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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 -
European Spine Journal : Official... Jun 2024Prader-Willi syndrome (PWS) represents a difficult challenge for spine surgeons, due to the association of a structural scoliosis, with a prevalence between 15 and 86%....
INTRODUCTION
Prader-Willi syndrome (PWS) represents a difficult challenge for spine surgeons, due to the association of a structural scoliosis, with a prevalence between 15 and 86%. Conservative therapy is a viable option, but surgery is increasingly becoming the treatment of choice.
METHODS
The authors reviewed a series of 15 patients affected by PWS treated at their institution between 2008 and 2023. The mean age at index treatment was 9 years and 3 months (range 1-15 years) with a prevalence of female subjects. Primary scoliotic curve ranged from 14 to 102°, and mean thoracic kyphosis was 56° (range 20-75°). Eleven patients underwent conservative treatment, while four were treated surgically.
RESULTS
Mean follow-up was 5 years and 3 months (range 2-12 years). Among the 11 patients treated conservatively, only two showed improvements of the coronal curve, while the remaining nine displayed a worsening of the deformity during follow-up. Complication rate after surgery was 75%. One patient developed paraplegia after pedicle screw positioning. One patient displayed rod breakage and PJK that required revision surgery proximally. Hardware deep infection was seen in one case where it was necessary to proceed with instrumentation removal after 10 years.
DISCUSSION AND CONCLUSIONS
Spine surgery represents a convincing option in patients affected by PWS, but the risks of complications are high. Correct patient selection must be the main objective, and multilevel pedicle screw fixation should be the procedure of choice. Traditional growing rod should be prudently evaluated in every single case.
Topics: Humans; Scoliosis; Female; Prader-Willi Syndrome; Adolescent; Child; Male; Child, Preschool; Infant; Rare Diseases; Treatment Outcome; Spinal Fusion; Retrospective Studies
PubMed: 38630248
DOI: 10.1007/s00586-024-08247-0 -
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 -
American Journal of Medical Genetics.... Apr 2024Feeding difficulties, aspiration, and failure to thrive in infancy are commonly seen in patients with Prader-Willi Syndrome (PWS) and attributed to hypotonia. Patients...
Feeding difficulties, aspiration, and failure to thrive in infancy are commonly seen in patients with Prader-Willi Syndrome (PWS) and attributed to hypotonia. Patients with PWS and laryngeal clefts were identified by review of medical records at three tertiary care children's hospitals between 2017 and 2022. We present three patients with PWS with feeding difficulties who were also found to have laryngeal clefts which likely contributed to their feeding difficulties. Additional factors such as airway anomalies should be considered in patients with PWS, especially when swallowing dysfunction, dysphagia, or abnormal swallow evaluations are present.
PubMed: 38619072
DOI: 10.1002/ajmg.a.63634 -
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 -
Clinical Obesity Apr 2024Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1...
Most patients with GNB1 encephalopathy have developmental delay and/or intellectual disability, brain anomalies and seizures. Recently, two cases with GNB1 encephalopathy caused by haploinsufficiency have been reported that also show a Prader-Willi-like phenotype of childhood hypotonia and severe obesity. Here we present three new cases from our expert centre for genetic obesity in which GNB1 truncating and splice variants, probably leading to haploinsufficiency, were identified. They all have obesity, hyperphagia and intellectual deficit. The clinical cases and their weight courses are presented, together with a review of all 68 published cases with GNB1 encephalopathy. Information on weight was not mentioned in most of these articles, so we contacted authors for additional clinical information on weight status and hyperphagia. Of the 42 patients whose weight status we could determine, obesity was present in 8 patients (19%). Obesity is significantly over-represented in the group with truncating and splicing variants. In this group, we see an obesity prevalence of 75%. Since GNB1 has been linked to several key genes in the hypothalamic leptin-melanocortin pathway, which regulates satiety and energy expenditure, our data support the potential association between GNB1 haploinsufficiency and genetic obesity. We also suggest GNB1 is a candidate gene for the known obesity phenotype of the 1p36 microdeletion syndrome given this chromosomal region includes the GNB1 gene. Knowledge of an additional obesity phenotype is important for prognosis, early interventions against obesity and awareness when prescribing weight-inducing medication.
PubMed: 38596856
DOI: 10.1111/cob.12661 -
MicroRNA (Shariqah, United Arab... Apr 2024Long non-coding RNA (lncRNA) plays a crucial role in various biolog-ical processes, and mutations or imbalances of lncRNAs can lead to several diseases, including...
BACKGROUND
Long non-coding RNA (lncRNA) plays a crucial role in various biolog-ical processes, and mutations or imbalances of lncRNAs can lead to several diseases, including cancer, Prader-Willi syndrome, autism, Alzheimer's disease, cartilage-hair hypoplasia, and hear-ing loss. Understanding lncRNA-protein interactions (LPIs) is vital for elucidating basic cellular processes, human diseases, viral replication, transcription, and plant pathogen resistance. Despite the development of several LPI calculation methods, predicting LPI remains challenging, with the selection of variables and deep learning structure being the focus of LPI research.
METHODS
We propose a deep learning framework called AR-LPI, which extracts sequence and secondary structure features of proteins and lncRNAs. The framework utilizes an auto-encoder for feature extraction and employs SE-ResNet for prediction. Additionally, we apply transfer learning to the deep neural network SE-ResNet for predicting small-sample datasets.
RESULTS
Through comprehensive experimental comparison, we demonstrate that the AR-LPI ar-chitecture performs better in LPI prediction. Specifically, the accuracy of AR-LPI increases by 2.86% to 94.52%, while the F-value of AR-LPI increases by 2.71% to 94.73%.
CONCLUSION
Our experimental results show that the overall performance of AR-LPI is better than that of other LPI prediction tools.
PubMed: 38591194
DOI: 10.2174/0122115366288068240322064431 -
BioRxiv : the Preprint Server For... Mar 2024Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions,...
Human cell line models, including the neuronal precursor line LUHMES, are important for investigating developmental transcriptional dynamics within imprinted regions, particularly the 15q11-q13 Angelman (AS) and Prader-Willi (PWS) syndrome locus. AS results from loss of maternal UBE3A in neurons, where the paternal allele is silenced by a convergent antisense transcript UBE3A-ATS, a lncRNA that normally terminates at PWAR1 in non-neurons. qRTPCR analysis confirmed the exclusive and progressive increase in UBE3A-ATS in differentiating LUHMES neurons, validating their use for studying UBE3A silencing. Genome-wide transcriptome analyses revealed changes to 11,834 genes during neuronal differentiation, including the upregulation of most genes within the 15q11-q13 locus. To identify dynamic changes in chromatin loops linked to transcriptional activity, we performed a HiChIP validated by 4C, which identified two neuron-specific CTCF loops between MAGEL2-SNRPN and PWAR1-UBE3A. To determine if allele-specific differentially methylated regions (DMR) may be associated with CTCF loop anchors, whole genome long-read nanopore sequencing was performed. We identified a paternally hypomethylated DMR near the SNRPN upstream loop anchor exclusive to neurons and a paternally hypermethylated DMR near the PWAR1 CTCF anchor exclusive to undifferentiated cells, consistent with increases in neuronal transcription. Additionally, DMRs near CTCF loop anchors were observed in both cell types, indicative of allele-specific differences in chromatin loops regulating imprinted transcription. These results provide an integrated view of the 15q11-q13 epigenetic landscape during LUHMES neuronal differentiation, underscoring the complex interplay of transcription, chromatin looping, and DNA methylation. They also provide insights for future therapeutic approaches for AS and PWS.
PubMed: 38586056
DOI: 10.1101/2024.03.26.586689