Prader-Willi Syndrome Patients Research Articles

Sleep cycling alternating pattern (CAP) expression is associated with hypersomnia and GH secretory pattern in Prader–Willi syndrome

Background and purposeHypersomnia, sleep-disordered breathing and narcoleptic traits such as rapid eye movement (REM) sleep onset periods (SOREMPs) have been reported in Prader–Willi syndrome (PWS). In a group of young adult patients with genetically confirmed PWS we evaluated sleep and breathing polysomnographically, including cycling alternating pattern (CAP), and we analyzed the potential interacting role of sleep variables, sleep-related breathing abnormalities, hypersomnia, severity of illness variables and growth hormone (GH) secretory pattern. Patients and methodsEleven males and 7 females (mean age: 27.5±5.5 years) were submitted to a full night of complete polysomnography and the multiple sleep latency test (MSLT). GH secretory pattern was evaluated by a standard GH-releasing hormone plus arginine test. Sixteen non-obese healthy subjects without sleep disturbances were recruited as controls. ResultsCompared to controls PWS patients showed reduced mean MSLT score (P<0.001), reduced mean latency of sleep (P=0.03), increased REM sleep periods (P=0.01), and increased mean CAP rate/non-rapid eye movement (NREM) (P<0.001). Only four PWS patients had apnea/hypopnea index (AHI)≥10. Conversely, significant nocturnal oxygen desaturation was frequent (83% of patients) and independent from apneas or hypopneas. In the PWS group, CAP rate/NREM showed a significant negative correlation with MSLT score (P=0.02) independently from arousals, respiratory disturbance variables, severity of illness measured by Holm's score or body mass index (BMI). PWS patients with CAP expression characterized by higher proportion of A1 subtypes presented less severe GH deficiency (P=0.01). ConclusionsOur study suggests a relationship between hypersomnia and CAP rate, and between CAP expression and GH secretory pattern in PWS, possibly reflecting underlying central dysfunctions.

Brain Developmental Abnormalities in Prader-Willi Syndrome Detected by Diffusion Tensor Imaging

The purpose of this work was to detect brain developmental abnormalities in Prader-Willi syndrome by using diffusion tensor imaging based on a high-field MRI system. Eight patients with Prader-Willi syndrome and 8 age- and gender-matched normal control subjects were examined using a high-field (3.0 T) MRI system. Trace value and fractional anisotropy were assessed simultaneously in multiple representative brain regions: the deep gray matter (putamen, caudate head, and dorsomedial thalamus) and the white matter structures (frontal and parietal white matter, posterior limb of internal capsule, and corpus callosum). In Prader-Willi syndrome patients, trace value was found to be significantly higher in the left frontal white matter and the left dorsomedial thalamus, whereas fractional anisotropy was significantly reduced in the posterior limb of the internal capsule bilaterally, the right frontal white matter, and the splenium of the corpus callosum. The observed diffusivity characteristics indicate developmental abnormalities in these areas, which are highly consistent with the clinical features of Prader-Willi syndrome. The study provides the first objective evidence that Prader-Willi syndrome patients indeed have developmental abnormalities in specific areas of the brain, providing a new window toward understanding the pathophysiology of Prader-Willi syndrome.

Growth hormone treatment and adverse events in Prader–Willi syndrome: data from KIGS (the Pfizer International Growth Database)

To evaluate the response to recombinant GH treatment and adverse events in children with Prader-Willi syndrome (PWS) from KIGS, the Pfizer International Growth Database. A total of 328 children (274 prepubertal, median age 6.0 years; 54 pubertal, median age 12.7 years) were treated for 1 year and 161 children were treated for 2 years with GH. Height standard deviation score (SDS) increased significantly during treatment; the response was greater in prepubertal (-0.7 vs.-1.8 pretreatment) compared with pubertal children (-1.5 vs.-1.8). Predictors of first-year height velocity in multiple regression analysis were GH dose, body weight (positively correlated), height SDS minus mid-parental height SDS and chronological age (negatively correlated), together accounting for 39% of the variation in response to GH. Body mass index (BMI) SDS did not change significantly during 2 years of treatment. Of all the 675 GH-treated PWS patients in KIGS, there were five cases of sudden death (age range 3-15 years). Three were obese (weight for height > 200%) and causes of death included bronchopneumonia, respiratory insufficiency and sleep apnoea. Scoliosis was the most commonly reported adverse event (n = 24), four children developed hyperglycaemia and six had presumptive diabetes (type 2 in five, and one case of type 1). Short-term growth improved in response to conventional doses of GH in children with PWS. Prior to commencement of GH, examination of the upper airways and sleep studies should be performed in PWS patients. GH should be used with caution in those with extreme obesity or disordered breathing and all patients should be closely monitored for adverse events.

Partial cerebellar hypoplasia in a patient with Prader-Willi syndrome

We report a 3-y-old male infant with Prader-Willi syndrome (PWS) caused by a de novo interstitial deletion of 15q11-q13. Additional features included a right cerebellar hemisphere hypoplasia. The extent of deletion was determined by FISH analysis using an SNRPN PW/AS probe that maps in the PWS/AS critical region (CR) and with specific 15q BACs. We unravelled an interstitial 15q11.2-q13.1 deletion spanning about 3 Mb. To date only a few other PWS patients--including autopsy cases--with CNS structural anomalies have been described. Our case report adds knowledge to the issue of brain involvement in Prader-Willi syndrome. Further MRI studies of PWS patients will be helpful to clarify a correlation between PWS and brain abnormalities.

Partial cerebellar hypoplasia in a patient with Prader‐Willi syndrome

AbstractWe report a 3‐y‐old male infant with Prader‐Willi syndrome (PWS) caused by a de novo interstitial deletion of 15q11‐q13. Additional features included a right cerebellar hemisphere hypoplasia. The extent of deletion was determined by FISH analysis using an SNRPN PW/AS probe that maps in the PWS/AS critical region (CR) and with specific 15q BACs. We unravelled an interstitial 15q11.2‐q13.1 deletion spanning about 3 Mb. Conclusion: To date only a few other PWS patients—including autopsy cases—with CNS structural anomalies have been described. Our case report adds knowledge to the issue of brain involvement in Prader‐Willi syndrome. Further MRI studies of PWS patients will be helpful to clarify a correlation between PWS and brain abnormalities.

Growth hormone therapy and scoliosis in patients with Prader–Willi syndrome

Growth hormone (GH) therapy for short stature in patients with Prader-Willi syndrome (PWS) has started worldwide, and various favorable effects have been reported. However, the possibility of progression of scoliosis arises as a new problem of the GH therapy. In this study, we analyzed whether 72 patients who have been followed up in our hospital have such a problem. They included 46 males and 26 females (41 patients with the GH therapy and 31 without it) aged from one to 49 years. Consequently, 33 (45.8%) of 72 patients had scoliosis with the Cobb angle of >10 degrees. Twenty (48.8%) of forty-one patients who received a GH therapy and 13 (41.9%) of 31 patients without the therapy had scoliosis, the frequency of scoliosis between the two groups showing no statistical difference (P = 0.56). Height velocity of scoliotic and non-scoliotic patients during the first year of the therapy was 8.59 +/- 1.92 and 10.70 +/- 2.54 cm, respectively, showing a significant difference (P < 0.001). This shows that accelerated height velocity may not induce scoliosis. Comparison of starting age of a GH treatment revealed that non-scoliotic patients received the therapy earlier than scoliotic patients (P = 0.021). Among 20 scoliotic patients who received the GH therapy, the degree of scoliosis progressed during the therapy in six patients, improved in three and fluctuated in one. Many patients showed progression of scoliosis with age irrespective of the use of GH, and some patients improved their scoliosis during the GH therapy. These findings showed that a GH therapy increases height velocity of PWS patients but does not necessarily develop scoliosis, and early start of the therapy may not be an exacerbating factor of scoliosis.

Hypocretin-1 levels in Angelman syndrome

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are neurodevelopmental disorders caused by deletion or mutation within maternal or paternal chromosome 15q11–q13, respectively. Patients with AS are poor sleepers and patients with PWS often exhibit excessive daytime sleepiness. Because of reports of low CSF hypocretin-1 levels in PWS patients with excessive daytime sleepiness, we decided to examine hypocretin-1 levels in the CSF of two AS patients with sleep abnormalities. CSF hypocretin-1 levels of our two AS patients were in the lower border of the normal range, which is similar to CSF hypocretin-1 levels found in PWS patients with excessive daytime sleepiness. The role of hypocretin-1 in the regulation of sleep in both syndromes remains undetermined.

Quantitative Analysis of SRNPN Gene Methylation by Pyrosequencing as a Diagnostic Test for Prader–Willi Syndrome and Angelman Syndrome

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are 2 distinct neurodevelopmental disorders caused primarily by deficiency of specific parental contributions at an imprinted domain within the chromosomal region 15q11.2-13. In most cases, lack of paternal contribution leads to PWS either by paternal deletion (approximately 70%) or maternal uniparental disomy (UPD; approximately 30%). Most cases of AS result from the lack of a maternal contribution from this same region by maternal deletion (approximately 70%) or by paternal UPD (approximately 5%). Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus can differentiate the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS. Sodium bisulfite-treated genomic DNA was PCR-amplified for the SNRPN gene. We used pyrosequencing to individually quantify the resulting artificial C/T sequence variation at CpG sites. Anonymized DNA samples from PWS patients (n = 40), AS patients (n = 31), and controls (n = 81) were analyzed in a blinded fashion with 2 PCR and 3 pyrosequencing reactions. We compared results from the pyrosequencing assays with those obtained with a commonly used methylation-specific PCR (MS-PCR) diagnostic protocol. The pyrosequencing assays had a sensitivity and specificity of 100% and provided quantification of methylation at 12 CpG sites within the SNRPN locus. The resulting diagnoses were 100% concordant with those obtained from the MS-PCR protocol. Pyrosequencing is a rapid and robust method for quantitative methylation analysis of the SNRPN locus and can be used as a diagnostic test for PWS and AS.

Non-chromosome 15 marker chromosome in a Prader-Willi syndrome patient with uniparental disomy

Non-chromosome 15 marker chromosome in a Prader-Willi syndrome patient with uniparental disomy

The snoRNA HBII-52 Regulates Alternative Splicing of the Serotonin Receptor 2C

The Prader-Willi syndrome is a congenital disease that is caused by the loss of paternal gene expression from a maternally imprinted region on chromosome 15. This region contains a small nucleolar RNA (snoRNA), HBII-52, that exhibits sequence complementarity to the alternatively spliced exon Vb of the serotonin receptor 5-HT(2C)R. We found that HBII-52 regulates alternative splicing of 5-HT(2C)R by binding to a silencing element in exon Vb. Prader-Willi syndrome patients do not express HBII-52. They have different 5-HT(2C)R messenger RNA (mRNA) isoforms than healthy individuals. Our results show that a snoRNA regulates the processing of an mRNA expressed from a gene located on a different chromosome, and the results indicate that a defect in pre-mRNA processing contributes to the Prader-Willi syndrome.

A long‐term population‐based clinical and morbidity review of Prader–Willi syndrome in Western Australia

An investigation of the clinical morbidity and genetic profiles of individuals with Prader-Willi syndrome (PWS) in Western Australia (WA) was undertaken as part of a wider study into the effects of intellectual disability (ID) on the life course of individuals. All persons with a diagnosis of PWS were identified from the records of the Disability Services Commission of WA (DSC). The DSC client files formed the main data source, and were supplemented by information from other state health data sets. The analysis was retrospective and quantitative in nature. A total of 56 individuals were identified, 10 of whom exhibited normal methylation patterns and so were analysed separately (PWS-like). The ages of the PWS group ranged from 0.9 to 48.3 years, with six persons deceased. Most people with PWS (76%) had mild or moderate ID, and 70% lived in their family home. The birth prevalence of the disorder was 1 in 29 500 births. Respiratory disorders, dentistry and gastrointestinal disorders were common reasons for hospital admission, with epilepsy or convulsions also reported at moderate frequency. The PWS-like group shared many clinical features in common with PWS patients, the principal exceptions being hypotonia and feeding difficulties in infancy. The estimated birth prevalence of PWS was lower than expected; however, the case ascertainment method may have excluded some individuals. Older people with PWS were generally living in sheltered accommodation. As the cohort ages, demand for places in similar accommodation will increase, adding to the existing burden on service providers. Substantial future increases in the use of medical services and hospital-based care also are predicted with the onset of age-associated disorders.

Short-Term Effects of Growth Hormone on Sleep Abnormalities in Prader-Willi Syndrome

GH was approved for Prader-Willi Syndrome (PWS) in 2000. Fatalities in individuals with PWS soon after beginning GH treatment prompted concern about GH worsening sleep apnea. We sought to determine whether GH affects sleep apnea in individuals with PWS. Twenty-five patients with PWS had overnight polysomnography (PSA) at baseline and 6 wk after starting GH. The study was conducted in a sleep lab using a standardized procedure. The patients studied had genetically confirmed PWS. PSA results were analyzed for frequency and severity of central and obstructive apnea/hypopnea events and total apnea/hypopnea index. As a group, GH improved apnea/hypopnea index by a mean of 1.2 events per hour (P = 0.02) and central events by a median of 1.7 events per hour (P < 0.001). Fourteen patients had improvement in obstructive events by a mean of 1.7 events per hour. Six patients had worsening of obstructive events on GH. Four of these patients had upper respiratory tract infections at the time of the second PSA and had tonsil/adenoid hypertrophy on otorhinolaryngological evaluation. Two patients with high serum IGF-I levels had increased obstructive events. Most of our PWS patients had improvement after short-term GH treatment, but 32% had worsening of sleep disturbance. A subset of PWS patients are at risk during this window of vulnerability shortly after initiation of GH. Because it is difficult to predict who will worsen with GH, patients with PWS should have PSA before and after starting GH and should be monitored for sleep apnea with upper respiratory tract infections. Otorhinolaryngological evaluation is warranted if sleep apnea worsens on GH. IGF-I levels should be monitored, with the goal being physiological levels.

Hormonal and Metabolic Defects in a Prader-Willi Syndrome Mouse Model with Neonatal Failure to Thrive

Prader-Willi syndrome (PWS) has a biphasic clinical phenotype with failure to thrive in the neonatal period followed by hyperphagia and severe obesity commencing in childhood among other endocrinological and neurobehavioral abnormalities. The syndrome results from loss of function of several clustered, paternally expressed genes in chromosome 15q11-q13. PWS is assumed to result from a hypothalamic defect, but the pathophysiological basis of the disorder is unknown. We hypothesize that a fetal developmental abnormality in PWS leads to the neonatal phenotype, whereas the adult phenotype results from a failure in compensatory mechanisms. To address this hypothesis and better characterize the neonatal failure to thrive phenotype during postnatal life, we studied a transgenic deletion PWS (TgPWS) mouse model that shares similarities with the first stage of the human syndrome. TgPWS mice have fetal and neonatal growth retardation associated with profoundly reduced insulin and glucagon levels. Consistent with growth retardation, TgPWS mice have deregulated liver expression of IGF system components, as revealed by quantitative gene expression studies. Lethality in TgPWS mice appears to result from severe hypoglycemia after postnatal d 2 after depletion of liver glycogen stores. Consistent with hypoglycemia, TgPWS mice appear to have increased fat oxidation. Ghrelin levels increase in TgPWS reciprocally with the falling glucose levels, suggesting that the rise in ghrelin reported in PWS patients may be secondary to a perceived energy deficiency. Together, the data reveal defects in endocrine pancreatic function as well as glucose and hepatic energy metabolism that may underlie the neonatal phenotype of PWS.

Death in two female Prader‐Willi syndrome patients during the early phase of growth hormone treatment

Reports on sudden death in Prader-Willi syndrome (PWS) patients after the start of growth hormone (GH) treatment have been published recently. We observed a 4.7-y-old girl who showed a continuous increase in pulmonary artery pressure and died of cardiorespiratory failure 7 wk after GH therapy had been initiated, and a 9.3-y-old girl with additional trisomy 21 who died during a minor respiratory infection 6 mo after GH had been started. Both patients were overweight (weight for height 127% and 224%, respectively). GH-induced fluid retention may have occurred in the younger girl. In contrast to the reported cases, our PWS patients were female. Our cases illustrate the difficulty of differentiation between possible GH side effects and the natural course of disease, in particular with respect to obesity-related comorbidity and mortality.

Death in two female Prader-Willi syndrome patients during the early phase of growth hormone treatment

Death in two female Prader-Willi syndrome patients during the early phase of growth hormone treatment

The Number of Hypothalamic Hypocretin (Orexin) Neurons Is Not Affected in Prader-Willi Syndrome

Narcoleptic patients with cataplexy have a general loss of hypocretin (orexin) in the lateral hypothalamus, possibly due to an autoimmune-mediated degeneration of the hypocretin neurons. In addition to excessive daytime sleepiness, Prader-Willi syndrome (PWS) patients may show narcolepsy-like symptoms, such as sleep-onset rapid eye movement sleep and cataplexy, independent of obesity-related sleep disturbances, which suggests a disorder of the hypocretin neurons. We hypothesized that the narcolepsy-like symptoms in PWS are caused by a decline in the number of hypocretin neurons. We estimated the number of hypocretin neurons in postmortem hypothalami using immunocytochemistry and an image analysis system. This study was conducted at the Netherlands Institute for Brain Research. Eight PWS adults, three PWS infants, and 11 controls were studied. The total number of hypocretin neurons in the lateral hypothalamus was measured. There was no significant difference in the total number of hypocretin-containing neurons among the seven PWS patients (in whom sufficient hypothalamic material was available to quantify total cell number) and seven age-matched controls, either in adults or in infants. A significant decline with age was found in adult PWS patients (r = -0.9; P = 0.037). We conclude that a decrease in the number of hypocretin neurons does not play a major role in the occurrence of narcolepsy-like symptoms in PWS.

Increased Density of Ghrelin-Expressing Cells in the Gastric Fundus and Body in Prader-Willi Syndrome

The levels of ghrelin, an orexigenic hormone secreted by oxyntic cells in the digestive tract, are elevated in Prader-Willi syndrome (PWS) and GH deficiency (GHD) patients. In this study, we hypothesized that the hyperghrelinemia observed in PWS is related to IGF-I or GH/IGF axis deficiency. We investigated the densities of ghrelin-expressing cells (GECs), the amounts of ghrelin in gastric tissues, and ghrelin levels in plasma in 16 PWS patients and compared these results with those of 13 GHD patients and comparison groups (19 normal lean and 10 normal obese subjects). In the gastric body and fundus, 2- to 3-fold increases in the numbers of GECs (P < 0.001) and in the amounts of ghrelin (P < 0.018) were noted in PWS patients vs. comparison groups, whereas GEC numbers in GHD patients were similar to those of the comparison group despite elevated fasting plasma ghrelin levels. In addition, IGF-I sd scores in PWS were not found to be correlated with GEC densities, the amounts of ghrelin expressed in gastric tissues, or plasma ghrelin levels. Our results suggest that IGF-I or GH/IGF axis deficiency appears to be unrelated to observed GEC increases in the stomach of patients with PWS.

Cause of sudden, unexpected death of Prader–Willi syndrome patients with or without growth hormone treatment

Patients with Prader-Willi syndrome (PWS) are recognized to have a tendency of sudden, unexpected death (SED), but its exact cause is unknown because of paucity of such case reports. Since growth hormone (GH) treatment was applied to PWS patients worldwide, several cases of death have been reported. However, whether the therapy is directly related to their SED remains unknown, too. We collected 13 deceased PWS patients (Group A, aged 9 months to 34 years) who had never received GH therapy, and seven deceased patients (Group B, all boys aged 0.7-15 years) having received the therapy from the registration in PWS-patient-support associations and from the literature, respectively. We then compared the cause of SED between the two groups. Irrespective of GH therapy, SED of infants under age 1 year was associated with milk aspiration or hypothalamic dysregulation of respiration, while SED of patients in early childhood or adolescence occurred at sleeping in association with preceding viral infections. In contrast, SED of four adult (>20 years of age) patients who never received GH therapy was associated with complications, such as leg cellulites and pulmonary embolism, secondary to massive obesity and diabetes mellitus (DM). Two Group-B patients (aged 14 and 20 years) without any obesity-related or diabetes-related complications died of drowning in a bath tub, and their drowning death could be related to poor respiratory control. These findings indicated that the cause of SED is not essentially different between PWS patients with and without GH treatment. Deceased PWS patients may have had underlying respiratory dysregulation and hypothalamic dysfunction, and GH therapy might have led to certain obstructive respiratory disturbances that exacerbated the respiratory conditions. This will call clinicians' attention when using GH in PWS patients, for example, careful determination of the dose of GH and careful monitoring of patient's respiratory conditions, especially in male obese patients with respiratory problems.

Increased Serum Resistin in Adults with Prader-Willi Syndrome Is Related to Obesity and Not to Insulin Resistance

Determinants of insulin resistance in Prader-Willi syndrome (PWS) are not completely understood. The discovery of several adipokines with relevant effects on insulin resistance and cardiovascular complications of metabolic syndrome offered new tools of investigation of insulin resistance in PWS. The purpose of this study was to measure serum resistin and mRNA in adipose tissue of patients with PWS, those with simple obesity, and healthy controls and correlate resistin levels with anthropometric and biochemical features. Twenty-eight adult PWS patients, 29 obese patients, and 25 healthy controls were studied. Anthropometric variables were measured and fasting serum and plasma were collected for measurement of resistin, adiponectin, leptin, lipid profile, glucose, and insulin. Serum resistin and resistin mRNA expression in adipose tissue was significantly higher in PWS patients, compared with both healthy lean controls and obese patients. Moreover, on regression analysis resistin was significantly correlated with body mass index, whereas no significant association was found between resistin and homeostasis model assessment index. A weak association between resistin and adiponectin was found in the PWS group only. However, on multivariate analysis only the correlation between resistin and body mass index remained significant. These results support a link between circulating resistin and obesity in humans but do not support a role for resistin in human insulin resistance.

Narrowed abrogation of the Angelman syndrome critical interval on human chromosome 15 does not interfere with epigenotype maintenance in somatic cells

Human chromosome 15q11-q13 involves a striking imprinted gene cluster of more than 2 Mb that is concomitant with multiple neurological disorders manifested by Prader-Willi syndrome (PWS) and Angelman syndrome (AS). PWS and AS patients with imprinting mutation have microdeletions, which share a 4.3 kb short region of overlap (SRO) at the 5' end of the paternal SNURF-SNRPN gene in PWS, or on the maternal allele, which shares a 880 bp SRO located at the 35 kb upstream of the SNURF-SNRPN promoter in AS. Recent studies have revealed an essential role of PWS-SRO in the postzygotic maintenance of the appropriate epigenotype on the paternal chromosome. For AS-SRO, however, there is insufficient experimental evidence exists to determine the direct functions. Here we show that the complete deletion of AS-SRO does not cause any anomalies of imprinted gene expression or DNA methylation on the mutated human chromosome 15, further supporting the idea that AS-SRO is dispensable for post implantation imprint maintenance. This implies that AS-SRO is not essential for the robust epigenotype preservation in somatic cells.