Plasma cholecystokinin levels in Prader‐Willi syndrome and obese subjects

The cardinal feature of individuals with Prader‐Willi syndrome (PWS) is severe hyperphagia‐mediated obesity resulting from a faulty satiety mechanism. PWS is the most common genetic cause of marked obesity. Cholecystokinin (CCK) is a 33‐amino‐acid peptide found in high levels in the gut and brain involved in mediating the satiety response to meals. Free fatty acids (FFA) are responsible for the stimulation of CCK release after a fatty meal, and CCK and plasma FFA levels rise in tandem in normal individuals. Fasting plasma CCK levels were measured by radio‐immunoassay in 33 PWS subjects with a mean age of 22.2 years ± 8.1 years and 24 obese control subjects without a known cause of their obesity with a mean age of 28.7 years ± 12.9 years. Consistent with previous findings, neither fasting plasma FFA levels (617.5 versus 486.8 μm/mL) or CCK levels (21.0 versus 19.1 pg/mL) were significantly different in PWS or control subjects, respectively. However, there was a significant correlation between fasting plasma FFA and CCK levels in obese subjects (r = 0.64, P < 0.01), this correlation was completely lacking in PWS subjects (r = −0.06, P = 0.79). This difference in correlation coefficients constitutes a large effect. There were no significant effects observed for genetic subtypes (15q11‐q13 deletion or maternal disomy 15), body mass index, percentage of fat, plasma levels of insulin, C‐peptide, glucagon or leptin, age, or gender on CCK levels in our PWS subjects. These results suggest that differences in the peripheral CCK response to FFA levels may be a factor contributing to the altered satiety response in PWS subjects. Am. J. Med. Genet. 95:67–70, 2000. © 2000 Wiley‐Liss, Inc.     

Plasma obestatin and ghrelin levels in subjects with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is an obesity syndrome characterized by rapid weight gain and excessive food intake. Food intake is regulated by the hypothalamus but directly influenced by gastrointestinal peptides responding to the nutritional status and body composition of an individual. Ghrelin, derived from preproghrelin, is secreted by the stomach and increases appetite while obestatin, a recently identified peptide derived post-translationally from preproghrelin, works in opposition to ghrelin by decreasing appetite. The objective of this study was to measure fasting obestatin and ghrelin levels in peripheral blood of subjects with PWS and compare to age and gender matched control subjects. Plasma obestatin and ghrelin levels were measured in subjects with PWS (n = 16, mean age = 16.0 +/- 13.3 years; age range 1-44 years) and age and gender matched control subjects (n = 16). Significantly higher obestatin levels were seen in the 16 PWS subjects (398 +/- 102 pg/ml) compared with 16 controls (325 +/- 109 pg/ml; matched t-test, P = 0.04), particularly in 5 young (< or =3 years old) PWS subjects (460 +/- 49 pg/ml) compared with 5 young controls (369 +/- 96 pg/ml; matched t-test, P = 0.03). No significant difference in ghrelin levels was seen between the PWS and comparison groups. No significant correlation was observed for either peptide when compared with body mass index but a significant negative correlation was seen for ghrelin and age in PWS subjects. Our observations suggest that obestatin may be higher in infants with PWS compared to comparison infants. The possibility that obestatin may contribute to the failure to thrive which is common in infants with PWS warrants further investigation.     

Coenzyme Q10 levels in Prader-Willi syndrome: comparison with obese and non-obese subjects

Coenzyme Q10 (CoQ10) is an essential component of the mitochondrial respiratory chain and an important scavenger of reactive oxygen species. Low levels are found in individuals with reduced energy expenditure, cardiac and skeletal muscle dysfunction, and mitochondrial disorders, many of these manifestations are seen in individuals with Prader-Willi syndrome (PWS). In addition, CoQ10 supplementation frequently is given to individuals with this syndrome. To determine if CoQ10 levels are decreased in PWS, we studied plasma CoQ10 levels in 16 subjects with PWS, 13 with obesity of unknown cause, and 15 subjects without obesity but of similar age and compared with body composition. Plasma CoQ10 levels were significantly decreased (P < 0.05), using several statistical approaches in subjects with PWS (0.45 +/- 0.16 microg/ml), compared to subjects without obesity (0.93 +/- 0.56 microg/ml), but not different from subjects with obesity (0.73 +/- 0.53 microg/ml). When plasma CoQ10 was normalized relative to cholesterol, triglyceride, and creatinine levels and fat and lean mass [determined by dual energy X-ray absorptiometry (DEXA)] in the subjects with either PWS or obesity, no significant differences were observed. However, a lower muscle mass was found in the PWS subjects.     

Insulin resistance and obesity-related factors in Prader-Willi syndrome: comparison with obese subjects

Prader-Willi syndrome (PWS), the most common genetic cause of marked obesity in humans, is usually due to a de novo paternally derived chromosome 15q11-q13 deletion or maternal disomy 15 [(uniparental disomy (UPD)]. Obesity is due to energy imbalance, but few studies have examined fat patterning and obesity-related factors in subjects with PWS (deletions and UPD) compared with subjects with simple obesity. We examined for differences in fatness patterning and lipid, leptin, and glucose and insulin levels in subjects with simple obesity and PWS and adjusted for gender, age, and body mass index (BMI). Fasting peripheral blood samples and cross-sectional magnetic resonance image scans at the level of the umbilicus were obtained in 55 subjects ranging in age from 10.4 to 49 years: 20 PWS deletion, 17 PWS UPD, and 18 obese controls. Subcutaneous fat area (SFA) and intra-abdominal visceral fat area (VFA) were calculated. No significant difference was seen between the PWS deletion subjects or PWS UPD subjects for fatness measurements or leptin levels. Twenty-three of 37 PWS subjects met the criteria for obesity (BMI > 95th percentile). No significant differences were observed for SFA and VFA between the PWS subjects judged to be obese and control subjects with simple obesity. There was an overall trend for decreased VFA in the PWS subjects but not significantly different. VFA was significantly positively correlated with both fasting insulin and total cholesterol in PWS deletion subjects but not in PWS UPD subjects or obese controls. Fasting insulin level was significantly lower in the obese PWS subjects compared with subjects with simple obesity, and insulin sensitivity (QUICKI) was significantly higher in PWS subjects with obesity. Homeostasis model assessment (HOMA) and QUICKI values were correlated and in opposite directions with triglycerides in the obese PWS subjects but not in the obese controls. Subjects in each group were stratified according to published criteria on the basis of their level of visceral fat (e.g. > or = 130 cm(2)) to assess the influence of VFA on metabolic abnormalities. In the obese PWS subjects, the fasting triglyceride, glucose, and insulin levels, and HOMA value were significantly elevated, while the QUICKI value was significantly lower in those with VFA > or = 130 cm(2). Such significant differences were not seen in the obese control group. Our results indicate that VFA may be regulated differently in PWS subjects compared to individuals with simple obesity. Insulin resistance is lower in PWS subjects and insulin sensitivity is higher compared with obese controls. PWS subjects with increased VFA may be at a higher risk of obesity-related complications compared to PWS subjects without increased VFA.     

Energy expenditure and physical activity in Prader-Willi syndrome: comparison with obese subjects

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder characterized by hypotonia, suck and feeding difficulties, hypogonadism, small hands and feet, developmental delay, hyperphagia and early childhood obesity and a particular facial appearance. The obesity associated with PWS is the result of a chronic imbalance between energy intake and energy expenditure (EE) due to hyperphagia, decreased physical activity, reduced metabolic rate and an inability to vomit. EE is affected by body composition as well as exercise. Individuals with PWS have a lower lean body mass (LBM) compared with controls which may contribute to reduced basal level EE. To determine the relationship among body composition, activity levels and metabolic rates, dual energy X-ray absorptiometry (DEXA) and a whole-room respiration chamber were used to measure body composition, total EE (TEE), resting EE (REE), physical activity, and mechanical work (MW) during an 8 hr monitoring period. The chamber consisted of a live-in whole-room indirect calorimeter equipped with a force platform floor to allow simultaneous measurement of EE, physical activity, and work efficiency during spontaneous activities and standardized exercise. Participants with PWS (27 with 15q11-q13 deletion and 21 with maternal disomy 15 with an average age of 23 years) had significantly decreased TEE by 20% and reduced LBM compared to 24 obese subjects. Similarly, REE was significantly reduced by 16% in the individuals with PWS relative to the comparison subjects. Total MW performed during the 8 hr monitoring period was significantly reduced by 35% in the PWS group. The energy cost of physical activity is related to the duration, intensity and type of activity and the metabolic efficiency of the individual. After adjusting group differences in LBM by analysis of variance, TEE and REE were no longer different between the two groups. Our data indicate that there is a significant reduction of EE in individuals with PWS resulting from reduced activity but also from lower energy utilization due to reduced LBM which consists primarily of muscle.     

Decreased bone mineral density in Prader-Willi syndrome: comparison with obese subjects.

Bone density, anthropometric data, and markers of bone turnover were collected on 21 subjects diagnosed with Prader-Willi syndrome (PWS) and compared with 9 subjects with obesity of unknown cause. In addition, urinary N-telopeptide levels were obtained in all subjects. N-telopeptides are the peptide fragments of type I collagen, the major bone matrix material. During periods of active bone degradation or high bone turnover, high levels of N-telopeptides are excreted in the urine. However, no significant difference was detected in the urinary N-telopeptide levels when corrected for creatinine excretion (raw or transformed data) between our subjects with obesity or PWS and the observed effect size of the between-group difference was small. Although N-telopeptide levels were higher but not significantly different in the subjects with PWS compared with obese controls, the subjects with PWS had significantly decreased total bone and spine mineral density and total bone mineral content (all P < 0.001). No differences in N-telopeptide levels or bone mineral density were observed between subjects with PWS and chromosome 15q deletion or maternal disomy. Thus, decreased bone mineral density in subjects with PWS may relate to the lack of depositing bone mineral during growth when bones are becoming more dense (e.g., during adolescence), possibly because of decreased production of sex or growth hormones and/or long-standing hypotonia. It may not be caused by loss, or active degradation, of bone matrix measurable by the methods described in this study further supporting the possible need for hormone therapy during adolescence.     

Methylation PCR analysis of Prader-Willi syndrome,Angelman syndrome,and control subjects

We report on a relatively large survey of Prader-Willi syndrome, Angelman syndrome, and control subjects with the newly described methylation polymerase chain reaction (PCR) method to determine its usefulness for molecular diagnosis. Sixty-one Prader-Willi syndrome (PWS) individuals (26 men and 35 women), 9 Angelman syndrome (AS) patients (5 men and 4 women), and 58 other individuals were studied with methylation PCR following sodium bisulfite treatment of genomic DNA. In addition, multiple tissues, including fetal tissue, were studied from several individuals to determine the effects of various tissues on methylation PCR results. The expected methylation PCR result was observed in each case. This PCR-based assay evaluates the methylation status of the CpG island of the SNRPN gene and allows for rapid molecular diagnosis of PWS or AS with less labor than Southern hybridization for methylation analysis. The PCR results were identical to those achieved by Southern hybridization in those individuals studied. Am. J. Med. Genet. 80:263–265, 1998. © 1998 Wiley-Liss, Inc.     

Comparison of leptin protein levels in Prader-Willi syndrome and control individuals

Prader-Willi syndrome (PWS) is characterized by early childhood obesity, mental deficiency, hypogonadism, hypotonia, hypopigmentation, short stature, small hands and feet, and a characteristic face. It is the most common genetic cause of obesity and obesity is the most significant health problem for PWS patients. Ob protein (leptin), which is produced by adipose tissue, is thought to play a significant role in obesity; thus, unusually low plasma leptin levels, or relative loss of sensitivity to leptin in PWS subjects, could be an important factor in their obesity. We measured plasma leptin levels in 19 obese and 14 non-obese PWS patients [mean body mass index (BMI) 37.2 and 22.0, respectively] and compared these levels to those of 28 obese controls (mean BMI 35.5) and 16 non-obese control individuals (mean BMI 21.6). The mean plasma leptin concentration (ng/ml) for obese PWS subjects was 33.4 and 23.6 for non-obese PWS subjects. Obese control leptin was 36.2 ng/ml and non-obese control was 9.9. Among the control groups, leptin levels in females were significantly higher than those in males; the obese males and females had significantly higher leptin than their respective non-obese counterparts. These differences did not hold true for the PWS subjects. Leptin levels in obese PWS males and females were similar, and the same was true of the non-obese PWS males and females. The differences between obese and non-obese PWS subjects of both sexes were small and not significant. Comparing control groups with their PWS counterparts revealed no significant differences, with one exception: circulating plasma leptin levels in non-obese PWS males were nearly five times higher than in non-obese control males with similar BMI. This difference may reflect a more female pattern of fat distribution and hypogonadism, which are characteristic of PWS males. Leptin levels in PWS patients were not obviously correlated with the chromosome 15 finding seen in the patients. Am. J. Med. Genet. 75:7–12, 1998. © 1998 Wiley-Liss, Inc.     

Carnitine and coenzyme Q10 levels in individuals with Prader-Willi syndrome

Carnitine deficiency or coenzyme Q10 (CoQ10) deficiency may present with hypotonia, poor growth, easy fatigability, and apnea. This constellation of findings can also be seen in individuals with Prader-Willi syndrome (PWS). Animal studies indicate that increased fat mass due to obesity negatively correlates with both carnitine and CoQ10 levels in skeletal muscle. Increased body fat and obesity are characteristic of individuals with PWS. Currently, there is no documentation of serum carnitine levels, and only one study investigating plasma CoQ10 levels, in individuals with PWS. Fasting serum carnitine and plasma CoQ10 levels were measured in 40 individuals with molecularly confirmed PWS (ages 1-27 years; 19 F/21 M), 11 individuals with early-onset morbid obesity of unknown etiology (ages 3-13 years; 5 F/6 M), and 35 control siblings from both groups (ages 1-24 years; 19 F/16 M). There were no significant differences among the three groups in either total carnitine, free carnitine, or CoQ10 levels. However, individuals with PWS had higher serum levels of carnitine esters (P = 0.013) and higher ester-to-free carnitine ratios (P = 0.0096) than controls suggesting a possible underlying impairment of peripheral carnitine utilization and mitochondrial energy metabolism in some individuals with PWS. Serum sampling identified no significant differences in total and free carnitine or CoQ10 levels between individuals with PWS, obese individuals, and sibling control groups. Muscle biopsy or measurement in leukocytes or cultured skin fibroblasts could be a better method to identify abnormalities in carnitine and CoQ10 metabolism in individuals with PWS than peripheral blood sampling.     

肥胖患者氧化应激和脂肪细胞因子变化

目的:研究男性单纯肥胖患者氧化应激(OS)和脂肪细胞因子变化及相互关系.方法:测定42例男性肥胖患者和32例健康非肥胖男性个体的血8-异前列腺素F2α(8-iso-PCF2α)、血浆超氧化物歧化酶(SOD)、血清丙二醛(MDA)、脂联素、瘦素、抵抗素、人肿瘤坏死因子可溶性受体1(TNF-R1)、白介素-1β(IL-1β)、白介素-6(IL-6).结果:肥胖患者8-iso-PGF2α、MDA、瘦素、TNF-RI、IL-1β和IL-6均明显高于正常对照组(P<0.05,P<0.01),脂联素和SOD均明显低于正常对照组(P<0.05,P<0.01),2组抵抗素水平无统计学意义(P>0.05).肥胖组相关分析:8-iso-PGF2α与BMI(r=0.54,P<0.05)呈正相关,与脂联素(r=-0.56,P<0.05)呈负相关,瘦素与体脂(r=-0.53,P<0.05)呈负相关,脂联素与LDL(r=-0.54,P<0.05)和IL-6(r=-0.41,P<0.05)呈负相关.多元逐步回归分析:脂联素和IL-6是影响肥胖患者OS变化的主要因素.结论:男性单纯肥胖患者存在OS和脂肪细胞因子变化,脂肪细胞因子与OS存在明显的相关性.     

Prader-Willi syndrome

Prader-Willi syndrome (PWS) is a highly variable genetic disorder affecting multiple body systems whose most consistent major manifestations include hypotonia with poor suck and poor weight gain in infancy; mild mental retardation, hypogonadism, growth hormone insufficiency causing short stature for the family, early childhood-onset hyperphagia and obesity, characteristic appearance, and behavioral and sometimes psychiatric disturbance. Many more minor characteristics can be helpful in diagnosis and important in management. PWS is an example of a genetic condition involving genomic imprinting. It can occur by three main mechanisms, which lead to absence of expression of paternally inherited genes in the 15q11.2-q13 region: paternal microdeletion, maternal uniparental disomy, and imprinting defect.     

Prader-Willi syndrome

Prader-Willi syndrome is characterized by severe infantile hypotonia with poor suck and failure to thrive; hypogonadism causing genital hypoplasia and pubertal insufficiency; characteristic facial features; early-childhood onset obesity and hyperphagia; developmental delay/mild intellectual disability; short stature; and a distinctive behavioral phenotype. Sleep abnormalities and scoliosis are common. Growth hormone insufficiency is frequent, and replacement therapy provides improvement in growth, body composition, and physical attributes. Management is otherwise largely supportive. Consensus clinical diagnostic criteria exist, but diagnosis should be confirmed through genetic testing. Prader-Willi syndrome is due to absence of paternally expressed imprinted genes at 15q11.2-q13 through paternal deletion of this region (65-75% of individuals), maternal uniparental disomy 15 (20-30%), or an imprinting defect (1-3%). Parent-specific DNA methylation analysis will detect >99% of individuals. However, additional genetic studies are necessary to identify the molecular class. There are multiple imprinted genes in this region, the loss of which contribute to the complete phenotype of Prader-Willi syndrome. However, absence of a small nucleolar organizing RNA gene, SNORD116, seems to reproduce many of the clinical features. Sibling recurrence risk is typically <1%, but higher risks may pertain in certain cases. Prenatal diagnosis is available.     

Assessment of fat-free mass from bioelectrical impedance analysis in obese women with Prader-Willi syndrome

Background: Fat-free mass (FFM) is lower in obese subjects with Prader-Willi syndrome (PWS) than in obese subjects without PWS. FFM prediction equations developed in non-PWS subjects may, thus, not work in PWS subjects.

Aim: To test whether the estimation of FFM from bioelectrical impedance analysis (BIA) in PWS subjects requires population-specific equations.

Methods: Using dual-energy X-ray absorptiometry, this study measured FFM in 27 PWS and 56 non-PWS obese women and evaluated its association with the impedance index at 50?kHz (ZI₅₀), i.e. the ratio between squared height and whole-body impedance at 50?kHz.

Results: At the same level of ZI₅₀, PWS women had a lower FFM than non-PWS women. However, when PWS-specific equations were used, FFM was accurately estimated at the population level. An equation employing a dummy variable coding for PWS status was able to explain 85% of the variance of FFM with a root mean squared error of 3.3?kg in the pooled sample (n?=?83).

Conclusion: Population-specific equations are needed to estimate FFM from BIA in obese PWS women.     

Pervasive developmental disorders in Prader-Willi syndrome: the Leuven experience in 59 subjects and controls

In the present study we investigated the co-morbidity of pervasive developmental disorder (PDD) in 59 Prader-Willi syndrome (PWS) individuals and in 59 non-specific mentally retarded controls, matched for IQ, gender, and age. The 'Pervasive Developmental Disorder Mentally Retardation Scale' (PDD-MRScale), a screening questionnaire based on the DSM-III-R criteria for PDD, has been applied in the PWS group and in the control group. Results of the present study revealed a striking autistic-like behavioral phenotype in the majority of the PWS individuals, particularly deficits in the quality of language and communication and of imagination and interests. This intersection with autistic symptomatology is an important addition to the behavioral phenotype in PWS persons. A first approach to delineate subtypes of autistic symptomalogy among PWS persons was performed. Nineteen percent of the PWS group did meet the full diagnostic DSM-III-R criteria for PDD in comparison with 15% in the control group. Results revealed that a higher IQ in PWS does not protect to develop genuine PDD and that uniparental disomy/imprinting mutation as genetic origin seems to be an additional risk factor for developing genuine PDD. The results of the present study suggest the importance of reconsidering the commonly recognized obsessive-compulsive like behavior in PWS persons within the broader spectrum of autism disorders.     

Rumination and vomiting in Prader-Willi syndrome

Inability to vomit has been cited as characteristic of Prader-Willi syndrome (PWS). Although post-prandial vomiting after gastric by-pass surgery has been reported, neither vomiting under "typical" circumstances or rumination have been described. Prompted by the discovery of several cases of vomiting and rumination, a questionnaire was sent to members of the PWS Association. Approximately 36% (113/313) of affected individuals reportedly experienced at least one episode of vomiting. Induced vomiting was unsuccessful in 9 of 14 cases in whom results were known. However, no complications of Ipecac were reported. We suggest that there is an alteration in the physiologic set-point at which vomiting occurs, leading to a decreased propensity to vomit. Liberal and strict definitions of rumination yielded 15.7% and 10.2% positive responses, respectively. Rumination was associated with a history of vomiting. Enamel deterioration consistent with rumination has been observed, and such changes should be looked for in all PWS children. In several instances, rumination was found to decrease when very strict weight control was lessened. Certain individuals may ruminate under too strict a weight control program, and weight control goals should be evaluated to achieve a reasonable compromise between ideal weight and obesity. Vomiting and rumination do not rule out the diagnosis of PWS.     

Prader-Willi syndrome.

Prader-Willi syndrome is a complex disorder affecting multiple systems with many manifestations relating to hypothalamic insufficiency. Major findings include infantile hypotonia, developmental delay and mental retardation, behaviour disorder, characteristic facial appearance, obesity, hypogonadism, and short stature. Obesity and the behavioural problems are the major causes of morbidity and mortality. Prader-Willi syndrome is caused by abnormalities of the imprinted region of proximal 15q and results from absence of the normally active paternal genes in this region. Such absence results from paternal interstitial deletion, maternal uniparental disomy, or a mutation or other abnormality in the imprinting process. Diagnostic identification of all causes has become available in recent years, permitting early detection and institution of appropriate management. This testing has permitted recent identification of some phenotypic differences among affected subjects of different race and between those with deletions and uniparental disomy as a cause.