Monoallelic intragenic POU3F2 variants lead to neurodevelopmental delay and hyperphagic obesity, confirming the gene's candidacy in 6q16.1 deletions.

While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.

Insulin secretion deficits in a Prader-Willi syndrome ß-cell model are associated with a concerted downregulation of multiple endoplasmic reticulum chaperones.

Prader-Willi syndrome (PWS) is a multisystem disorder with neurobehavioral, metabolic, and hormonal phenotypes, caused by loss of expression of a paternally-expressed imprinted gene cluster. Prior evidence from a PWS mouse model identified abnormal pancreatic islet development with retention of aged insulin and deficient insulin secretion. To determine the collective roles of PWS genes in ß-cell biology, we used genome-editing to generate isogenic, clonal INS-1 insulinoma lines having 3.16 Mb deletions of the silent, maternal- (control) and active, paternal-allele (PWS). PWS ß-cells demonstrated a significant cell autonomous reduction in basal and glucose-stimulated insulin secretion. Further, proteomic analyses revealed reduced levels of cellular and secreted hormones, including all insulin peptides and amylin, concomitant with reduction of at least ten endoplasmic reticulum (ER) chaperones, including GRP78 and GRP94. Critically, differentially expressed genes identified by whole transcriptome studies included reductions in levels of mRNAs encoding these secreted peptides and the group of ER chaperones. In contrast to the dosage compensation previously seen for ER chaperones in Grp78 or Grp94 gene knockouts or knockdown, compensation is precluded by the stress-independent deficiency of ER chaperones in PWS ß-cells. Consistent with reduced ER chaperones levels, PWS INS-1 ß-cells are more sensitive to ER stress, leading to earlier activation of all three arms of the unfolded protein response. Combined, the findings suggest that a chronic shortage of ER chaperones in PWS ß-cells leads to a deficiency of protein folding and/or delay in ER transit of insulin and other cargo. In summary, our results illuminate the pathophysiological basis of pancreatic ß-cell hormone deficits in PWS, with evolutionary implications for the multigenic PWS-domain, and indicate that PWS-imprinted genes coordinate concerted regulation of ER chaperone biosynthesis and ß-cell secretory pathway function.

Non-coding RNAs associated with Prader-Willi syndrome regulate transcription of neurodevelopmental genes in human induced pluripotent stem cells.

Mutations and aberrant gene expression during cellular differentiation lead to neurodevelopmental disorders, such as Prader-Willi syndrome (PWS), which results from the deletion of an imprinted locus on paternally inherited chromosome 15. We analyzed chromatin-associated RNA in human induced pluripotent cells (iPSCs) upon depletion of hybrid small nucleolar long non-coding RNAs (sno-lncRNAs) and 5' snoRNA capped and polyadenylated long non-coding RNAs (SPA-lncRNAs) transcribed from the locus deleted in PWS. We found that rapid ablation of these lncRNAs affects transcription of specific gene classes. Downregulated genes contribute to neurodevelopment and neuronal maintenance, while upregulated genes are predominantly involved in the negative regulation of cellular metabolism and apoptotic processes. Our data reveal the importance of SPA-lncRNAs and sno-lncRNAs in controlling gene expression in iPSCs and provide a platform for synthetic experimental approaches in PWS studies. We conclude that ncRNAs transcribed from the PWS locus are critical regulators of a transcriptional signature, which is important for neuronal differentiation and development.

Deleting Snord115 genes in mice remodels monoaminergic systems activity in the brain toward cortico-subcortical imbalances.

The neuronal-specific SNORD115 has gathered interest because its deficiency may contribute to the pathophysiology of Prader-Willi syndrome (PWS), possibly by altering post-transcriptional regulation of the gene encoding the serotonin (HTR2C) receptor. Yet, Snord115-KO mice do not resume the main symptoms of PWS, and only subtle-altered A-to-I RNA editing of Htr2c mRNAs was uncovered. Because HTR2C signaling fine-tunes the activity of monoaminergic neurons, we addressed the hypothesis that lack of Snord115 alters monoaminergic systems. We first showed that Snord115 was expressed in both monoaminergic and non-monoaminergic cells of the ventral tegmental area (VTA) and the dorsal raphe nucleus (DRN) harboring cell bodies of dopaminergic and serotonergic neurons, respectively. Measuring the tissue level of monoamines and metabolites, we found very few differences except that the content of homovanillic acid-a metabolite of dopamine-was decreased in the orbitofrontal and prefrontal cortex of Snord115-KO mice. The latter effects were, however, associated with a few changes in monoamine tissue content connectivity across the 12 sampled brain regions. Using in vivo single-cell extracellular recordings, we reported that the firing rate of VTA dopaminergic neurons and DRN serotonergic neurons was significantly increased in Snord115-KO mice. These neural circuit dysfunctions were not, however, associated with apparent defects in binge eating, conditioned place preference to cocaine, cocaine-induced hyperlocomotion or compulsive behavior. Altogether, our multiscale study shows that the absence of Snord115 impacts central monoaminergic circuits to an extent that does not elicit gross behavioral abnormalities.

Pathological analysis of Prader-Willi syndrome using adipocytes.

Prader-Willi syndrome (PWS) is a complex epigenetic disorder caused by the deficiency of paternally expressed genes in chromosome 15q11-q13. This syndrome also includes endocrine dysfunction, leading to short stature, hypogonadism, and obscure hyperphagia. Although recent progress has been made toward understanding the genetic basis for PWS, the molecular mechanisms underlying its pathology in obesity remain unclear. In this study, we examined the adipocytic characteristics of two PWS-induced pluripotent stem cell (iPSC) lines: those with the 15q11-q13 gene deletion (iPWS cells) and those with 15q11-q13 abnormal methylation (M-iPWS cells). The transcript levels of the lipid-binding protein aP2 were decreased in iPWS and M-iPWS adipocytes. Flow-cytometry analysis showed that PWS adipocytes accumulated more lipid droplets than did normal individual adipocytes. Furthermore, glucose uptake upon insulin stimulation was attenuated compared to that in normal adipocytes. Overall, our results suggest a significantly increased lipid content and defective in glucose metabolism in PWS adipocytes.

Genotype-phenotype correlation in Prader-Willi syndrome: A large-sample analysis in China.

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.

Microglial phagolysosome dysfunction and altered neural communication amplify phenotypic severity in Prader-Willi Syndrome with larger deletion.

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.

Feeding tube use and complications in Prader-Willi syndrome: Data from the Global Prader-Willi Syndrome Registry.

Guidance on indications for, and types of, feeding tubes recommended in Prader-Willi syndrome (PWS) is needed. A Global PWS Registry survey was developed to investigate nasogastric (NG) and gastrostomy (G) tube use and associated complications. Of 346 participants, 242 (69.9%) had NG-tubes, 17 (4.9%) had G-tubes, and 87 (25.1%) had both NG- and G-tubes. Primary indication for placement was "feeding difficulties and/or poor weight gain" for both NG- (90.2%) and G-tubes (71.2%), while "aspiration/breathing difficulties" was the procedural indication for 6.4% of NG-tubes and 23.1% of G-tubes. NG-tubes were generally removed by age 6 months (NG Only: 82.9%; NG/G: 98.8%), while G-tubes were often removed by age 2 years (G Only: 85.7%; NG/G: 70.5%). The severe complication rate from G-tubes was 31.7% and from NG-tubes was 1.2%. Overall, caregivers indicated the presence of an NG- or G-tube had a positive effect on quality of life. Feeding difficulties in PWS are largely managed by NG-tube alone. The severe complication rate from G-tubes was about 25 times higher than from NG-tubes; yet, G-tube placement rates have generally increased. G-tube placement puts individuals with PWS at risk for anesthesia and surgery-related complications and should be considered judiciously by a multidisciplinary team.

Laryngeal clefts in Prader-Willi syndrome: Feeding difficulties and aspiration not always caused by hypotonia.

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.

Prevalence and genotypic associations of epilepsy in Prader-Willi Syndrome: A systematic review and meta-analysis.

OBJECTIVE: To estimate the prevalence of epilepsy and febrile seizures and their association with genotype, i.e., 15q11-q13 deletions, uniparental chromosome 15 disomy (UPD) and other mutations, in the population with Prader-Willi syndrome (PWS). METHODS: A systematic search of Medline, Scopus, Web of Science and the Cochrane Library was conducted. Studies estimating the prevalence of seizures, epilepsy and febrile seizures in the PWS population were included. Meta-analyses of the prevalence of epilepsy and febrile seizures and their association with genotype using the prevalence ratio (PR) were performed. RESULTS: Fifteen studies were included. The prevalence of epilepsy was 0.11 (0.07, 0.15), similar to the prevalence of febrile seizures, with a prevalence of 0.09 (0.05, 0.13). The comparison "deletion vs. UPD" had a PR of 2.03 (0.90, 4.57) and 3.76 (1.54, 9.18) for epilepsy and febrile seizures. CONCLUSIONS: The prevalence of seizure disorders in PWS is higher than in the general population. In addition, deletions in 15q11-q13 may be associated with a higher risk of seizure disorders. Therefore, active screening for seizure disorders in PWS should improve the lives of these people. In addition, genotype could be used to stratify risk, even for epilepsy, although more studies or larger sample sizes are needed.

Aberrant brain intra- and internetwork functional connectivity in children with Prader-Willi syndrome.

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.

Early psychomotor development and growth hormone therapy in children with Prader-Willi syndrome: a review.

Prader-Willi syndrome (PWS) is a rare genetic disorder caused by the loss of imprinted gene expression on the paternal chromosome 15q11-q13. PWS is characterized by varying degrees of early psychomotor developmental deficits, primarily in cognition, language, and motor development. This review summarizes the early mental cognitive development, language development, and motor development in patients with PWS, compares the correlation of genotype with phenotype, and provides an update regarding the effects and concerns related to potential main side effects of treatment with recombinant human growth hormone on early psycho-cognitive and motor function development along with the linear growth and body composition of children with PWS.Conclusion: Early psychomotor development is strongly correlated with the prognosis of patients with PWS; moreover, current studies support that the initiation of interventions at an early age can exert significant beneficial effects on enhancing the cognitive and linguistic development of patients with PWS and allow them to "catch up" with motor development.  What is Known: • Prader-Willi syndrome is a rare genetic disorder characterized by multisystem damage, and children with Prader-Willi syndrome are typically characterized by early developmental delays, specifically in the areas of cognitive and motor development. • Recombinant human growth hormone therapy is the only medical treatment approved for Prader-Willi syndrome. What is New: • Extensive presentation of psycho-cognitive and motor development features and genotype-phenotype correlation in children with Prader-Willi syndrome.  • The effects of growth hormone on early psychomotor development in children with Prader-Willi syndrome were thoroughly reviewed, including their short- and long-term outcomes and any associated adverse effects.

SPArking Interest in the Long Noncoding RNA World: A New Class of 5' SnoRNA-Stabilized LncRNA that Influences Alternative Splicing.

Delving deeply into the locus deleted in Prader-Willi syndrome, in this issue of Molecular Cell, Wu et al. (2016) identify SPA RNAs, a new class of 5' snoRNA-capped lncRNAs that sequester RNA binding proteins and influence alternative splicing.

Unusual Processing Generates SPA LncRNAs that Sequester Multiple RNA Binding Proteins.

We identify a type of polycistronic transcript-derived long noncoding RNAs (lncRNAs) that are 5' small nucleolar RNA (snoRNA) capped and 3' polyadenylated (SPAs). SPA processing is associated with nascent mRNA 3' processing and kinetic competition between XRN2 trimming and Pol II elongation. Following cleavage/polyadenylation of its upstream gene, the downstream uncapped pre-SPA is trimmed by XRN2 until this exonuclease reaches the co-transcriptionally assembled snoRNP. This snoRNP complex prevents further degradation, generates a snoRNA 5' end, and allows continuous Pol II elongation. The imprinted 15q11-q13 encodes two SPAs that are deleted in Prader-Willi syndrome (PWS) patients. These lncRNAs form a nuclear accumulation that is enriched in RNA binding proteins (RBPs) including TDP43, RBFOX2, and hnRNP M. Generation of a human PWS cellular model by depleting these lncRNAs results in altered patterns of RBPs binding and alternative splicing. Together, these results expand the diversity of lncRNAs and provide additional insights into PWS pathogenesis.

Gut microbiota, a potential cause of higher insulin sensitivity in children with Prader-Willi syndrome.

PURPOSE: Obesity is the main driving factor for comorbidities in Prader-Willi syndrome (PWS) patients due to overeating behaviors. The gut microbiota has been implicated in the etiology of obesity and associated comorbidities. The purpose of the present study was to characterize the fecal microbiota in Chinese patients with PWS and compare it to that of patients with obesity as well as healthy controls. METHODS: We conducted a cross-sectional study with 35 PWS patients (PWS), 35 patients with obesity (OB), and 35 healthy controls (HC). Metagenomic sequencing was performed in stool samples. RESULTS: The composition of the fecal microbiota in PWS patients differed from that of participants in the OB and HC groups. It was characterized by increased Akkermansia Eubacterium, Eubacterium rectale, and Roseburia intestinalis and decreased Parabacteroides and Phascolarctobacterium. Additionally, the homeostatic model assessment of insulin resistance (HOMA-IR) was lower in PWS patients than in patients with obesity. Spearman rank correlation analysis showed that Achromobacter, Acidiphilium, Xylophilus, and Frisingicoccus were significantly negatively correlated with HOMA-IR. CONCLUSION: The composition of the gut microbiota in Chinese PWS patients differed from that in patients with obesity, which might contribute to higher insulin sensitivity in PWS patients.

Advancing in Schaaf-Yang syndrome pathophysiology: from bedside to subcellular analyses of truncated MAGEL2.

BACKGROUND: Schaaf-Yang syndrome (SYS) is caused by truncating mutations in MAGEL2, mapping to the Prader-Willi region (15q11-q13), with an observed phenotype partially overlapping that of Prader-Willi syndrome. MAGEL2 plays a role in retrograde transport and protein recycling regulation. Our aim is to contribute to the characterisation of SYS pathophysiology at clinical, genetic and molecular levels. METHODS: We performed an extensive phenotypic and mutational revision of previously reported patients with SYS. We analysed the secretion levels of amyloid-ß 1-40 peptide (Aß1-40) and performed targeted metabolomic and transcriptomic profiles in fibroblasts of patients with SYS (n=7) compared with controls (n=11). We also transfected cell lines with vectors encoding wild-type (WT) or mutated MAGEL2 to assess stability and subcellular localisation of the truncated protein. RESULTS: Functional studies show significantly decreased levels of secreted Aß1-40 and intracellular glutamine in SYS fibroblasts compared with WT. We also identified 132 differentially expressed genes, including non-coding RNAs (ncRNAs) such as HOTAIR, and many of them related to developmental processes and mitotic mechanisms. The truncated form of MAGEL2 displayed a stability similar to the WT but it was significantly switched to the nucleus, compared with a mainly cytoplasmic distribution of the WT MAGEL2. Based on the updated knowledge, we offer guidelines for the clinical management of patients with SYS. CONCLUSION: A truncated MAGEL2 protein is stable and localises mainly in the nucleus, where it might exert a pathogenic neomorphic effect. Aß1-40 secretion levels and HOTAIR mRNA levels might be promising biomarkers for SYS. Our findings may improve SYS understanding and clinical management.

Orthopedic manifestations in children with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare genetic disease often associated with bone problems, mainly scoliosis and hip dysplasia (HD). This study aimed to analyze the clinical characteristics of orthopedic deformities in patients with PWS. METHODS: A retrospective study was conducted on 175 patients up to March 2023. The Cobb angle(CA) of the spine, the alpha angle of the hip joint, and the acetabular index (AI) were measured. This study aimed to evaluate the relationship between demographic parameters and bone deformities. RESULTS: Scoliosis was found in 66 patients (43.7%), including 52 (78.8%) with mild scoliosis, 10 (15.2%) with moderate scoliosis, and 4 (6.1%) with severe scoliosis. Only seven patients received orthopedic treatment (10.6%). The median age of scoliosis was 4.5 years old, and the prevalence of scoliosis increased rapidly at the age of 5 years and adolescence. The mean CA in this study increased gradually with age. HD was found in 47 patients (38.2%), and 6 patients received orthopedic treatment (12.7%). The median age at HD was 1.8 years old. The mean AI of the study population decreased with age. The prevalence of HD treated with recombinant human growth hormone (rhGH) was low. No significant differences were observed in sex, genotype, body mass index (BMI), obesity rate, or onset of scoliosis and HD. CONCLUSION: The prevalence of scoliosis and HD was higher in patients with PWS. The onset age and developmental trends of the different skeletal malformations were different. Early diagnosis and treatment are important for the prognosis and treatment of orthopedic diseases in patients with PWS.

Evaluating the effect of recombinant human growth hormone treatment on sleep-related breathing disorders in toddlers with Prader-Willi syndrome: a one-year retrospective cohort study.

BACKGROUND: Recombinant human growth hormone (rhGH) therapy is beneficial for children with Prader-Willi syndrome (PWS) in improving short stature and metabolism, but the effect of early rhGH treatment on respiratory and sleep parameters for PWS children under three years old remains elusive. Thus, this study aimed to investigate the impact of rhGH treatment on sleep-related breathing disorders (SRBDs) for toddlers with PWS. METHODS: A total of 17 age-matched PWS patients receiving rhGH treatment (rhGH group) and 17 control individuals not receiving rhGH treatment (non-rhGH group) were recruited for this study between October 2018 and January 2023. Data related to polysomnography-polygraphy (PSG) and serum levels of insulin-like growth factor (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) were collected. RESULTS: The mean age in the rhGH group was 20.76 ± 9.22 months, which was comparable to that of the non-rhGH group (25.23 ± 13.81 months). The demographic and anthropometric parameters were similar across the two groups after 52 weeks of treatment. Administration of rhGH to toddlers did not exert adverse effects on the obstructive apnea-hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), mean percutaneous oxygen saturation (SpO2), lowest SpO2, duration when SpO2 is lower than 90%, or proportion of the patients with SpO2 lower than 90%. Furthermore, the increased IGF-1 z-score and IGFBP-3 level did not worsen SRBDs. CONCLUSION: Treatment with rhGH for 52 weeks on young toddlers with PWS showed no deleterious effects on SRBDs. This shed more light on the importance of initiating rhGH therapy early in PWS patients.

Scoliosis and rare diseases: our experience with the Prader-Willi syndrome.

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.

Effectiveness of the Kaufman Brief Intelligence Test in people with Prader-Willi syndrome.

BACKGROUND: Evaluating intelligence using conventional tools is very complex in patients with Prader-Willi Syndrome (PWS), as it is time consuming and requires levels of care that are difficult to sustain for this population. Therefore, we explore the ability of a brief test to assess intelligence in these patients. METHODS: This study included individuals with a genetically confirmed diagnosis of PWS, with regular attendance at transdisciplinary treatment in an institution dedicated to the care of rare diseases in Argentina. The Wechsler Intelligence Scale for Children (WISC-IV), the Wechsler Adult Intelligence Scale (WAIS-III) and the Kaufman Brief Intelligence Test (K-BIT) were used. RESULTS: Correlation was obtained between the scales in paediatric and adult populations. Within the paediatric population, no significant differences were identified between the WISC-IV scale (Wechsler for paediatrics) and the K-BIT (56.4 ± 8.6, vs. 53.4 ± 10.1, P = 0.28), with a good agreement between the methods {intraclass correlation 0.79 [95% confidence interval (CI) 0.15-0.95]}. Regarding the adult population, the discrimination of the WAIS-III scale (Wechsler for adults) and the K-BIT of adults (16 years and over) presented an acceptable concordance [0.77 (95% CI -0.09; 0.93)], although also underestimating the results (58.3 ± 7.2 vs. 51.1 ± 11.2, P < 0.0001). CONCLUSIONS: We observed the feasibility and potential usefulness of a brief intelligence test (K-BIT) in patients with PWS with an acceptable agreement with conventional tools.