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BMJ Paediatrics Open May 2024
PubMed: 38719566
DOI: 10.1136/bmjpo-2019-000630corr1 -
Neurotherapeutics : the Journal of the... Apr 2024Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological... (Review)
Review
Prader-Willi syndrome (PWS) is a complex, genetic disorder characterized by multisystem involvement, including hyperphagia, maladaptive behaviors and endocrinological derangements. Recent developments in advanced neuroimaging have led to a growing understanding of PWS as a neural circuit disorder, as well as subsequent interests in the application of neuromodulatory therapies. Various non-invasive and invasive device-based neuromodulation methods, including vagus nerve stimulation (VNS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and deep brain stimulation (DBS) have all been reported to be potentially promising treatments for addressing the major symptoms of PWS. In this systematic literature review, we summarize the recent literature that investigated these therapies, discuss the underlying circuits which may underpin symptom manifestations, and cover future directions of the field. Through our comprehensive search, there were a total of 47 patients who had undergone device-based neuromodulation therapy for PWS. Two articles described VNS, 4 tDCS, 1 rTMS and 2 DBS, targeting different symptoms of PWS, including aberrant behavior, hyperphagia and weight. Multi-center and multi-country efforts will be required to advance the field given the low prevalence of PWS. Finally, given the potentially vulnerable population, neuroethical considerations and dialogue should guide the field.
Topics: Humans; Prader-Willi Syndrome; Vagus Nerve Stimulation; Transcranial Magnetic Stimulation; Deep Brain Stimulation; Transcranial Direct Current Stimulation
PubMed: 38430811
DOI: 10.1016/j.neurot.2024.e00339 -
Orphanet Journal of Rare Diseases Feb 2024Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder resulting from absent paternal expression of maternally imprinted genes at chromosomal... (Review)
Review
BACKGROUND
Prader-Willi syndrome (PWS) is a rare and complex neurodevelopmental disorder resulting from absent paternal expression of maternally imprinted genes at chromosomal locus 15q11-13. This absence of expression occurs as a consequence of a deletion on the chromosome 15 of paternal origin (ca. 70%), a chromosome 15 maternal uniparental disomy (mUPD; ca. 25%), or an imprinting centre defect (IC; ca. 1-3%). At birth, individuals with PWS are severely hypotonic and fail to thrive. Hyperphagia and characteristic physical and neuropsychiatric phenotypes become apparent during childhood. The risk for the development of a co-morbid psychotic illness increases during the teenage years, specifically in those with PWS due to the presence of an mUPD. The primary aim of this literature review is to inform clinical practice. To achieve this, we have undertaken a systematic analysis of the clinical research literature on prevalence, presentation, course, characteristics, diagnosis and treatment of psychotic illness in people with PWS. The secondary aim is to identify clinical aspects of psychotic illness in PWS in need of further investigation.
METHODS AND FINDINGS
A systematic literature review on psychosis in PWS was conducted on the databases Web of Knowledge, PubMed and Scopus, using the terms "((Prader-Willi syndrome) OR (Prader Willi Syndrome)) AND ((psychosis) OR (psychotic illness))". All articles written in English and reporting original human research were reviewed. In all but three of the 16 cohort studies in which the genetic types were known, the authors reported higher rates of psychosis in people with PWS resulting from an mUPD, compared to those with the deletion subtype of PWS. When psychosis was present the presentation was psychosis similar regardless of genetic type and was usually characterised by an acute onset of hallucinations and delusions accompanied by confusion, anxiety and motor symptoms.
CONCLUSIONS
The onset of confusion, an affective cyclical pattern with the presence of abnormal mental beliefs and experiences, usually of rapid onset is suggestive of the development of psychotic illness. Phenomenologically, this psychosis in people with PWS is atypical in comparison to schizophrenia and bipolar disorder in the general population. The relationship to psychosis in the general population and the optimum treatments remain uncertain.
Topics: Adolescent; Infant, Newborn; Humans; Prader-Willi Syndrome; Psychotic Disorders; Comorbidity; Family; Anxiety; Chromosomes, Human, Pair 15
PubMed: 38360662
DOI: 10.1186/s13023-024-03026-y -
Frontiers in Endocrinology 2024[This corrects the article DOI: 10.3389/fendo.2023.1168648.].
[This corrects the article DOI: 10.3389/fendo.2023.1168648.].
PubMed: 38318297
DOI: 10.3389/fendo.2024.1357219 -
Frontiers in Endocrinology 2023Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and...
BACKGROUND
Prader-Willi syndrome (PWS) is a rare, complex, genetic disorder characterized by hyperphagia, hypotonia, delayed psychomotor development, low muscle mass and hypothalamic dysfunction. Adults with PWS often have obesity, hypertension and type 2 diabetes mellitus (DM2), known risk factors for cardiovascular disease (CVD) and chronic kidney disease (CKD). Early symptoms of CVD and CKD may be masked by intellectual disability and inability to express physical complaints. Furthermore, kidney diseases are often asymptomatic. Therefore, renal and cardiovascular disease might be missed in patients with PWS. Microalbuminuria is an early sign of microvascular damage in the kidneys and other vascular beds. Therefore, we screened our adult PWS cohort for the presence of elevated urinary albumin and (micro)albuminuria.
METHODS
We retrospectively collected anthropometric measurements, blood pressure, medical history, medication use, urine dipstick and biochemical measurements form electronic patient files. In addition, we performed a systematic literature review on kidney disease in PWS.
RESULTS
We included 162 adults with genetically confirmed PWS (56% male, median age 28 years), of whom 44 (27%) had DM2. None had known CVD. All subjects had normal estimated glomerular filtration rate (eGFR) according to non-PWS reference intervals. Elevated urinary albumin or (micro)albuminuria was present in 28 (18%); 19 out of 75 (25%) had an increased urinary albumin-to-creatinine ratio (UACR) and 10 out of 57 (18%) had an increased urinary protein-to-creatinine ratio. Elevated urinary albumin was present at a young age (median age 26 (IQR 24-32) years) and was associated with an significantly higher BMI and LDL-cholesterol levels and higher prevalence of DM2, hypertension and dyslipidemia than those with normal UACR (=0.027, =0.019, <0.001, <0.001, =0.011 and respectively).
CONCLUSION
Upon screening, one in every five adults with PWS had increased urinary albumin or (micro)albuminuria, early signs of microvascular disease. All had normal eGFR, according to non-PWS reference intervals, and none had a formal diagnosis of CVD. As muscle mass is low in PWS, creatinine levels and eGFR may be spuriously normal. Urinalysis in this patient group can be used as a screening tool for microvascular (kidney) disease. We propose an algorithm for the detection and management of microvascular disease in adults with PWS.
Topics: Humans; Adult; Male; Young Adult; Female; Cohort Studies; Prader-Willi Syndrome; Diabetes Mellitus, Type 2; Retrospective Studies; Creatinine; Albuminuria; Hypertension; Cardiovascular Diseases; Renal Insufficiency, Chronic; Albumins
PubMed: 37547314
DOI: 10.3389/fendo.2023.1168648 -
BMC Medical Research Methodology May 2023There is a pressing need to improve the accuracy of rare disease clinical study endpoints. Neutral theory, first described here, can be used to assess the accuracy of...
BACKGROUND
There is a pressing need to improve the accuracy of rare disease clinical study endpoints. Neutral theory, first described here, can be used to assess the accuracy of endpoints and improve their selection in rare disease clinical studies, reducing the risk of patient misclassification.
METHODS
Neutral theory was used to assess the accuracy of rare disease clinical study endpoints and the resulting probability of false positive and false negative classifications at different disease prevalence rates. Search strings were extracted from the Orphanet Register of Rare Diseases using a proprietary algorithm to conduct a systematic review of studies published until January 2021. Overall, 11 rare diseases with one disease-specific disease severity scale (133 studies) and 12 rare diseases with more than one disease-specific disease severity scale (483 studies) were included. All indicators from clinical studies were extracted, and Neutral theory was used to calculate their match to disease-specific disease severity scales, which were used as surrogates for the disease phenotype. For those with more than one disease-severity scale, endpoints were compared with the first disease-specific disease severity scale and a composite of all later scales. A Neutrality score of > 1.50 was considered acceptable.
RESULTS
Around half the clinical studies for half the rare diseases with one disease-specific disease severity score (palmoplantar psoriasis, achalasia, systemic lupus erythematosus, systemic sclerosis and Fournier's gangrene) met the threshold for an acceptable match to the disease phenotype, one rare disease (Guillain-Barré syndrome) had one study with an acceptable match, and four diseases (Behcet's syndrome, Creutzfeldt-Jakob disease, atypical hemolytic uremic syndrome and Prader-Willi syndrome) had no studies. Clinical study endpoints in almost half the rare diseases with more than one disease-specific DSS (acromegaly, amyotrophic lateral sclerosis, cystic fibrosis, Fabry disease and juvenile rheumatoid arthritis) were a better match to the composite, while endpoints in the remaining rare diseases (Charcot Marie Tooth disease, Gaucher disease Type I, Huntington's disease, Sjogren's syndrome and Tourette syndrome) were a worse match. Misclassifications varied with increasing disease prevalence.
CONCLUSIONS
Neutral theory confirmed that disease-severity measurement needs improvement in rare disease clinical studies, especially for some diseases, and suggested that the potential for accuracy increases as the body of knowledge on a disease increases. Using Neutral theory to benchmark disease-severity measurement in rare disease clinical studies may reduce the risk of misclassification, ensuring that recruitment and treatment effect assessment optimise medicine adoption and benefit patients.
Topics: Humans; Rare Diseases; Endpoint Determination; Clinical Studies as Topic
PubMed: 37210484
DOI: 10.1186/s12874-023-01947-z -
Neuroscience and Biobehavioral Reviews Jun 2023We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and... (Review)
Review
The future of child and adolescent clinical psychopharmacology: A systematic review of phase 2, 3, or 4 randomized controlled trials of pharmacologic agents without regulatory approval or for unapproved indications.
We aimed to identify promising novel medications for child and adolescent mental health problems. We systematically searched https://clinicaltrials.gov/ and https://www.clinicaltrialsregister.eu/ (from 01/01/2010-08/23/2022) for phase 2 or 3 randomized controlled trials (RCTs) of medications without regulatory approval in the US, Europe or Asia, including also RCTs of dietary interventions/probiotics. Additionally, we searched phase 4 RCTs of agents targeting unlicensed indications for children/adolescents with mental health disorders. We retrieved 234 ongoing or completed RCTs, including 26 (11%) with positive findings on ≥ 1 primary outcome, 43 (18%) with negative/unavailable results on every primary outcome, and 165 (70%) without publicly available statistical results. The only two compounds with evidence of significant effects that were replicated in ≥ 1 additional RCT without any negative RCTs were dasotraline for attention-deficit/hyperactivity disorder, and carbetocin for hyperphagia in Prader-Willi syndrome. Among other strategies, targeting specific symptom dimensions in samples stratified based on clinical characteristics or established biomarkers may increase chances of success in future development programmes.
Topics: Humans; Child; Adolescent; Psychopharmacology; Randomized Controlled Trials as Topic; Attention Deficit Disorder with Hyperactivity; Prader-Willi Syndrome; Clinical Trials, Phase II as Topic
PubMed: 37001575
DOI: 10.1016/j.neubiorev.2023.105149 -
Surgery For Obesity and Related... Aug 2023Obesity is the leading cause of morbidity and mortality in patients with Prader-Willi Syndrome (PWS). Our objective was to compare changes in body mass index (BMI) after... (Meta-Analysis)
Meta-Analysis
Obesity is the leading cause of morbidity and mortality in patients with Prader-Willi Syndrome (PWS). Our objective was to compare changes in body mass index (BMI) after metabolic and bariatric surgery (MBS) for the treatment of obesity (BMI ≥35 kg/m) in PWS. A systematic review of MBS in PWS was performed using PubMed, Embase, and Cochrane Central, identifying 254 citations. Sixty-seven patients from 22 articles met criteria for inclusion in the meta-analysis. Patients were organized into 3 groups: laparoscopic sleeve gastrectomy (LSG), gastric bypass (GB), and biliopancreatic diversion (BPD). No mortality within 1 year was reported in any of the 3 groups after a primary MBS operation. All groups experienced a significant decrease in BMI at 1 year with a mean reduction in BMI of 14.7 kg/m (P < .001). The LSG groups (n = 26) showed significant change from baseline in years 1, 2, and 3 (P value at year 3 = .002) but did not show significance in years 5, 7, and 10. The GB group (n = 10) showed a significant reduction in BMI of 12.1 kg/m in the first 2 years (P = .001). The BPD group (n = 28) had a significant reduction in BMI through 7 years with an average reduction of 10.7 kg/m (P = .02) at year 7. Individuals with PWS who underwent MBS had significant BMI reduction sustained in the LSG, GB, and BPD groups for 3, 2, and 7 years, respectively. No deaths within 1 year of these primary MBS operations were reported in this study or any other publication.
Topics: Humans; Bariatric Surgery; Biliopancreatic Diversion; Gastric Bypass; Obesity; Prader-Willi Syndrome; Body Mass Index
PubMed: 36872159
DOI: 10.1016/j.soard.2023.01.017 -
PloS One 2022This systematic review aims to describe 1) the epidemiology of the diseases indicated for treatment with growth hormone (GH) in Italy; 2) the adherence to the GH...
OBJECTIVES
This systematic review aims to describe 1) the epidemiology of the diseases indicated for treatment with growth hormone (GH) in Italy; 2) the adherence to the GH treatment in Italy and factors associated with non-adherence; 3) the economic impact of GH treatment in Italy; 4) the quality of life of patients treated with GH and their caregivers in Italy.
METHODS
Systematic literature searches were performed in PubMed, Embase and Web of Science from January 2010 to March 2021. Literature selection process, data extraction and quality assessment were performed by two independent reviewers. Study protocol has been registered in PROSPERO (CRD42021240455).
RESULTS
We included 25 studies in the qualitative synthesis. The estimated prevalence of growth hormone deficiency (GHD) was 1/4,000-10,000 in the general population of children; the prevalence of Short Stature HOmeoboX Containing gene deficiency (SHOX-D) was 1/1,000-2,000 in the general population of children; the birth prevalence of Turner syndrome was 1/2,500; the birth prevalence of Prader-Willi syndrome (PWS) was 1/15,000. Treatment adherence was suboptimal, with a range of non-adherent patients of 10-30%. The main reasons for suboptimal adherence were forgetfulness, being away from home, pain/discomfort caused by the injection. Economic studies reported a total cost for a complete multi-year course of GH treatment of almost 100,000 euros. A study showed that drug wastage can amount up to 15% of consumption, and that in some Italian regions there could be a considerable over- or under-prescribing. In general, patients and caregivers considered the GH treatment acceptable. There was a general satisfaction among patients with regard to social and school life and GH treatment outcomes, while there was a certain level of intolerance to GH treatment among adolescents. Studies on PWS patients and their caregivers showed a lower quality of life compared to the general population, and that social stigma persists.
CONCLUSION
Growth failure conditions with approved GH treatment in Italy constitute a significant burden of disease in clinical, social, and economic terms. GH treatment is generally considered acceptable by patients and caregivers. The total cost of the GH treatment is considerable; there are margins for improving efficiency, by increasing adherence, reducing drug wastage and promoting prescriptive appropriateness.
Topics: Adolescent; Child; Child, Preschool; Female; Human Growth Hormone; Humans; Italy; Male; Prader-Willi Syndrome; Prevalence; Quality of Life; Treatment Adherence and Compliance; Turner Syndrome
PubMed: 35213607
DOI: 10.1371/journal.pone.0264403 -
European Journal of Medical Genetics Jan 2022Prader-Willi Syndrome (PWS) is a multi-system genetically determined neurodevelopmental disorder and the commonest cause of syndromal obesity. The development of... (Meta-Analysis)
Meta-Analysis
Prader-Willi Syndrome (PWS) is a multi-system genetically determined neurodevelopmental disorder and the commonest cause of syndromal obesity. The development of hyperphagia in early childhood is part of the phenotype arising as a result of an impaired neural response to food intake and the inability to regulate food intake in line with energy needs. Severe obesity develops if access to food is not controlled. In this review we evaluate the evidence for increased morbidity and mortality in PWS in order to establish the extent to which it is directly related to the obesity; a consequence of the eating behaviour itself independent of obesity; or associated with other characteristics of the syndrome. Medline, Cochrane, PsychINFO, CINAHL, Web of Science and Scopus databases were used to systematically identify published material on PWS and hyperphagia and syndrome-related morbidity and mortality. One hundred and ten key papers were selected. Data on 500 people with PWS indicated that the average age of death was 21 years and obesity was, as expected, a significant factor. However, the behaviour of hyperphagia itself, independent of obesity, was also important, associated with choking, gastric rupture, and/or respiratory illness. Other syndrome-related factors increased the risk for, and seriousness of, co-morbid illness or accidents. We conclude that improving life-expectancy largely depends on managing the immediate non-obesity and obesity-related consequences of the hyperphagia, through improved support. The development of new treatments that significantly reduce the drive to eat are likely to decrease morbidity and mortality improving quality of life and life expectancy.
Topics: Humans; Hyperphagia; Morbidity; Prader-Willi Syndrome
PubMed: 34748997
DOI: 10.1016/j.ejmg.2021.104379