial to identify the targets and functions of snoRNAs because all reported PWS cases lack their expression. To address this, we engineered two different deletions modelling PWS in two distinct human embryonic stem cell (hESC) lines to control for effects of genetic background. Utilizing an inducible expression system enabled quick, reproducible differentiation of these lines into neurons. Systematic comparisons of neuronal gene expression across deletion types and genetic backgrounds revealed a novel list of 42 consistently dysregulated genes. Employing the recently described computational tool snoGloBe, we discovered these dysregulated genes are significantly enriched for predicted targeting versus multiple control analyses. Importantly, our results showed it is critical to use multiple isogenic cell line pairs, as this eliminated many spuriously differentially expressed genes. Our results indicate a novel gene regulatory network controlled by is likely perturbed in PWS patients.
PubMed: 37873184
DOI: 10.1101/2023.10.03.560773 -
Genetics in Medicine : Official Journal... Jan 2024Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the...
PURPOSE
Current and emerging treatments for Duchenne muscular dystrophy (DMD) position DMD as a candidate condition for newborn screening (NBS). In anticipation of the nomination of DMD for universal NBS, we conducted a prospective study under the Early Check voluntary NBS research program in North Carolina, United States.
METHODS
We performed screening for creatine kinase-MM (CK-MM), a biomarker of muscle damage, on residual routine newborn dried blood spots (DBS) from participating newborns. Total creatine kinase testing and next generation sequencing of an 86-neuromuscular gene panel that included DMD were offered to parents of newborns who screened positive. Bivariate and multivariable analyses were performed to assess effects of biological and demographic predictors on CK-MM levels in DBS.
RESULTS
We screened 13,354 newborns and identified 2 males with DMD. The provisional 1626 ng/mL cutoff was raised to 2032 ng/mL to improve specificity, and additional cutoffs (900 and 360 ng/mL) were implemented to improve sensitivity for older and low-birthweight newborns.
CONCLUSION
Population-scale screening for elevated CK-MM in DBS is a feasible approach to identify newborns with DMD. Inclusion of birthweight- and age-specific cutoffs, repeat creatine kinase testing after 72 hours of age, and DMD sequencing improve sensitivity and specificity of screening.
Topics: Male; Humans; Infant, Newborn; Muscular Dystrophy, Duchenne; Neonatal Screening; Birth Weight; North Carolina; Prospective Studies; Creatine Kinase
PubMed: 37864479
DOI: 10.1016/j.gim.2023.101009 -
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 -
Molecular Therapy. Methods & Clinical... Dec 2023Individuals with Prader-Willi syndrome (PWS) exhibit several metabolic and behavioral abnormalities associated with excessive food-seeking activity. PWS is thought to be...
Individuals with Prader-Willi syndrome (PWS) exhibit several metabolic and behavioral abnormalities associated with excessive food-seeking activity. PWS is thought to be driven in part by dysfunctional hypothalamic circuitry and blunted responses to peripheral signals of satiety. Previous work described a hypothalamic transcriptomic signature of individuals with PWS. Notably, PWS patients exhibited downregulation of genes involved in neuronal development and an upregulation of neuroinflammatory genes. Deficiencies of brain-derived neurotrophic factor (BDNF) and its receptor were identified as potential drivers of PWS phenotypes. Our group recently applied an adeno-associated viral (AAV)-BDNF gene therapy within a preclinical PWS model, -null mice, to improve metabolic and behavioral function. While this proof-of-concept project was promising, it remained unclear how AAV-BDNF was influencing the hypothalamic microenvironment and how its therapeutic effect was mediated. To investigate, we hypothalamically injected AAV-BDNF to wild type and -null mice and performed mRNA sequencing on hypothalamic tissue. Here, we report that (1) deficiency is associated with neuroinflammation in the hypothalamus and (2) AAV-BDNF gene therapy reverses this neuroinflammation. These data newly reveal -null mice as a valid model of PWS-related neuroinflammation and furthermore suggest that AAV-BDNF may modulate obesity-related neuroinflammatory phenotypes through direct or indirect means.
PubMed: 37766791
DOI: 10.1016/j.omtm.2023.09.004 -
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 -
Case Reports in Genetics 2023Loss of expression of paternally imprinted genes in the 15q11.2-q13 chromosomal region leads to the neurodevelopmental disorder Prader-Willi Syndrome (PWS). The PWS...
Loss of expression of paternally imprinted genes in the 15q11.2-q13 chromosomal region leads to the neurodevelopmental disorder Prader-Willi Syndrome (PWS). The PWS critical region contains four paternally expressed protein-coding genes along with small nucleolar RNA (snoRNA) genes under the control of the promoter, including the snoRNA gene cluster that is implicated in the PWS disease etiology. A 5-7 Mb deletion, maternal uniparental disomy, or an imprinting defect of chromosome 15q affect multiple genes in the PWS critical region, causing PWS. However, the individual contributions of these genes to the PWS phenotype remain elusive. Reports of smaller, atypical deletions may refine the boundaries of the PWS critical region or suggest additional disease-causing mechanisms. We describe an adult female with a classic PWS phenotype due to a 78 kb microdeletion that includes only exons 2 and 3 of with apparently preserved expression of .
PubMed: 37736297
DOI: 10.1155/2023/4225092