Prader-Willi Syndrome Children Research Articles

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

BackgroundRecombinant 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.MethodsA 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.ResultsThe 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.ConclusionTreatment 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.

Distinct Lipids Profiles and Associations With Clinical Indicators and Gut Microbiota in Children With Prader-Willi Syndrome.

Lipid metabolism is closely linked to adiposity. Prader-Willi syndrome (PWS) is a typical genetic disorder causing obesity; however, the distinct lipidomic profiles in PWS children have not been thoroughly investigated. Herein, serum lipidomics analyses were simultaneously explored in PWS, simple obesity (SO), and normal children (Normal). Results indicated that the total concentration of phosphatidylcholine (PC) and lysophosphatidylcholine (LPC) in the PWS group were significantly deceased compared with both the SO and the Normal group. In contrast, compared with the Normal group, there was an overall significant increase in triacylglycerol (TAG) levels in both the PWS and the SO groups, with the highest found in SO group. Thirty-nine and 50 differential lipid species were screened among 3 groups: between obesity (PWS and SO) and the Normal group. Correlation analysis revealed distinct profiles in PWS that was different from other 2 groups. Notably, PC (P16:0/18:1), PE (P18:0-20:3), PE (P18:0-20:4)) showed significant negative correlation with body mass index (BMI) only in the PWS group. PE (P16:0-18:2) showed a negative association with BMI and weight in the PWS group, but significant positive correlation in the SO group; no statistically significant association was found in the Normal group. We also found a significant negative correlation between Blautia genus abundance and several significantly changed lipids, including LPC (14:0), LPC (16:0), TAG (C50:2/C51:9), TAG (C52:2/C53:9), TAG (C52:3/C53:10), and TAG (C52:4/C53:11), but no significant correlation in the Normal group and the SO group. Similarly, in the PWS group, the Neisseria genus was significantly negatively associated with acylcarnitine (CAR) (14:1), CAR (18:0), PE (P18:0/20:3), and PE (P18:0/20:4), and extremely positively associated with TAG (C52:2/C53:9); no obvious correlations were observed in the Normal group and the SO group.

Children with Prader-Willi Syndrome and COVID-19: a longitudinal study of the effect of social re-opening after the lockdown.

This study longitudinally investigated mental health indicators, body mass index (BMI), and access to school and health-care services in children with Prader-Willi syndrome (PWS) and community controls (CC) during the first wave of the COVID-19 pandemic. The parents of 71 children (34 PWS and 37 CC) aged 6-17 years completed an online questionnaire during the initial COVID-19 lockdown (T0) and the subsequent partial (T1) and full re-opening (T2). We examined access to school and health-care services, BMI, and mental health (DSM-5 Parent/Guardian Rated Cross-Cutting Syndrome Measure) across the three time-points. For BMI and DSM-5 measure, we tested within- (Friedman's ANOVA repeated measures) and between- (robustified linear mixed-models, rLMM) group differences over time. Around 30% of PWS children maintained contact with medical personnel through telemedicine. PWS children kept contact with both teachers and classmates at a lower rate than CC. At all time-points, BMI was higher in PWS than CC. During partial reopening, while children with PWS had a decrease in BMI, CC showed an increase, with a significant interaction time*group interaction. Mental symptoms significantly declined in both groups, although in CC the decrease was greater than in PWS. PWS children were at a disadvantage during the COVID-19 outbreak for lower access to school than CC. The improvement of mental health in both groups with the reopening confirms the importance of social activities outside the family. The decrease in BMI in the PWS group indicates the positive role of caregivers' monitoring on eating habits of children.

What underlies emotion regulation abilities? An innovative programme based on an integrative developmental approach to improve emotional competencies: Promising results in children with Prader-Willi syndrome.

This study aimed to test the effect of a new training programme on emotional competencies, named EMO-T, and to show the value of an integrative developmental approach. This approach postulates that the emotion regulation disturbances commonly observed in neurodevelopmental disorders are the consequence of potential disruptions in the prerequisite emotion skills. This integrative approach is particularly suitable in the case of complex and multidimensional disorders such as Prader-Willi syndrome (PWS), a rare genetic disease. We examined the emotion expression, recognition, comprehension, and regulation skills in 25 PWS children aged 5-10 and 50 typically developing children (TD) aged 3-10. After a pre-test session, half of the PWS children participated in the EMO-T programme with their regular therapist for 6 weeks, while the other half continued their usual rehabilitation programme. Two post-test sessions were conducted, one at the end of the programme and one 3 months later. At pre-test, PWS children displayed a deficit in the four emotional competencies (EC). PWS children who participated in the EMO-T programme showed a significant and sustainable post-test improvement regarding voluntary expression and emotion recognition abilities, such that the level reached was no longer different from the baseline level of TD children. They also tended to improve in their emotion regulation, although they received no specific training in this skill. These results support that emotion regulation abilities require prerequisite emotion skills, which should be more fully considered in current training programmes. Because emotion regulation disorders strongly impact all areas of life, an integrative developmental approach appears crucial especially in the case of neurodevelopmental disorders. Further studies should be conducted to explore this perspective.

Preserved Sleep for the Same Level of Respiratory Disturbance in Children with Prader-Willi Syndrome.

Debate remains as to how to balance the use of recombinant human growth hormone (rhGH) as an important treatment in Prader-Willi syndrome (PWS) with its potential role in obstructive sleep apnea. This single-center, retrospective study assessed differences in overnight polysomnography results between children with and without PWS and changes in respiratory parameters before and after the initiation of rhGH treatment in those with PWS. Compared with age-, sex-, and body-mass-index-matched controls (n = 87), children with PWS (n = 29) had longer total sleep time (434 ± 72 vs. 365 ± 116 min; p < 0.01), higher sleep efficiency (86 ± 7 vs. 78 ± 15%; p < 0.05), and lower arousal events (8.1 ± 4.5 vs. 13.0 ± 8.9 events/h; p < 0.05). Mean oxygen saturation was lower in PWS children (94.3 ± 6.0 vs. 96.0 ± 2.0%; p < 0.05), with no other differences in respiratory parameters between groups. Eleven children with PWS (38%) met the criteria for further analyses of the impact of rhGH; polysomnography parameters did not change with treatment. Compared with other children undergoing polysomnography, children with PWS had more favorable markers of sleep continuity and lower oxygen saturation for the same level of respiratory disturbance. rhGH administration was not associated with changes in respiratory parameters in PWS.

Dysregulated adipose tissue expansion and impaired adipogenesis in Prader-Willi syndrome children before obesity-onset

ObjectivePrader-Willi syndrome (PWS) is a rare genetic imprinting disorder resulting from the expression loss of genes on the paternally inherited chromosome 15q11–13. Early-onset life-thriving obesity and hyperphagia represent the clinical hallmarks of PWS. The noncoding RNA gene SNORD116 within the minimal PWS genetic lesion plays a critical role in the pathogenesis of the syndrome. Despite advancements in understanding the genetic basis for PWS, the pathophysiology of obesity development in PWS remains largely uncharacterized. Here, we aimed to investigate the signatures of adipose tissue development and expansion pathways and associated adipose biology in PWS children without obesity-onset at an early stage, mainly from the perspective of the adipogenesis process, and further elucidate the underlying molecular mechanisms. MethodsWe collected inguinal (subcutaneous) white adipose tissues (ingWATs) from phase 1 PWS and healthy children with normal weight aged from 6 M to 2 Y. Adipose morphology and histological characteristics were assessed. Primary adipose stromal vascular fractions (SVFs) were isolated, cultured in vitro, and used to determine the capacity and function of white and beige adipogenic differentiation. High-throughput RNA-sequencing (RNA-seq) was performed in adipose-derived mesenchymal stem cells (AdMSCs) to analyze transcriptome signatures in PWS subjects. Transient repression of SNORD116 was conducted to evaluate its functional relevance in adipogenesis. The changes in alternative pre-mRNA splicing were investigated in PWS and SNORD116 deficient cells. ResultsIn phase 1 PWS children, impaired white adipose tissue (WAT) development and unusual fat expansion occurred long before obesity onset, which was characterized by the massive enlargement of adipocytes accompanied by increased apoptosis. White and beige adipogenesis programs were impaired and differentiated adipocyte functions were disturbed in PWS-derived SVFs, despite increased proliferation capacity, which were consistent with the results of RNA-seq analysis of PWS AdMSCs. We also experimentally validated disrupted beige adipogenesis in adipocytes with transient SNORD116 downregulation. The transcript and protein levels of PPARγ, the adipogenesis master regulator, were significantly lower in PWS than in control AdMSCs as well as in SNORD116 deficient AdMSCs/adipocytes than in scramble (Scr) cells, resulting in the inhibited adipogenic program. Additionally, through RNA-seq, we observed aberrant transcriptome-wide alterations in alternative RNA splicing patterns in PWS cells mediated by SNORD116 loss and specifically identified a changed PRDM16 gene splicing profile in vitro. ConclusionsImbalance in the WAT expansion pathway and developmental disruption are primary defects in PWS displaying aberrant adipocyte hypertrophy and impaired adipogenesis process, in which SNORD116 deficiency plays a part. Our findings suggest that dysregulated adiposity specificity existing at an early phase is a potential pathological mechanism exacerbating hyperphagic obesity onset in PWS. This mechanistic evidence on adipose biology in young PWS patients expands knowledge regarding the pathogenesis of PWS obesity and may aid in developing a new therapeutic strategy targeting disturbed adipogenesis and driving AT plasticity to combat abnormal adiposity and associated metabolic disorders for PWS patients.

Prader-Willi Syndrome: Possibilities of Weight Gain Prevention and Treatment.

Prader–Willi syndrome (PWS) is a complex genetic disorder which involves the endocrine and neurologic systems, metabolism, and behavior. The aim of this paper is to summarize current knowledge on dietary management and treatment of PWS and, in particular, to prevent excessive weight gain. Growth hormone (GH) therapy is the recommended standard treatment for PWS children, because it improves body composition (by changing the proportion of body fat and lean body mass specifically by increasing muscle mass and energy expenditure), linear growth, and in infants, it promotes psychomotor and IQ development. In early childhood, the predominant symptom is hyperphagia which can lead to early onset, severe obesity with different obesity-related comorbidities. There are several studies on anti-obesity medications (metformin, topiramate, liraglutide, setmelanotide). However, these are still limited, and no widely accepted consensus guideline exists concerning these drugs in children with PWS. Until there is a specific treatment for hyperphagia and weight gain, weight must be controlled with the help of diet and exercise. Below the age of one year, children with PWS have no desire to eat and will often fail to thrive, despite adequate calories. After the age of two years, weight begins to increase without a change in calorie intake. Appetite increases later, gradually, and becomes insatiable. Managing the progression of different nutritional phases (0–4) is really important and can delay the early onset of severe obesity. Multidisciplinary approaches are crucial in the diagnosis and lifelong follow-up, which will determine the quality of life of these patients.

Circulating insulin-like growth factor 1 levels are reduced in very young children with Prader-Willi syndrome independent of anthropometric parameters and nutritional status.

Insulin growth factor-1 (IGF-1) is used to evaluate growth hormone (GH) sufficiency and is decreased in children with Prader-Willi syndrome (PWS). Although IGF-1 is negatively affected by body size and nutritional status, both of which are impaired in PWS children, these variables are typically not considered when assessing IGF-1 levels in these subjects. Here, we compared IGF-1 levels in PWS children to controls matched for age, sex, anthropometric parameters, and nutritional status. The retrospective analysis included genetically diagnosed PWS subjects (n = 65, median age; 14.0 months) and controls (n = 111, 14.3 months) matched for age, sex, anthropometric parameters (height-standard deviation score [SDS], weight-SDS, body mass index-SDS), and serum albumin levels, a marker for nutritional status. IGF-1 SDS was compared between PWS subjects and controls after adjustment for confounding variables. The GH provocation test was performed in 29 PWS subjects, and IGF-1 SDS was compared between GH-sufficient (n = 20) and GH-deficient (n = 9) subjects. Spearman's rank correlation coefficient was performed to investigate the association between age and IGF-1 SDS. None had received GH or levothyroxine treatment. After adjustment for confounding variables, IGF-1 SDS was significantly lower in PWS subjects than controls (-1.56 vs. -1.01, p = .003), while it was not different between GH-sufficient and GH-deficient PWS subjects. Correlation analysis failed to show an association between age and IGF-1 SDS both in control and PWS groups. IGF-1 SDS is lower in very young children with PWS independent of anthropometric parameters and nutritional status, suggesting the presence of hypothalamic dysfunction of GH secretion.

Growth Hormone Treatment for Adults With Prader-Willi Syndrome: A Meta-Analysis.

ContextFeatures of Prader-Willi syndrome (PWS) overlap with features of growth hormone (GH) deficiency, like small hands and feet, short stature, increased body fat, and low muscle mass and strength. In children with PWS, GH treatment (GHt) improves physical health and cognition. GHt has become the standard of care in PWS children, but in adults this is not yet the case.ObjectiveThis work aims to provide an overview of the current knowledge on GHt in PWS adults.MethodsMedline, Embase, and the Cochrane Central Register of Controlled Trials databases were searched. Study selection included randomized clinical trials (RCTs) and nonrandomized (un)controlled trials (NRCTs) that reported data for adults with PWS, who received GHt for at least 6 months. Data on body composition, body mass index (BMI), cardiovascular end points, bone, cognitive function, quality of life, and safety were extracted.ResultsNine RCTs and 20 NRCTs were included. Body composition improved during 12 months of GHt with an increase in mean (95% CI) lean body mass of 1.95 kg (0.04 to 3.87 kg) and a reduction of mean (95% CI) fat mass of –2.23% (–4.10% to –0.36%). BMI, low-density lipoprotein cholesterol levels, fasting glucose levels, and bone mineral density did not change during GHt. There were no major safety issues.ConclusionGHt appears to be safe and improves body composition in adults with PWS. Because poor body composition is closely linked to the observed high incidence of cardiovascular morbidity in adults with PWS, improving body composition might reduce cardiovascular complications in this vulnerable patient group.

Central hypothyroidism improves with age in very young children with Prader-Willi syndrome.

Abnormalities in the hypothalamic-pituitary-thyroid (HPT) axis have been implicated in Prader-Willi syndrome (PWS); however, limited information is currently available on age-dependent alterations in the HPT axis. We herein investigated age-dependent differences in thyroid hormone levels in PWS children. Free T4 (FT4), free T3 (FT3) and thyroid-stimulating hormone (TSH) concentrations were retrospectively compared between genetically confirmed PWS children (N=43, median age: 11.2months) and controls (N=85, median age: 14.5months) matched for age, sex, body weight-SD score (SDS), height-SDS, body mass index-SDS and serum albumin level, a marker of the nutritional status. Subjects were subdivided into two groups based on their age: an infant group aged between 1 and 11months (PWS: N=22, controls: N=30) and a toddler group aged between 12 and 47months (PWS: N=21, controls: N=55). None of the subjects had ever been treated with growth hormone or levothyroxine. After adjustments for confounding variables, in the infant group, FT4 levels (pmol/L) were significantly lower in PWS (11.24 in PWS vs 14.32 in controls, P=.0002), whereas no significant differences were observed in FT3 or TSH levels. In the toddler group, no significant differences were noted in FT4 (12.23 in PWS vs 15.31 in controls, P=.10), FT3 or TSH levels. The FT3/FT4 ratio was significantly increased in PWS in both groups. FT4 levels were positively correlated with age in PWS. Infants with PWS had lower FT4 levels, but FT3 levels were normal, indicating that the levothyroxine replacement therapy may not need to be routinely performed.

Effects of growth hormone on cognitive, motor, and behavioral development in Prader-Willi syndrome children: a meta-analysis of randomized controlled trials.

The benefits of growth hormone (GH) therapy in Prader-Willi syndrome (PWS) children are well established, but there is still considerable controversy regarding whether GH treatment can improve cognitive, motor, and behavioral development in PWS children. The objectives of this meta-analysis were to quantitatively evaluate the effects of GH on cognitive, motor function, and behavioral development in PWS children. Randomized controlled trials (RCTs) examining the effects of GH on cognitive, motor, and behavioral development in PWS children were identified by searching the MEDLINE, EMBASE, and Cochrane Library databases. Intervention effects were represented by Hedges'g and pooled to calculate effect sizes using a random-effects model. Ten relevant studies comprising data from 302 participants were finally included. We observed no significant difference in cognitive performance between the GH treatment group and the control group (p = 0.197). GH treatment was shown to remarkably improve motor development in PWS children compared with the control treatment (p < 0.001), with moderate positive treatment effects (Hedges'g [95% CI] = 0.71 [0.38, 1.03]). There were no significant differences between the GH group and the control group based on objective assessments of behavioral development (p = 0.53). The meta-analysis suggested that GH treatment had a significantly positive effect on motor development, with moderate treatment effects in PWS children; however, there was no evidence of effects on cognitive or behavioral development.

Premature Adrenarche in Children with Prader-Willi Syndrome Treated with Recombinant Human Growth Hormone Seems to Not Influence the Course of Central Puberty and the Efficacy and Safety of the Therapy.

Puberty in children with Prader-Willi syndrome (PWS) is usually delayed and/or incomplete but in some patients premature/early adrenarche is observed. We assessed the premature adrenarche (PA) in PWS patients during the recombinant human growth hormone (rhGH) therapy and influence of PA on the course of central puberty (CP), rhGH efficacy and safety, and patients’ metabolic state. Forty-nine PWS patients were treated with rhGH, 11 presented with PA (group 1) and 14 had normal course of adrenarche (group 2). PA was observed in 22.5% of the PWS children treated with rhGH. The mean time between the rhGH start and the adrenarche, the rhGH dose, the growth velocity and the insulin-like growth factor 1 SD (IGF1 SD) during the treatment, as well as the time of CP, final height SD and BMI SD were similar in both groups. There were also no significant differences in the metabolic assessment—the oral glucose tolerance test (OGTT) and lipid profile results. PA may be a part of the clinical picture of PWS, apart from hypogonadotrophic hypogonadism and it seems to have no influence on CP in PWS patients. The rhGH efficacy and safety were comparable in the patients with PA and the normal course of adrenarche.

Dietary macronutrient regulation of acyl and desacyl ghrelin concentrations in children with Prader-Willi syndrome (PWS).

The effects of dietary macronutrients on orexigenic and anorexigenic hormones in children are poorly understood. To explore effects of varying dietary macronutrients on appetite-regulating hormones [acyl ghrelin (AG) and desacyl ghrelin (DAG), glucagon-like peptide 1 (GLP-1), peptide tyrosine tyrosine (PYY) and insulin] in children with PWS and healthy children (HC). Randomized, cross-over experiments compared two test diets [high protein-low carbohydrate (HP-LC) and high protein-low fat (HP-LF)] to a STANDARD meal (55% carbohydrate, 30% fat, 15% protein). Experiment 1 included ten children with PWS (median age 6.63years; BMI z 1.05); experiment 2 had seven HC (median age 12.54years; BMI z 0.95). Blood samples were collected at baseline and at 60-minute intervals for 4hours. Independent linear mixed models were adjusted for age, sex and BMI z-score. Fasting and post-prandial AG and DAG concentrations are elevated in PWS children; the ratio of AG/DAG is normal. Food consumption reduced AG and DAG concentrations in both PWS and HC. GLP-1 levels were higher in PWS after the HP-LC and HP-LF meals than the STANDARD meal (P=.02-0.04). The fasting proinsulin to insulin ratio (0.08 vs 0.05) was higher in children with PWS (P=.05) than in HC. Average appetite scores in HC declined after all three meals (P=.02) but were lower after the HP-LC and HP-LF meals than the STANDARD meal. Altered processing of proinsulin and increased GLP-1 secretion in children with PWS after a high protein meal intake might enhance satiety and reduce energy intake.

Sleep-Disordered Breathing in Children with Prader-Willi Syndrome in Relation to Growth Hormone Therapy Onset

Objective: The aim of this study was to consider sleep apnea in Prader-Willi syndrome (PWS) children depending on age at growth hormone (GH) therapy onset. Study Design: We analyzed longitudinally cardiorespiratory polygraphy of 62 PWS children (aged 0–2.5 years at baseline). Twenty-one children (Group A) started GH-therapy during and 41 children (Group B) after their first year of life. Data were acquired before, at 3 and 6 months, then 1.2, 2.2, and 3.2 years after GH onset. Outcomes were determined with the obstructive apnea hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), and by measuring obstructive sleep apnea (OSA) and peripheral blood oxygen saturation (SpO₂). Results: We observed no significant differences in OAHI, CAI, ODI, and SpO₂ depending on treatment onset. At baseline, 5/21 patients (23.8%) in Group A versus 15/41 patients (36.6%) in Group B showed pathological sleep apnea (OAHI ≥1.5). Pathological OSA increased significantly in Group A during the first 3 months of therapy but dropped below baseline after 1 year in both groups. ODI changed during GH therapy in both groups (from 4.0 to 2.6 in Group A, and 3.6 to 1.6 in Group B; baseline to 3.2 years; p < 0.05). Conclusions: OSA in PWS children appears to develop independently of treatment onset. Treatment may therefore safely be initiated early but should be accompanied by regular sleep analysis.

Equivocal expression of emotions in children with Prader-Willi syndrome: what are the consequences for emotional abilities and social adjustment?

BackgroundPeople with Prader-Willi Syndrome (PWS) experience great difficulties in social adaptation that could be explained by disturbances in emotional competencies. However, current knowledge about the emotional functioning of people with PWS is incomplete. In particular, despite being the foundation of social adaptation, their emotional expression abilities have never been investigated. In addition, motor and cognitive difficulties - characteristic of PWS - could further impair these abilities.MethodTo explore the expression abilities of children with PWS, twenty-five children with PWS aged 5 to 10 years were assessed for 1) their emotional facial reactions to a funny video-clip and 2) their ability to produce on demand the facial and bodily expressions of joy, anger, fear and sadness. Their productions were compared to those of two groups of children with typical development, matched to PWS children by chronological age and by developmental age. The analyses focused on the proportion of expressive patterns relating to the target emotion and to untargeted emotions in the children’s productions.ResultsThe results showed that the facial and bodily emotional expressions of children with PWS were particularly difficult to interpret, involving a pronounced mixture of different emotional patterns. In addition, it was observed that the emotions produced on demand by PWS children were particularly poor and equivocal.ConclusionsAs far as we know, this study is the first to highlight the existence of particularities in the expression of emotions in PWS children. These results shed new light on emotional dysfunction in PWS and consequently on the adaptive abilities of those affected in daily life.

Visceral adipose tissue resides within the reference range in children with Prader-Willi syndrome receiving nutritional intervention on a regular basis.

Nutritional intervention for maintaining an appropriate body composition is central to the management of Prader-Willi syndrome (PWS). Despite evidence that visceral adipose tissue (VAT) is associated with increased metabolic risks, the effects of nutritional intervention on fat distribution have not been evaluated for PWS children. We herein investigated fat distribution in 20 genetically diagnosed PWS children (9 males and 11 females); 17 of which received nutritional intervention with or without growth hormone (GH) treatment [GH-treated group (n = 8), GH-untreated group (n = 9)]. GH treatment continued for median of 4.9 years. GH treatment significantly increased height standard deviation score (SDS) whereas body weight SDS and body mass index SDS were not affected in GH-treated group. In GH-untreated group, height SDS significantly decreased during approximately 5 years of follow-up. Fat distribution was evaluated at the median age of 6.93 years in GH-treated group and 7.01 years in GH-untreated group. VAT was maintained within the reference range in both groups. Subcutaneous adipose tissue (SAT) was elevated in GH-untreated groups compared to reference values whereas it was not in GH-treated group. The remaining three subjects, who had never received nutritional intervention or GH treatment, showed increased VAT and SAT. In conclusion, nutritional intervention is beneficial in maintaining VAT within the reference range during childhood, although excessive nutritional intervention may cause unfavorable effect on linear growth.

Early Diagnosis in Prader-Willi Syndrome Reduces Obesity and Associated Co-Morbidities.

Prader–Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11–q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity in PWS. We studied 352 subjects with PWS, recruited from the NIH Rare Disease Clinical Research Network, to determine if age at diagnosis, ethnicity, gender, and PWS molecular class influenced the age they first become heavy, as determined by their primary care providers, and the age they first developed an increased appetite and began seeking food. The median ages that children with PWS became heavy were 10 years, 6 years and 4 years for age at diagnosis < 1 year, between 1 and 3 years, and greater than 3 years of age, respectively. The age of diagnosis and ethnicity were significant factors influencing when PWS children first became heavy (p < 0.01), however gender and the PWS molecular class had no influence. Early diagnosis delayed the onset of becoming heavy in individuals with PWS, permitting early GH and other treatment, thus reducing the risk of obesity-associated co-morbidities. Non-white individuals had an earlier onset of becoming heavy.

Quality of life in caregivers of young children with Prader–Willi syndrome

This study aimed to measure quality of life (QOL) in primary caregivers of young childrenwith Prader-Willi syndrome (PWS). The caregivers of 32 children aged from 6.1 to 71.2 months completed the Chinese version of the World Health Organization Quality of Life-BREF (WHOQOL-BREF). We also evaluated the social adaption capacity of these children with Infants-Junior Middle School Students' Social-Life Abilities Scale. Correlation test was used to explore the related factors to caregivers' QOL. Caregivers of young children with PWS had significantly lower QOL. The correlation analyses revealed that caregivers' QOL was lower in children with young age, combined diseases or symptoms or poor social adaption, or caregivers having concerns about the child. Rearing a chilld with PWS may lead to decreased QOL. Psychological status of caregivers should be highlighted and social support should be given to families with PWS children.

Epilepsy in Prader-Willi syndrome: clinical characteristics and related analysis

Objective To analyze the incidence and clinical characteristics of epilepsy in children with Prader-Willi syndrome (PWS), and to explore the relationship with genotype. Methods Ninety-five children with PWS were chosen from Department of Pediatric Neurology in Shengjing Hospital of China Medical University during 2008 to 2018.The general information of all children included in the study were collected and analyzed at the same time.At first, 95 children with PWS were divided into two groups according to epilepsy or not(epilepsy group 23 cases and non-epilepsy group 72 cases), the relationship between incidence of epilepsy and genotype or gender was analyzed.Furthermore, 23 PWS children with epilepsy were divided into two groups according to genotype: paternal 15q11-13 region deletion genotype group (20 cases) and maternal uni-parental disomy(UPD) group (3 cases), then the relationship between clinical characteristics and genotype was analyzed. Results A retrospective analysis of 95 patients with PWS found that the proportion of deletion in 15q11-13 was significantly higher in the epilepsy group than that in the non-epilepsy group, and the difference was statistically significant (87.0% vs.56.9%, χ2=6.832, P=0.009), while there was no statistical difference in gender (χ2=0.603, P=0.437). Among the 23 PWS children with epilepsy, 18 cases (78.2%) were generalized epilepsy, and 5 cases (21.8%) were focal epilepsy.The proportion of generalized epilepsy of deletion genotype group was higher than UPD group, and there was statistical difference(85.0% vs.33.3%, P 0.05). The effective epilepsy control rate was 91.3% in 23 children with epilepsy. Conclusion PWS children have a higher incidence of epilepsy, which can manifest with generalized features.PWS patients with a deletion genotype in paternal 15q11-13 region show a trend toward developing seizures, especially generalized epilepsy.But the seizure onset age and seizure frequency have no correlation with genotype.There is a good prognosis in most PWS with epilepsy. Key words: Prader-Willi syndrome; Epilepsy; Clinical characteristics; Genotype

Hormonal and metabolic effects of carbohydrate restriction in children with Prader-Willi syndrome.

Macronutrient regulation of hyperphagia and adiposity in Prader-Willi syndrome (PWS) is poorly understood. We compared fasting and postprandial concentrations of hormones and metabolites in eight PWS children (age 9-18years) fed, in random order, low carbohydrate, high-fat (LC, 15% carb; 65% fat; 20% protein) and low-fat, high carbohydrate (LF, 65% carb, 15% fat, 20% protein) diets matched for calories and protein. Participants were randomized to consume either the LC or LF diet during a first hospital admission and the second diet during a subsequent admission. Blood samples were obtained after overnight fasting and 1hour after a mixed meal. Relative to subjects consuming the LF diet, subjects consuming the LC diet had: lower postprandial insulin concentrations (P=0.02); higher fasting GLP-1 AND GIP concentrations and increased postprandial GLP-1 (P<0.02); reduced ratio of fasting ghrelin to GLP-1 (P=0.0078); increased FFA and fatty acid oxidation, as assessed by concentrations of even-chain acylcarnitines (P<0.001); lower fasting TG and TG/HDL ratio (P<0.01); and higher concentrations of branch chain amino acids (P<0.01). There were no changes in glucose, PYY, or adiponectin. CRP, AST and ALT were all higher (P<0.01) on the LC diet. Increases in GLP-1 with low carbohydrate feeding and reductions in the ratio of ghrelin to GLP-1 might limit food intake and improve glycaemic control in PWS. Other potential benefits of carbohydrate restriction may include fat mobilization and oxidation and reductions in the TG/HDL ratio, a marker of insulin resistance. However, increases in CRP, AST and ALT necessitate longer-term studies of low carbohydrate efficacy and safety.