Agitation and Aggression in Prader-Willi Syndrome

American College of Medical Genetics Statement on Diagnostic Testing for Uniparental Disomy

Introduction Prader- Willi syndrome (PWS) is a genetic condition commonly associated with hyperphagia and obesity. PWS is thought to have hypothalamic dysfunction which is the head ganglion of autonomic nervous system (ANS). In current literature, ANS is believed to be defective in PWS. ANS may also have a role in controlling orexigenic hormone ghrelin and energy expenditure. One study reported higher resting energy expenditure adjusted for lean body mass in growth hormone naive PWS group but another study found lower activity associated energy expenditure compared to controls. Other studies found adjusted basal and sleeping metabolic rates were not different to the controls. Complete profile of energy expenditure in PWS remains unclear. We hypothesize that there is defective ANS in PWS, as a result of hypothalamus dysfunction, and it leads to high orexigenic hormone, acyl ghrelin, and low energy expenditure that in turn cause obesity. Methods We compared the ANS functions, acyl ghrelin status and energy expenditure in children with PWS and controls. We recruited 16 genetically- confirmed children with PWS and 16 controls. Exclusion criteria were diabetes mellitus, psycho-trophic medications, and other hypothalamic pathologies. We performed a mixed meal challenge to assess ANS function and acyl ghrelin status of PWS and control groups. We used Bodystat 1500® to measure body composition. Orthostatic hypotension, due to gravity, stimulates baroreceptors and activates sympathetic nervous system to counter regulate postural drop in blood pressure by increasing pulse rate, stroke volume and vasoconstriction. We used orthostatic change in pulse rate (PR), blood pressure (BP), and mean arterial pressure (MAP) expressed as per cent change of PR (%ΔPR), BP (%ΔBP), and MAP (%ΔMAP) from lying to standing to access sympathetic nervous function. ANS was further stimulated by a mixed meal and we examined %ΔPR, %ΔBP, and %ΔMAP at 15 and 30 seconds after standing from recumbent position; at fasting, and post-prandial periods. We also measured plasma gastrin, catecholamines (Pcat) and urinary catecholamines (Ucat) at fasting and post- prandial periods to complement autonomic cardiovascular data. Using Actiheart®, we compared weight and fat free mass adjusted total, resting, activity- associated and non- exercise associated thermogenesis between two groups. Results PWS group was younger, shorter, and had reduced lean mass than the controls. Post-prandial %ΔPR at both 15 and 30 seconds were significantly lower in PWS group than controls. The difference in %Δ systolic BP and diastolic BP did not reach statistical significance but %ΔMAP at 60 min and 120 min after meal was significantly lower in PWS. Postprandial plasma gastrin and Ucat were higher in PWS group than controls but Pcat were not different in two groups. Fasting plasma acyl ghrelin (AG) was significantly higher in PWS but it decreased to similar level of controls at 60 and 120 minutes after a meal. The rate of fall of plasma acyl ghrelin was faster in the PWS group than the controls. Fasting AG is negatively correlated to fasting %ΔPR at 30s (r value -0.52, p= 0.04). When adjusted for both weight and fat- free- mass, PWS group had lower total, resting, activity- associated and non- exercise associated thermogenesis than the controls. Conclusions We report that there is dysautonomia, high fasting acyl ghrelin and low energy expenditures in children with PWS. In PWS, there is reduction in GABA-A receptor number and its actions as a result of the deleted genes of β3, α5, and γ3 subunit of GABA-A receptors in the PWS gene region; and probable exaggerated GABA-B receptors actions due to effect of compensatory hyper-gamma- amino- butyric- acidaemia on the normal GABA-B receptors. The abnormities lead to GABA system dysfunction in PWS. GABA is the key neurotransmitter between Nucleus Tractus Solitarius and C1 neurons that connect to the thoracic spinal cord that sends efferent neurons to sympathetic ganglions. GABA system dysfunction, therefore, may be the cause of sympathetic failure. Moreover, GABA is generally an inhibitory neurotransmitter and GABA dysfunction may be the cause of poor vagal inhibitory function that lead to high post-prandial plasma gastrin production, and increased catecholamine production from adrenal medulla probably by increase chromaffin cells gap junction communications. Our findings of dysautonomia can be explained by GABA dysfunction in PWS. Dysautonomia may also be the cause of high fasting acyl ghrelin and low energy expenditures. Therefore in PWS, there is imbalance in energy intake and expenditure resulting in obesity.

Prader–Willi and Angelman syndromes are often referred to as a sister pair of neurodevelopmental disorders, resulting from different genetic and epigenetic alterations to the same chromosomal region, 15q11-q13. Some of the primary phenotypes of the two syndromes have been suggested to be opposite to one another, but this hypothesis has yet to be tested comprehensively, and it remains unclear how opposite effects could be produced by changes to different genes in one syndrome compared to the other. We evaluated the evidence for opposite effects on sleep and eating phenotypes in Prader–Willi syndrome and Angelman syndrome, and developed physiological–genetic models that represent hypothesized causes of these differences. Sleep latency shows opposite deviations from controls in Prader–Willi and Angelman syndromes, with shorter latency in Prader–Willi syndrome by meta-analysis and longer latency in Angelman syndrome from previous studies. These differences can be accounted for by the effects of variable gene dosages of UBE3A and MAGEL2, interacting with clock genes, and leading to acceleration (in Prader–Willi syndrome) or deceleration (in Angelman syndrome) of circadian rhythms. Prader–Willi and Angelman syndromes also show evidence of opposite alterations in hyperphagic food selectivity, with more paternally biased subtypes of Angelman syndrome apparently involving increased preference for complementary foods (“baby foods”); hedonic reward from eating may also be increased in Angelman syndrome and decreased in Prader–Willi syndrome. These differences can be explained in part under a model whereby hyperphagia and food selectivity are mediated by the effects of the genes SNORD-116, UBE3A and MAGEL2, with outcomes depending upon the genotypic cause of Angelman syndrome. The diametric variation observed in sleep and eating phenotypes in Prader–Willi and Angelman syndromes is consistent with predictions from the kinship theory of imprinting, reflecting extremes of higher resource demand in Angelman syndrome and lower demand in Prader–Willi syndrome, with a special emphasis on social–attentional demands and attachment associated with bedtime, and feeding demands associated with mother-provided complementary foods compared to offspring-foraged family-type foods.

We have evaluated serum leptin concentrations in two forms of genetic obesity. The subjects examined were eight women with Down syndrome and eight women with Prader-Willi syndrome. All patients were in the reproductive age range and were obese (body mass index ≥ 21 kg/m2). Plasma leptin values ,analyzed as a function of body mass index showed a statistically significant correlation in both Prader-Willi (r = 0.985; p < 0.001) and Down syndrome patients (r = 0.943; p < 0.001). Obese Down syndrome women exhibited significantly lower leptin values (10.8 ± 1.1) as compared to patients with Prader-Willi syndrome (31 ± 2.6; p < 0.01). The linear correlation between leptin and insulin in the two groups of patients was not statistically significant. The data suggested that obesity in Prader-Willi subjects could be caused by failure of leptin to reach its target in the brain ,as a consequence of defects in the receptor or in postreceptor processing ,whereas data on obese patients with Down syndrome could be due to a different pathogenetic origin.

Hypocretin (Hcrt) is a neurotransmitter of the dorsal and lateral hypothalamus that regulates sleep, appetite, and energy consumption. Recent evidence indicates that it is also involved in pleasure/reward-seeking. Mutation of the Hcrt-receptor gene causes narcolepsy in canines, and Hcrt knockout mice exhibit narcolepsy-like symptoms. Human narcoleptics do not commonly have mutations in the ligand or receptor but do have degeneration of Hcrt-containing neurons, possibly through an autoimmune mechanism. When Hcrt neurons degenerate in mice, hypophagia and obesity are observed, symptoms that are also present in some human narcoleptics. This article reviews the recent literature with regard to the many functions of this single molecule. The authors suggest that eating habits and impulsivity may be topics worth exploring in the evaluation of narcoleptic patients.

Prader-Willi syndrome is characterized by severe hypotonia in infancy, with decreased lean mass and increased fat mass in childhood followed by severe hyperphagia and consequent obesity. Scoliosis and other orthopaedic manifestations of hypotonia are common in children with Prader-Willi syndrome and cause significant morbidity. The relationships among hypotonia, reduced muscle mass and scoliosis have been difficult to establish. Inactivating mutations in one Prader-Willi syndrome candidate gene, MAGEL2, cause a Prader-Willi-like syndrome called Schaaf-Yang syndrome, highlighting the importance of loss of MAGEL2 in Prader-Willi syndrome phenotypes. Gene-targeted mice lacking Magel2 have excess fat and decreased muscle, recapitulating altered body composition in Prader-Willi syndrome. We now demonstrate that Magel2 is expressed in the developing musculoskeletal system, and that loss of Magel2 causes muscle-related phenotypes in mice consistent with atrophy caused by altered autophagy. Magel2-null mice serve as a preclinical model for therapies targeting muscle structure and function in children lacking MAGEL2 diagnosed with Prader-Willi or Schaaf-Yang syndrome.

It's not about the height: Prader–Willi Syndrome. Effects of Growth Hormone Treatment

Disclosure: R. Sritharan: None. J. Lodge: None. S. Tadros: None. L. Menzies: None. E.F. Gevers: None. PWS is a complex neurodevelopmental disorder characterised by neonatal hypotonia,failure to thrive, hypothalamic and endocrine dysfunction, behavioural and learning difficulties and hyperphagia. It is caused by absence of expression of paternally imprinted genes on chromosome 15q11-q13. PWS is confirmed by genetic methylation analysis of this region. Most patients with PWS are referred for genetic investigations in the first months of life due to severe hypotonia and/or failure to thrive. However, it is known that some patients are still only diagnosed in adulthood, with resulting missed opportunities for prompt early treatments for PWS, such as growth hormone therapy. Little information is available on age of diagnosis of PWS, and whether opportunities to request genetic investigation are missed in childhood. We therefore aimed to study age at diagnosis of PWS in the UK. To do so, we assessed data as reported to the UK patient association PWSA-UK from 1968-2023, and additionally audited PWS genetic testing by the North Thames Genomics Laboratory Hub from 2019-22. Of 1145 people registered at PWSA as having PWS, 945 had an age of diagnosis recorded. Of these, 254 (28%) were diagnosed over 1 year of age. From March 2021 to Sept 2023, 13 were diagnosed over 1 year of age with a mean age at diagnosis of 9.27 yr (95% CI 4.15 to 14.4) and with 8 patients below 5 years of age. We assessed PWS diagnoses made in blocks of 4 years from 1968, and the number of PWS diagnoses in people over age 1 year in those time blocks. The number of diagnoses in people over 1 year of age appeared to decrease since 1996 to 7 but from 2015 this has been fluctuating. North Thames Genomics Laboratory Hub provides testing for around 10 million people in and around London. Over a 3-year period between 2019-2022, there were 59 requests for PWS testing. 28 of these were positive (a 47% diagnostic yield). 20/28 (71%) of patients were diagnosed under 1 month of age, 7% were diagnosed at 1-24 months of age, 3.5% at 2-5 yrs and 18% at &amp;gt;5 yrs of age (one at age 9, two at age 18, one at age 29 and one at 33 yrs of age). Most tests were performed in children under1 month of age (91% yield), followed by those over 5 yrs of age (30% yield). For 10 individuals, microarray was requested, however methylation studies would have been more appropriate. All patients diagnosed over 5 years of age had hypotonia and were described as hyperphagic and having intellectual disability, and 75% were obese. Patients diagnosed after age 8were described as having neonatal hypotonia and may have been eligible for genetic testing soon after birth. These data suggest that a considerable percentage of patients are diagnosed with PWS after the first year of life in the UK. Further root analysis, interventions, and education is required to reduce age at diagnosis in patients with PWS to allow for optimal management starting in the first few months of life. Presentation: 6/1/2024

To the Editor.— Dr Wett's 1 article in A PIECE OF MY MIND did it to my peace of mind. Delay of recognizing the Prader-Willi (PW) syndrome occurs ever so often. The average age when PW syndrome is diagnosed in boys is close to 10 years and older than 10 years in girls. Many cases remain undiagnosed, notably in girls. This may account for the unexplained and probably spurious sex difference: the ratio of PW syndrome boys to PW syndrome girls is ten to four. All this is in spite of the fact that close to 200 articles on PW syndrome have been published in the last 25 years. A recent monograph on PW syndrome lists more than 600 cases collected from the world literature. 2 An additional 137 cases have been collected in Japan. 3 Thus, the condition is not at all rare and there is no reason to

An Obese Female with Prader-Willi Syndrome and Daytime Sleepiness

Quality of life in children with Prader Willi Syndrome: Parent and child reports

Excessive daytime sleepiness is common in Prader-Willi syndrome (PWS), with prevalence ranging from 52% to 100%. The goal of this study was to establish the content validity (ie, evidence that an instrument measures an intended concept of interest) of the parent/caregiver version of the Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD), a measure of daytime sleepiness, in PWS. Qualitative, dyadic semistructured video interviews were conducted with 18 caregivers and their children with PWS from April to June 2020. Concept elicitation and cognitive interview techniques were implemented. Thematic analyses allowed for examination of themes and data patterns. All caregivers (mean age 49 years) were mothers of individuals with PWS who experienced troublesome daytime sleepiness (mean age 14 years). The most prevalent observable signs/symptoms of daytime sleepiness were sleepy/sleepiness (n = 17; 94.4%), tired/tiredness (n = 16; 88.9%), exhaustion/exhausted (n = 5; 27.8%), anxious/stressed (n = 5; 27.8%), irritable/frustrated (n = 5; 27.8%), having tantrums/outbursts (n = 5; 27.8%), and lethargy (n = 4; 22.2%). Daytime sleepiness impacted various aspects of health including mental, emotional, physical, and social well-being. When caregivers were asked about the activities associated with daytime sleepiness, all salient concepts elicited mapped to the ESS-CHAD; saturation was met after the first 4 interviews. Only 2 concepts, after physical exertion and while inactive/bored, did not map. Caregiver statements indicated that these concepts, although related to daytime activities, were atypical of daily routines. The ESS-CHAD was well understood and relevant to caregivers. This study supports the content validity of the ESS-CHAD and its appropriateness for evaluating treatment efficacy of daytime sleepiness in PWS. Patel VP, Patroneva A, Glaze DG, Davis K, Merikle E, Revana A. Establishing the content validity of the Epworth Sleepiness Scale for Children and Adolescents in Prader-Willi syndrome. J Clin Sleep Med. 2022;18(2):485-496.

The Sins of the Fathers and Mothers: Genomic Imprinting in Mammalian Development

Eighty seven referrals with Prader-Willi syndrome and 49 with Angelman's syndrome were studied. High resolution cytogenetics was performed on all probands. Molecular studies, performed on the proband and both parents in each case, utilised multiple probes from within and distal to the 15(q11-13) region in order to establish the presence of DNA deletion or uniparental disomy. In addition, FISH, with probes at D15S11 and GABR beta 3 from the Prader-Willi syndrome/Angelman's syndrome region, was performed on a subset of 25 of these patients. In the referral group with Prader-Willi syndrome, 62 patients had a normal karyotype and 25 were deleted on high resolution cytogenetics. Twenty nine were found to be deleted with DNA techniques. In the Angelman's syndrome group, 37 had a normal karyotype and 12 were deleted on high resolution cytogenetics while 26 were deleted on molecular studies. The diagnosis was reassessed in 35 referrals with Prader-Willi syndrome and 11 with Angelman's syndrome following a non-deleted, non-disomic result. Of individuals who were neither deleted nor disomic on DNA studies, a false positive rate of 11.4% (4/35) for Prader-Willi syndrome and 16.7% (2/12) for Angelman's syndrome was found for a cytogenetically detected deletion. The false negative rate for deletion detected on high resolution cytogenetics was 19.5% (12/62) for Prader-Willi syndrome and 35% (13/37) for Angelman's syndrome. Thus high resolution cytogenetics was shown to be unreliable for deletion detection and should not be used alone to diagnose either syndrome. There were no discrepancies with FISH in 25 cases when FISH was compared with the DNA results, indicating that FISH can be used reliably for deletion detection in both syndromes.

Obesity is a common component of NIDDM and plays an important role in the development of insulin resistance and hyperinsulinemia. Prader-Willi Syndrome(PWS) has been associated with morbid obesity and an increased propensity for early development of NIDDM. In order to shed light on the glucoregulatory mechanisms in PWS, we studied pediatric and adult PWS with normoglycemia. The objectives of this study were 1) to examine glucose (glu), insulin (ins) and c-peptide (cpep) responses to OGTT and IVGTT 2) to characterize first and second phases ins secretion 3) to assess hepatic ins extraction (HIE) in PWS subjects and 4) to determine whether beta cell function in PWS is age-dependent.. Group I consisted of 9 pediatric (PED) PWS and 22 age-, weight- and puberty stage-matched obese subjects who had OGTT. Group II consisted of 14 adult (AD) PWS and 10 age-, weight-, and BMI-matched obese AD who had OGTT. Group III consisted of 9 AD PWS and 8 age- and weight-matched obese AD who had FSIVGTT. During the OGTT in the PED group, glu levels were not significantly (sig) different in PWS vs. obese children. In contrast, the fasting, (20±6 vs. 37±4uU/ml), peak (114±24 vs. 214±23uU/ml) and total AUC for ins (12,673±2176 vs. 26,734±2608uU/ml × min) were sig lower in the PED PWS. During the OGTT in the AD groups, ins levels were not sig different in the AD PWS and obese groups. During IVGTT in AD, both the first (138±42 vs. 454±102uU/ml × min) and second (295±66 vs. 1015±231uU/ml × min) phase ins release were sig reduced in the PWS. Similarly, first and second phase cpep responses were also sig reduced in the PWS. In contrast, the mean HIE was 33% higher in PWS vs. obese group(15.4±1.5 vs. 10.3±1.6). Similarly, the post-stimulation HIE was sig greater (5.2±0.8 vs. 2.4±0.4) in the PWS group when compared to obese group. In summary, PWS manifest a) reduced β-cell responses b) increased HIE and c) a dissociation of obesity and ins resistance in contrast to obese subjects. Increased ins sensitivity as well as enhanced HIE appear to be compensatory mechanisms for the reduced β-cell function in PWS.