Medical Management for Adults with Prader–Willi Syndrome

Introduction

P rader–Willi syndrome (PWS) was first described in 1956. ¹ This neurodevelopmental disorder arises from a lack of expression of paternally inherited genes that are imprinted and located in the chromosome 15q11–q13 region. The de novo paternally derived deletion is the cause of more than 70% of PWS cases, whereas 25% of the cases rely on maternal disomy 15. Genomic imprinting defects of the chromosome 15 region, like microdeletions or epimutations, as well as chromosome 15 translocations, account for around 5% of PWS cases. Thus, most carriers of this defect are identified by sequencing. No consistent biological marker exists to describe PWS, but consensus diagnostic criteria were developed to identify PWS patients. ² The worldwide incidence is between 1:20,000 and 1:10,000 live births. ³ Particular for PWS are morbid obesity and abnormal body composition with reduced lean tissue and increased fat mass resulting from insatiable appetite, short stature, amyosthenia, hypogonadism, scoliosis, small hands and feet, low average intelligence, somnolence, and compulsive behavior. ⁴ The complex phenotype is most probably caused by a hypothalamic dysfunction being responsible for hormonal dysfunctions ⁵ regarding growth hormones and sex hormones ^6,7 and for the absence of the sense of satiety. Thyroid function may be impaired in PWS patients. ⁸ The mortality among adults is about three times higher than in the remaining population. ^9,10 Typically, secondary diseases occur in the course of a lifetime. Most adults with PWS die from cardiovascular complications or respiratory diseases. Due to the high occurrence of obesity, diabetes is a common concomitant disease and accelerates the risk of cardiovascular events in these patients. ¹¹

The aim of this survey was to show the effect of the nutritional, medical, psychological, and pedagogical concepts on the development of body weight and cardiovascular risk factors in this population.

Methods

Eight adults (31.4±6.4 years, 5 males, 3 females) with a PWS diagnosis confirmed by genetic testing who live in an assisted living environment took part in this follow-up observation. At study entry, the nutritional concept consisted of a 1500 kcal/day diet; the patients were advised to do sports at least twice a week for 60 min and to take part in a structured intensive pedagogic care. The subjects were living for 7.6±2.2 years before study entry in the assisted living environment. There were 5 regularly working days per week with a scheduled time plan. On these days, residents worked in a sheltered workshop for at least 35 h per week. The patients had spare time on the weekend (Saturday and Sunday).

Two medical surveys, in which body mass index (BMI), blood pressure (RR), and laboratory values for glycosylated hemoglobin (HbA1c), metabolic parameters like low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were determined, took place. As markers for the underlying atherosclerotic situation, carotid duplex was performed and intima media thickness (IMT) was determined (LOGIC7Pro, 7L, GE Healthcare, Buckinghamshire, UK). Longitudinal and transversal scanning of the aorta carotis communa, aorta carotis externa, and aorta carotis interna was performed to evaluate atherosclerotic risk in terms of plaques or stenosis. In a second measurement, IMT of the aorta carotis communis was determined ∼1 cm proximal of the carotid bifurcation. In a third measurement, the aorta vertebralis was examined to determine flow disturbances. The visits took place within 12.9±1.5 months at the endocrinology service of the Diabetes Center at the Heart and Diabetes Center NRW in Bad Oeynhausen.

For patients in whom diabetes was not diagnosed, an additional oral glucose tolerance test (OGTT) was performed to exactly evaluate the metabolic state. BMI and drug history at the entry in the specialized residential group and during this evaluation period were available. By using bioelectrical impedance analysis (TANITA TBF410M, Tokyo, Japan), the basal metabolism, the body lean mass, and body fat were determined at the beginning and at the end of the evaluation period.

The study was reviewed by the ethics committee of the Ruhr-University Bochum in Bad Oeynhausen and conducted in accordance with the Declaration of Helsinki. The supervisors and the patients were informed about the scope and significance of the observation and agreed in writing (informed consent).

All values are presented as means±standard deviation (SD). Statistical analysis was done using paired t-tests, and p values <0.05 were regarded as statistically significant.

Results

Eight persons whose characteristics are listed in Table 1a and 1b took part in the study. They had been living in the residential group for about 7.6±2.2 years at the beginning of the survey (=study entry). Their basal metabolism was 1.692±171 kcal. Six people of the study population had suffered from diabetes since the beginning of the first survey; diabetes treatments are listed in Table 2.

Two residents were taking antihypertensive medications; none of them had taken lipid-lowering medication (Table 2). Of the male subjects, 2 persons received testosterone supplementation and 2 of 3 female participants received estrogen supplementation.

Body mass index

Weight reduction could be shown within the time interval of the survey. BMI decreased by more than one unit from 29.9±4.8 kg/m² to 28.7±4.1 kg/m² (P=0.10). On average the patients lost 1.8±4.0 kg weight from the first to the second survey (time elapse 12.9 months). A significant weight reduction was detected from the time of the entry in the residential group until the time of the first examination, which is described as first survey in this manuscript. BMI was lowered from 38.1±7.4 kg/m² to 29.9±4.8 kg/m² (P<0.05) (Fig. 1).

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FIG. 1.

Developing of body mass index (BMI) during life in assisted living and after start of the survey. Each square represents 1 individual; the trend is given in gray, means±standard deviation (SD).

During the survey, the fat proportion could be reduced from 27.1±8.9% to 25.2±8.1% (Fig. 2). There were no changes in the lean mass (from 57.0±7.4 kg to 57.1±8.1 kg). Thus, the improvement in BMI is attributable to the loss of fat mass.

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FIG. 2.

Development of fat proportion during life in assisted living after the start of the survey measured by bioelectrical impedance analysis. Each square represents 1 individual; the trend is given in grey, means±standard deviation (SD).

Diabetes mellitus type 2

Two persons were tested by using OGTT for diabetes; both were negative at enrollment, and 1 subject developed impaired glucose tolerance during follow-up. Regarding the persons with diabetes, a significant reduction in HbA1c was achieved during the survey (6.5–6.0%, P<0.05) (Fig. 3, Table 1b). Mild hypoglycemia was reported by 1 person, and antidiabetic medication was adapted. Common antidiabetics were oral antidiabetics (metformin, repaglinid, sitagliptin) or for 1 person in combination with insulin. For a detailed overview, please refer to Table 2. The oral therapy was intensified during the observation period. Metformin therapy was initiated for 1 patient. During the stay in the assisted living group, the number of diabetics requiring insulin for glycemic control could be reduced from 3 to 1 subject during the stay in the group.

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FIG. 3.

Development of glycosylated hemoglobin (HbA1c) during life in assisted living after start of the survey. Each square represents 1 individual; the trend is given in gray, means±standard deviation (SD).

Discussion

This survey clearly demonstrates that a scheduled daily plan, including occupation and sports, a restriction of caloric intake, and psychological support is useful for the management of PWS. People with PWS clearly benefit from an assisted life in a group. The concept of living in a group rather than in the familiar environment proved to be of advantage in terms of physiologic and psychological health. The survey done in this group of patients was able to show a further improvement of the clinical situation of the subjects. The close medical guidance throughout their life was helpful and obligated treatment of metabolic diseases to prevent late complications that are triggered by obesity and diabetes mellitus. Effective weight reduction was achieved, and weight gain during the survey could be prevented by lifestyle intervention. The loss of weight was mainly due to the reduction of body fat detected by bioelectrical impedance analysis. Although this measurement has several limitations, we can assume that caloric intake in combination with lifestyle modification has beneficial effects in terms of reduction of fat mass. Keeping body weight on a constant and tolerable level should be regarded as success in PWS patients. Regarding the fatty acid metabolism, the dietary concept shows that the caloric limitation not only resulted in weight reduction but also resulted in an improvement of blood pressure. The fact that statin therapy had to be started in 2 patients may be in correlation with diabetes duration and previous or ongoing insulin therapy.

The use of glucagon-like peptide-1 (GLP-1) mimetics and dipeptidyl peptidase-4 (DPP4) inhibitors has been discussed with regard to weight management and HbA1c control in PWS patients to avoid or replace insulin therapy. ¹² The effects on satiety and glucose levels should lead to an improvement of the metabolic situation. To conclude, the primary goal of treating PWS patients should be increasing life quality and prevention of late complications. Weight management serves both goals and is therefore the primary objective in this context. The assistance in a group instead of individual therapy proved to be of benefit for PWS patients regarding mental and medical health.