SEARCH WITHIN CONTENT
Citation Information : North American Journal of Medicine and Science. VOLUME 10 , ISSUE 4 , ISSN (Online) 2156-2342, DOI: 10.7156/najms.2017.1004156, December 2017 © 2017.
License : (Transfer of Copyright)
Received Date : 17-September-2017 / Accepted: 19-October-2017 / Published Online: 18-December-2017
As the first recognized human genetic imprinting disorder, Prader-Willi Syndrome (PWS) has an estimated prevalence in several studied populations of 1/10,000-1/30,000.1 This multisystem genetic disorder could be caused by the absence of paternally expressed imprinted genes at 15q11.2-q13 through paternal deletion, maternal uniparental disomy (UPD) of chromosome 15, or an imprinting defect.2 The characteristic features of PWS include severe hypotonia in early infancy, subsequent hyperphagia and morbid obesity from early-childhood, developmental delay, mild intellectual disability, and a distinct behavioral phenotype.1,3
For adult patients with PWS, the leading cause of death is complications of obesity.4 Though its etiology has remained unclear so far, the cause of hyperphagia for patients with PWS is usually considered to be hypothalamic dysfunction, which is also responsible for growth hormone (GH), sex hormone, and thyroid-stimulating hormone (TSH) deficiencies.3,5 Current treatments for PWS include: well established clinical use of Growth Hormone (GH), and emerging new therapies such as Oxytocin (OXT), and drugs for diabetes mellitus and obesity such as Metformin, Beloranib, and GLP-1 receptor agonist. The objective of this systematic review is to summarize the most effective treatments for PWS based on clinical trials.
A systematic review protocol was developed to explore the most promising treatments for PWS. The evaluation of different categories of medications was based on the published clinical trial data.
A systematic search was conducted in the following databases: PubMed, MEDLINE, and Scopus. In order to conduct a thorough systematic search about treatments for PWS, multiple searches were undertaken using the following terms: “Prader-Willi Syndrome AND/OR treatment” “Prader-Willi Syndrome AND/OR medication treatment” “Prader-Willi Syndrome AND/OR growth hormone” “Prader-Willi Syndrome AND/OR oxytocin” “Prader-Willi Syndrome AND/OR Metformin” “Prader-Willi Syndrome AND/OR GLP-1 Receptor Agonist” “prader-Willi Syndrome AND/OR Exenatide” “Prader-Willi Syndrome AND/OR Beloranib” “Prader-Willi Syndrome AND/OR Liraglutide” “Prader-Willi Syndrome AND/OR behavior treatment” “Soles of the Feet”.
1139 articles were identified after the search. After duplication removal and screening the articles with inclusion and exclusion criteria, 34 articles were included in this systematic review. (Figure 1)
Articles were included when they were: 1) English-written clinical trials (including nonrandomized open trials and randomized controlled trials); 2) studied the efficacy or effect of one or multiple treatments for PWS; and 3) published between January of 2000 and October of 2017. Studies published before 2000 or not strongly related to PWS treatments were excluded.
Based on the above inclusion and exclusion criteria, our final search selected 34 articles. Among these articles, twenty were reports of clinical trials studying the effect of medication treatments for PWS, whose details were showed in three tables (Table 1-5). The other thirteen articles focused on other treatment aspects and one focused on the stress level of caregivers, which will be presented in the following discussion section.
GH is the well-established medication for PWS. We selected nine clinical trials focusing on GH after filtration.6-14 (Table 1, 2) Among these nine studies, six were published between 2010 and 2017, and the other three were published between 2000 and 2010. These studies focused on the effects of GH treatment on the body composition and metabolic index of affected individuals with PWS. In six out of nine studies, patients have either reduced body fat percent or increased lean body mass significantly, covered the age group from age 5 to 30s, treatment time from 12 months to 6 years, two of them were randomized trials.9-14 Among these trials, there is a large-scale retrospective cohort study, average age 4-6, with treatments of 3 years or longer. It reports significant height improvement after the treatment.6 Greater motor strength was reported in one study.11 Lipid profile HDL and LDL were tested in three trials, and two of them showed decreased LDL and increased HDL.8,9,11 These studies showed no significant adverse effect or safety issue with the treatments except transient blood sugar elevation in one study, and 12 deaths out of 2332 safety analysis in the retrospective cohort, which was lower than the reported 3% annual mortality rate in patients with PWS.6
Four studies on OXT published between 2011 and 2017 were selected. (Table 3)
Effects of OXT treatment on the behaviors of patients with PWS were mainly investigated. Three of the studies showed behavioral improvements after OXT treatment, which included less food-related behavior, decreased sadness and anger tendencies, increased trust in others and improved social behaviors. However, one out of the four studies showed no significant change.17 There was only one study showed a modest increase in height after treatment.16 Meanwhile, none of those studies showed any significant changes in BMI, even though a reported appetite decrease in two studies.15,16
All of these studies focus on the effects of diabetes and obesity drugs on patients with PWS. After 4 weeks’ Beloranib treatment in 17 adult patients, body weight, and body mass reduction were detected along with improved biochemical indexes including triglycerides, the decrease in BMI was dose-dependent.25 As for the five studies focusing on GLP-1 receptor agonists, results showed that patients had decreased appetite and reduced BMI in three trials, decreased body fat and waist circumference in two trials, and mostly with reduced HbA1c level after treatments.19-23 The Metformin study involved 31 patients with treatment of 3 months, showed reduced appetite and BMI, and blood sugar level.24 None of seven trials included height as a measurement. No significant adverse effect was observed in these studies.
As an emerging focus area for researchers, OXT has been considered a promising medication for PWS. Most characteristics of PWS result from the absence of expression of the paternally derived genes located on chromosome 15 at the locus q11·2-13, and one of the not expressed genes in this region is MAGEL2, whose deficiency might lead to a major reduction of OXT.29 OXT has an important role in influencing the life quality of patients with PWS, such as feeding behaviors, social interactions, and emotional reactivity.15 Most of our selected studies confirmed the improvement in behavior after OXT treatment. However, there was one study by Einfeld failed to show any impact.17 We believe that this could be related to multiple factors. First, OXT works better in younger children. In the study of Kuppens et al, significant changes in behaviors after OXT treatment were only reported in the group of children under 11 years old, whereas subjects in Einfeld’s study were all over 12 years old. Secondly, the delivery of OXT may also be a concern. In Einfeld’s study, there was no plasma analysis, therefore it was hard to determine whether OXT was successfully delivered.
Although some results indicated increase in height and decrease in appetite with OXT treatment, the data is very limited this point. To validate OXT’s effect on body mass and height, further studies with longer duration and bigger sample size are needed, set both body fat composition and lean body mass as well as BMI, metabolic profile as outcome measurements, in addition the efficacy of delivery and bioavailability of intranasal oxytocin will also need to be studied. Furthermore, the data of OXT effect on behaviors is far from enough, the future studies should focus on OXT treatment on social communication and behavioral profiles cross different age groups, and different severity or comorbidity subgroups. We foresee extending clinical usage with more data collected.
As pointed out above, some drugs for diabetes mellitus also could potentially play an important role in the treatment of PWS.
Metformin is the first line treatment for Type 2 Diabetes Mellitus (T2DM), with the main effect to decrease liver glucose production. Researchers currently relate this medication to the treatment of patients with PWS since T2DM and PWS share a lot of similarities and connections. With its known weight loss capacity, we believe that Metformin has the potential to be an important part of treatment for PWS especially those associated glucose intolerance and insulin resistance. More studies with larger scale are needed to confirm the efficacy, the best time to initiate, with or without diabetes.
GLP-1 receptor agonists started to catch the attention as well. Multiple studies have been conducted to investigate the effectiveness of GLP-1 agonist treatment in patients with PWS, whose results supported the efficacy in different levels.19-23 In view of its weight loss benefit and anti-diabetes effect, similar to metformin, there should be some value of this group of medications in the treatment of PWS, particularly those with glucose intolerance or diabetes. Further studies are necessary to investigate the long-term effects of GLP-1 receptor agonists on body mass and composition in PWS, as well as their adverse event profile. Their administration route as an injection might limit its use.
Apart from Diabetes medications, there is another noteworthy drug called Beloranib, an inhibitor of the enzyme METAP2, is a former drug candidate to treat obesity. It has approved efficacy in body weight loss and hyperphagia reduction, which are very important for PWS. Beloranib should have some potential to serve as a medication for patients with PWS, however this medication halted during phase III clinical trail due to unclear second deaths, further studies need to be conducted to assure the safety before it could move forward.
We discussed three major drug categories in PWS, there are other important aspects of treatments should be addressed here. First of all, early detection and intervention are paramount and currently still lag behind.30,31 Prenatal screening methods including DNA methylation and high-resolution chromosomal SNP microarrays should be considered and newborn screening (NBS) could be applied basing on the utilization of next-generation sequencing and focusing on multiple PCR-based fragments from copy-number-determining chromosomal regions.32 Early detection and early intervention lead a much better prognosis.
Secondly, caregivers play a very important role33 in PWS treatment, however, most parents suffer from significant stress and require a great deal of counseling and training.34 Their stress level and parenting style directly impact on the outcome. Haig and Woodcock investigated 10 caregivers of patients with PWS through interviews and questionnaires, suggested the importance for caregivers to increase their flexibility and assure smooth transition.35
Third, behavioral intervention has been essential for PWS treatment. Patients with PWS share a lot in common in social-cognitive challenges with ASD patients, whose most empirically studied and validated treatment is behavioral treatment.36 Dimitropoulos, Zyga, and Russ directly delivered a 6-week play-based intervention to eight children through telehealth37 the participants completed the program without much difficulty and showed good acceptability to the behavioral intervention. Adolescents with PWS usually show aggressive reactions.38 Soles of the Feet (SoF) is a mindfulness-based meditation technique developed by ONE Research Institute.39 It kept away from the situations which cause anger and aggressive reactions. To evaluate the effectiveness of this meditation on patients with PWS, Singh, Lancioni, and Myers et al40 found patients’ physical aggression was almost completely resolved and verbal aggression significantly decreased after SoF, and these improvements were maintained after 12 months.
This systematic review discussed the latest clinical trials for PWS and discussed the current treatment advancement. Of 1,139 potentially relevant articles from PubMed, MEDLINE, and Scopus from 2000 to 2017, we extracted 34 relevant articles with 20 clinical trials. As discussed above, in addition to the well-established therapy GH with further confirmed efficacy, the newer experimental OXT and diabetes and obesity drugs (Metformin, GLP-1 agonists, and Beloranib) have demonstrated certain positive effect on improving the symptoms of PWS which worth further investigations. Concomitant application among these drugs is also potentially important since they have divergent and complementary functions. Further studies particularly for these new emerging drugs, might also include GH too, are needed to look into their correlation with different PWS subtypes, such as those with different genetic or phenotypes, those co-existed with ASD, Depression, DM, GI disturbances, hypothyroidism or others, correlation of behavioral changes and hormonal parameters, the molecular mechanism of these therapies, and more specific target solutions. The future direction we believe should be, detect early and treat early with effective drug therapies in the combination of behavioral interventions for different subtypes, establish effective protocols, ultimately serve PWS population for better outcomes.