Prader-Willi syndrome: A primer for clinicians

PubMed Central

2011-01-01

The advent of sensitive genetic testing modalities for the diagnosis of Prader-Willi syndrome has helped to define not only the phenotypic features of the syndrome associated with the various genotypes but also to anticipate clinical and psychological problems that occur at each stage during the life span. With advances in hormone replacement therapy, particularly growth hormone children born in circumstances where therapy is available are expected to have an improved quality of life as compared to those born prior to growth hormone. This manuscript was prepared as a primer for clinicians-to serve as a resource for those of you who care for children and adults with Prader-Willi syndrome on a daily basis in your practices. Appropriate and anticipatory interventions can make a difference. PMID:22008714

Mathematical Skills in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Bertella, L.; Girelli, L.; Grugni, G.; Marchi, S.; Molinari, E.; Semenza, C.

2005-01-01

This paper investigates mathematical skills in Prader-Willi Syndrome (PWS), a pathological condition because of congenital alterations of chromosome pair 15. The following questions were addressed: (1) Are mathematical skills in PWS relatively more impaired with respect to other cognitive functions (as has been repeatedly but anecdotally…

Prader-Willi Syndrome: Genetics and Behavior.

ERIC Educational Resources Information Center

Thompson, Travis; Butler, Merlin G.; MacLean, William E., Jr.; Joseph, Beth

1996-01-01

Reviews the behavioral, cognitive, and other psychological features of Prader-Willi Syndrome (PWS), exploring their relationships to known genetic mechanisms. PWS is a genetic developmental disability characterized by a group of specific behavioral features, including an insatiable appetite. The article briefly touches on PWS-related research at…

Prader-Willi Disease: A Case Study.

ERIC Educational Resources Information Center

Forbus, William R., III

A case study focuses on the characteristics and physical management of a 15-year-old with Prader-Willi Syndrome, a birth defect associated with hypotonia, insatiable appetite, hypogonadism, central nervous system dysfunction, and abnormal growth and development . A literature review addresses studies dealing with behavior modification of obesity…

Using Stable Isotopes to Assess Reduced Physical Activity of Individuals with Prader-Willi Syndrome.

ERIC Educational Resources Information Center

Davies, Peter S. W.; Joughlin, C.

1993-01-01

This study found that the physical activity levels of 10 children with Prader-Willi syndrome were significantly reduced in comparison to children without the syndrome. Increasing activity levels in children with Prader-Willi syndrome is suggested as a way to raise total energy expenditure and control weight gain. (Author/JDD)

Anomalous basal ganglia connectivity and obsessive–compulsive behaviour in patients with Prader Willi syndrome

PubMed Central

Pujol, Jesus; Blanco-Hinojo, Laura; Esteba-Castillo, Susanna; Caixàs, Assumpta; Harrison, Ben J.; Bueno, Marta; Deus, Joan; Rigla, Mercedes; Macià, Dídac; Llorente-Onaindia, Jone; Novell-Alsina, Ramón

2016-01-01

Background Prader Willi syndrome is a genetic disorder with a behavioural expression characterized by the presence of obsessive–compulsive phenomena ranging from elaborate obsessive eating behaviour to repetitive skin picking. Obsessive–compulsive disorder (OCD) has been recently associated with abnormal functional coupling between the frontal cortex and basal ganglia. We have tested the potential association of functional connectivity anomalies in basal ganglia circuits with obsessive–compulsive behaviour in patients with Prader Willi syndrome. Methods We analyzed resting-state functional MRI in adult patients and healthy controls. Whole-brain functional connectivity maps were generated for the dorsal and ventral aspects of the caudate nucleus and putamen. A selected obsessive–compulsive behaviour assessment included typical OCD compulsions, self picking and obsessive eating behaviour. Results We included 24 adults with Prader Willi syndrome and 29 controls in our study. Patients with Prader Willi syndrome showed abnormal functional connectivity between the prefrontal cortex and basal ganglia and within subcortical structures that correlated with the presence and severity of obsessive–compulsive behaviours. In addition, abnormally heightened functional connectivity was identified in the primary sensorimotor cortex–putamen loop, which was strongly associated with self picking. Finally, obsessive eating behaviour correlated with abnormal functional connectivity both within the basal ganglia loops and between the striatum and the hypothalamus and the amygdala. Limitations Limitations of the study include the difficulty in evaluating the nature of content of obsessions in patients with Prader Willi Syndrome and the risk of excessive head motion artifact on brain imaging. Conclusion Patients with Prader Willi syndrome showed broad functional connectivity anomalies combining prefrontal loop alterations characteristic of OCD with 1) enhanced coupling in the

[Prader-Willi syndrome].

PubMed

Beccaria, L; Bosio, L; Benzi, F; Bregani, P; Achutegui, I; Chiumello, G; Livieri, C; Trifirò, G; de Toni, T; Iughetti, L; Ragusa, L; Salvatoni, A; Tonini, G; Corrias, A; Crinò, A

1999-01-01

Prader-Willi syndrome (PWS) is the most frequent cause of secondary obesity, characterized by neonatal hypotonia, dysmorphic facies, acromicria, hypogonadism, stunted growth, obesity, behavioural disturbances and cognitive impairment. Clinical diagnosis is confirmed by alteration of imprinted genes on the proximal long arm of chromosome 15 (15q11-13) for deletion, translocation, uniparental disomy for maternal chromosome 15 or imprinting center defect. Methylation test is the most reliable test for diagnosis. This issue explains diagnostic tests, clinical, metabolic, endocrinological features, and the most frequent complications observed in this syndrome. Precocious diagnosis and multidisciplinary approach allow in these patients to prevent the severe obesity and linked complications.

Prader-Willi syndrome.

PubMed

Cassidy, Suzanne B; Driscoll, Daniel J

2009-01-01

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.

Benefits and Limitations of Prenatal Screening for Prader-Willi Syndrome

PubMed Central

Butler, Merlin G.

2016-01-01

This review the status of genetic laboratory testing in Prader-Willi syndrome (PWS) due to different genetic subtypes, most often a paternally derived 15q11-q13 deletion, with benefits and limitations related to prenatal screening. Medical literature was searched for prenatal screening and genetic laboratory testing methods in use or under development and discussed in relationship to PWS. Genetic testing includes six established laboratory diagnostic approaches for PWS with direct application to prenatal screening. Ultrasonographic, obstetric and cytogenetic reports were summarized in relationship to the cause of Prader-Willi syndrome and identification of specific genetic subtypes including maternal disomy 15. Advances in genetic technology were described for diagnosing PWS specifically DNA methylation and high-resolution chromosomal SNP microarrays as current tools for genetic screening and incorporating next generation DNA sequencing for noninvasive prenatal testing (NIPT) using cell-free fetal DNA. Positive experiences are reported with NIPT for detection of numerical chromosomal problems (aneuploidies) but not for structural problems (microdeletions). These reports will be discussed along with future directions for genetic screening of PWS. In summary, this review describes and discusses the status of established and ongoing genetic testing options for PWS applicable in prenatal screening including NIPT and future directions for early diagnosis in Prader-Willi syndrome. PMID:27537837

Prader-Willi Syndrome: Causes, Characteristics, Interventions, Long-Term Consequences.

ERIC Educational Resources Information Center

Otto, Tracy L.; Barber, William H.

1992-01-01

An overview of Prader-Willi syndrome, the most common form of dysmorphic genetic obesity associated with mental retardation, is presented, with an emphasis on associated causes, characteristics, diagnosis and counseling, intervention, and long-term consequences. (Author/DB)

The Prader-Willi phenotype of fragile X syndrome.

PubMed

Nowicki, Stephen T; Tassone, Flora; Ono, Michele Y; Ferranti, Jessica; Croquette, Marie Francoise; Goodlin-Jones, Beth; Hagerman, Randi J

2007-04-01

The Prader-Willi phenotype (PWP) of fragile X syndrome (FXS) is associated with obesity and hyperphagia similar to Prader-Willi syndrome (PWS), but without cytogenetic or methylation abnormalities at 15q11-13. Thirteen cases of PWP and FXS are reported here that were identified by obesity and hyperphagia. Delayed puberty was seen in 5 of 9 cases who had entered puberty, a small penis or testicles in seven of 13 cases, and infant hypotonia and/or a poor suck in seven of 13 cases. Autism spectrum disorder occurred in 10 of 13 cases, and autism was diagnosed in seven of 13 cases. We investigated cytoplasmic interacting FMR1 protein (CYFIP) expression, which is a protein that interacts with FMR1 protein (FMRP) because the gene for CYFIP is located at 15q11-13. CYFIP mRNA levels were significantly reduced in our patients with the PWP and FXS compared to individuals without FXS (p < .001) and also individuals with FXS without PWP (p = .03).

Prader-Willi Syndrome. ARC Q&A #101-52.

ERIC Educational Resources Information Center

Arc, Arlington, TX.

This fact sheet uses a question-and-answer format to summarize what is known about Prader-Willi Syndrome (PWS), a complex genetic disorder resulting in short stature, mental retardation or learning disabilities, incomplete sexual development, characteristic behavior problems, low muscle tone, and an involuntary urge to eat constantly, which…

Prader-Willi Syndrome: A Review and Implications for Educational Intervention.

ERIC Educational Resources Information Center

Scott, Ellen M.; Smith, Tom E. C.; Hendricks, Mary D.; Polloway, Edward A.

1999-01-01

This review of Prader-Willi Syndrome notes characteristics (mental retardation and excessive overeating). Educational interventions including weight management, cognitive and educational development, behavioral interventions, and transition to adulthood are discussed. (DB)

Birth prevalence of Prader-Willi syndrome in Australia.

PubMed

Smith, A; Egan, J; Ridley, G; Haan, E; Montgomery, P; Williams, K; Elliott, E

2003-03-01

This is the first population based study to estimate the birth prevalence of DNA proven Prader-Willi syndrome. Thirty infants were reported to the Australian Paediatric Surveillance Unit between 1998 and 2000, a prevalence of 4 per 100,000 live births or approximately 1/25,000 live births per annum.

Behavioral Phenotype in Adults with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Sinnema, Margje; Einfeld, Stewart L.; Schrander-Stumpel, Constance T. R. M.; Maaskant, Marian A.; Boer, Harm; Curfs, Leopold M. G.

2011-01-01

Prader-Willi syndrome (PWS) is characterized by temper tantrums, impulsivity, mood fluctuations, difficulty with change in routine, skinpicking, stubbornness and aggression. Many studies on behavior in PWS are limited by sample size, age range, a lack of genetically confirmed diagnosis of PWS and inconsistent assessment of behavior. The aim of…

Academic Underachievement by People with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Whittington, J.; Holland, A.; Webb, T.; Butler, J.; Clarke, D.; Boer, H.

2004-01-01

Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder that is associated with the under-expression of maternally imprinted genes at the 15q11-q13 chromosomal locus. In addition to a characteristic physical and behavioural phenotype, those with the syndrome have impaired social cognition, literal mindedness and…

Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey.

PubMed

Butler, Merlin G; Manzardo, Ann M; Heinemann, Janalee; Loker, Carolyn; Loker, James

2017-06-01

Prader-Willi syndrome (PWS) is a rare, complex, neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans and leads to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS. The US Prader-Willi Syndrome Association (PWSA (USA)) syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA (USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox proportional hazards. A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015, with mean age of 29.5 ± 16 years (2 months-67 years); 70% occurred in adulthood. Respiratory failure was the most common cause, accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries and cardiopulmonary factors compared to females. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype. These findings highlight the heightened vulnerability to obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS.Genet Med advance online publication 17 November 2016.

Brief Report: Repetitive Behaviour Profiles in Williams Syndrome: Cross Syndrome Comparisons with Prader-Willi and Down Syndromes

ERIC Educational Resources Information Center

Royston, R.; Oliver, C.; Moss, J.; Adams, D.; Berg, K.; Burbidge, C.; Howlin, P.; Nelson, L.; Stinton, C.; Waite, J.

2018-01-01

This study describes the profile of repetitive behaviour in individuals with Williams syndrome, utilising cross-syndrome comparisons with people with Prader-Willi and Down syndromes. The Repetitive Behaviour Questionnaire was administered to caregivers of adults with Williams (n = 96), Prader-Willi (n = 103) and Down (n = 78) syndromes. There were…

Genetics and Mathematics: Evidence from Prader-Willi Syndrome

ERIC Educational Resources Information Center

Semenza, Carlo; Pignatti, Riccardo; Bertella, Laura; Ceriani, Francesca; Mori, Ileana; Molinari, Enrico; Giardino, Daniela; Malvestiti, Francesca; Grugni, Graziano

2008-01-01

Mathematical abilities were tested in people with Prader-Willi syndrome (PWS), using a series of basic mathematical tasks for which normative data are available. The difference between the deletion and the disomy variants of this condition was explored. While a wide phenotypic variation was found, some basic findings emerge clearly. As expected…

Characterisation of Balance Capacity in Prader-Willi Patients

ERIC Educational Resources Information Center

Capodaglio, Paolo; Menegoni, Francesco; Vismara, Luca; Cimolin, Veronica; Grugni, Graziano; Galli, Manuela

2011-01-01

Being severely overweight is a distinctive clinical feature of Prader-Willi Syndrome (PWS). This explorative study aims to characterise balance capacity in PWS as compared to non-genetically obese patients (O) and to a group of normal-weight individuals (CG). We enrolled 14 PWS patients: 8 females and 6 males (BMI = 41.3 [plus or minus] 7.3…

Visual-Motor Integration in Children with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Lo, S. T.; Collin, P. J. L.; Hokken-Koelega, A. C. S.

2015-01-01

Background: Prader-Willi syndrome (PWS) is characterised by hypotonia, hypogonadism, short stature, obesity, behavioural problems, intellectual disability, and delay in language, social and motor development. There is very limited knowledge about visual-motor integration in children with PWS. Method: Seventy-three children with PWS aged 7-17 years…

Deficits in Social Attribution Ability in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Koenig, Kathleen; Klin, Ami; Schultz, Robert

2004-01-01

Prader-Willi syndrome (PWS), a genetic form of mental retardation, involves a myriad of physical and behavioral problems. Poor social adjustment has been reported, but the origin of this difficulty is unknown. The Social Attribution Task, a measure of one's ability to make appropriate social attributions from an ambiguous visual display [Klin…

[Behavioural phenotypes in Prader-Willi syndrome].

PubMed

Rosell-Raga, L

2003-02-01

The behavioural phenotype of Prader-Willi syndrome (PWS) is defined by a neurological profile and a characteristic pattern of behavioural disorders which include cognitive deficits, learning difficulties and behavioural problems, which increase with age, both in number and gravity. We review the behavioural phenotype of the cases of PWS in the Valencian Community, together with their peculiar behaviours, and analyse how these generate family and social problems. The description of a peculiar behaviour opens up new horizons when understanding and treating PWS, both from a pharmacological and neuropsychological perspective.

ADHD Symptoms and Insistence on Sameness in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Wigren, M.; Hansen, S.

2005-01-01

Background: Apart from a pervasive eating disorder, the Prader-Willi (PWS) syndrome is characterized by a distinct behavioural profile comprising maladaptive behaviours, obsessive-compulsive traits and skin picking, all included in the PWS behavioural phenotype. In this study, we present a further delineation of this characteristic behavioural…

Postural Strategies in Prader-Willi and Down Syndrome Patients

ERIC Educational Resources Information Center

Cimolin, Veronica; Galli, Manuela; Grugni, Graziano; Vismara, Luca; Precilios, Helmer; Albertini, Giorgio; Rigoldi, Chiara; Capodaglio, Paolo

2011-01-01

Patients affected by Down (DS) and Prader-Willi syndrome (PWS) are characterised by some common clinical and functional features including gait disorders and reduced postural control. The aim of our study was to quantitatively compare postural control in adult PWS and DS. We studied 12 PWS and 19 DS adult patients matched for age, height, weight…

Cognitive Strengths and Weaknesses Associated with Prader-Willi Syndrome.

ERIC Educational Resources Information Center

Conners, Frances A.; Rosenquist, Celia J.; Atwell, Julie A.; Klinger, Laura Grofer

2000-01-01

Nine adults with Prader-Willi syndrome (PWS) and nine age- and IQ-matched adults with PWS completed standardized tests of long-term and short-term memory, visual and auditory processing, and reading and mathematics achievement. Contrary to previous findings, long-term memory in PWS subjects was strong relative to IQ and there was no evidence that…

Life Satisfaction among Mothers of Individuals with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Shivers, Carolyn M.; Leonczyk, Caroline L.; Dykens, Elisabeth M.

2016-01-01

Mothers of individuals with Prader-Willi syndrome (PWS) often experience numerous stressors, even when compared to mothers of children with other intellectual and developmental disabilities. Despite this, these mothers show great variability in self-reported life satisfaction. Using data from a longitudinal study of individuals with PWS and their…

Clinical management of a child with Prader-Willi Syndrome from maternal uniparental disomy (UPD) genetic inheritance.

PubMed

Bellon-Harn, Monica L

2005-01-01

Prader-Willi Syndrome (PWS) is reported in 1 in 10,000-15,000 individuals. Unfortunately, many cases are missed due to clinicians' lack of familiarity with the syndrome as well as clinical and laboratory diagnostic criteria. Although common clinical characteristics are reported, variety exists in the nature and severity of dysfunction associated with PWS. Case studies can provide information to understand relationships between phenotypic characteristics and genetic inheritance, which can in turn lead to effective clinical management. The purpose of this case study was to describe the characteristics of a child with PWS due to maternal uniparental disomy inheritance pattern and to describe clinical management and treatment outcomes. The reader will obtain information about: (1) the genetic inheritance patterns and clinical characteristics of Prader-Willi Syndrome, (2) genotypic/phenotypic relationships specific to Prader-Willi Syndrome, and (3) clinical implications, management, and outcomes in a case description of a child with PWS due to maternal uniparental disomy inheritance pattern.

Prader-Willi Syndrome: Quality of Life Issues in Home, School and Community.

ERIC Educational Resources Information Center

James, Terrance N.; Brown, Roy I.

1993-01-01

Management of psychosocial aspects of Prader-Willi syndrome is considered for several quality of life issues, including social change, increased life expectancy, parent stress, child stress, independence, residential options, and access to services. (JDD)

Imprinting mutations suggested by abnormal DNA methylation patterns in familial angelman and Prader-Willi syndromes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Reis, A.; Dittrich, B.; Buiting, K.

1994-05-01

The D15S9 and D15S63 loci in the Prader-Willi/Angelman syndrome region on chromosome 15 are subject to parent-of-origin-specific DNA methylation. The authors have found two Prader-Willi syndrome families in which the patients carry a maternal methylation imprint on the paternal chromosome. In one of these families, the patients have a small deletion encompassing the gene for the small nuclear ribonucleoprotein polypeptide N, which maps 130 kb telomeric to D15S63. Furthermore, they have identified a pair of nondeletion Angelman syndrome sibs and two isolated Angelman syndrome patients who carry a paternal methylation imprint on the maternal chromosome. These Angelman and Prader-Willi syndromemore » patients may have a defect in the imprinting process in 15q11-13. The authors propose a model in which a cis-acting mutation prevents the resetting of the imprinting signal in the germ line and thus disturbs the expression of imprinted genes in this region. 39 refs., 4 figs., 1 tab.« less

A Neuropsychological Assessment of Frontal Cognitive Functions in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Jauregi, J.; Arias, C.; Vegas, O.; Alen, F.; Martinez, S.; Copet, P.; Thuilleaux, D.

2007-01-01

Background: Prader-Willi syndrome (PWS) is associated with a characteristic behavioural phenotype whose main features are, alongside compulsive hyperphagia, deficits in social behaviour: social withdrawal, temper tantrums, perseverative speech and behaviour, mental rigidity, stereotyped behaviour, impulsiveness, etc. Similar symptoms may also be…

Tenth annual scientific conference of the Prader-Willi Syndrome Association (USA), July 19, 1995, Seattle, Washington

DOE Office of Scientific and Technical Information (OSTI.GOV)

Holm, V.A.; Hudgins, L.; Cassidy, S.B.

Each year for the last 10 years, scientists conducting research on Prader-Willi syndrome have come together to exchange information during a scientific conference held in conjunction with the annual Prader-Willi Syndrome Association (USA) meeting. Presentations based on submitted abstracts encompass such varied fields as genetics, endocrinology, pediatrics, nutrition, psychology, psychiatry, and education. This year`s scientific conference was held in Seattle, Washington, on July 19, 1995, in conjunction with the 14th PWSA (USA) meeting held July 20-23. Seventeen reports were presented at the scientific meeting, the abstracts of which follow.

Severe tooth wear in Prader-Willi syndrome. A case–control study

PubMed Central

2012-01-01

Our study provides evidence that tooth wear, in terms of both erosion and attrition, is a severe problem in Prader-Willi syndrome. There is therefore considerable need for prosthodontic rehabilitation in young adults with PWS. PMID:22639910

Severe tooth wear in Prader-Willi syndrome. A case-control study.

PubMed

Saeves, Ronnaug; Espelid, Ivar; Storhaug, Kari; Sandvik, Leiv; Nordgarden, Hilde

2012-05-28

wear, in terms of both erosion and attrition, is a severe problem in Prader-Willi syndrome. There is therefore considerable need for prosthodontic rehabilitation in young adults with PWS.

Students with Prader-Willi Syndrome: Case Law under the IDEA

ERIC Educational Resources Information Center

Zirkel, Perry A.

2017-01-01

Prader-Willi Syndrome (PWS) is one of the low-incidence physical disabilities that the literature has not addressed in relation to the Individuals with Disabilities Education Act and its case law applications. To help fill the gap, this relatively brief article provides (a) an introduction of PWS from legal sources; (b) an overview of the IDEA,…

Water Intake and Risk of Hyponatraemia in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Akefeldt, A.

2009-01-01

Background and Methods: Unusual water intake and drinking behaviour has occasionally been observed in individuals with Prader-Willi syndrome (PWS). The aim of this study is to explore whether this observation is a part of the PWS phenotype and what the consequences may be. The parents of 51 individuals with PWS (age range 2-40 years) were asked by…

Refining Behavioral Phenotypes: Personality-Motivation in Williams and Prader-Willi Syndromes.

ERIC Educational Resources Information Center

Dykens, Elisabeth M.; Rosner, Beth A.

1999-01-01

Personality-motivation was compared for age- and gender-matched individuals with Williams (n=35) or Prader-Willi (n=35) syndromes or mental retardation due to nonspecific causes (n=35). Each syndrome featured aberrant motivational profiles and similarities were found across groups in social interaction, anxiety, and orderliness. Recommendations…

Exploring Patterns of Unwanted Behaviours in Adults with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Pignatti, Riccardo; Mori, Ileana; Bertella, Laura; Grugni, Graziano; Giardino, Daniela; Molinari, Enrico

2013-01-01

Background: Obsessive-compulsive (O-C) traits, and excessive food intake are well known behavioural manifestations among individuals with Prader-Willi Syndrome (PWS). Other unwanted behaviours are also frequently observed, but they need a more specific investigation, especially in the adult population. Methods: The behaviour of 31 PWS adults was…

Behavior in Prader-Willi Syndrome: Relationship to Genetic Subtypes and Age

ERIC Educational Resources Information Center

Dykens, Elisabeth M.; Roof, Elizabeth

2008-01-01

Background: Some behavioral features of Prader-Willi syndrome (PWS) are associated with the major genetic subtypes of this disorder. While most agree that those with maternal uniparental disomy (UPD) have a distinctive cognitive and psychiatric profile, findings are more controversial regarding possible differences among persons who vary in…

A Measure of Food Seeking in Individuals with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Young, J.; Zarcone, J.; Holsen, L.; Anderson, M. C.; Hall, S.; Richman, D.; Butler, M. G.; Thompson, T.

2006-01-01

Background: Individuals with Prader-Willi syndrome (PWS), a chromosome 15 genetic disorder, often have a significant preoccupation with food and problem behaviour related to food seeking is often prevalent. Methods: In the present study, we compared how individuals with PWS responded on a survey regarding the acceptability of food in various…

Prader-Willi Syndrome, Management of Impulsivity, and Hyperphagia in an Adolescent.

PubMed

Puri, M Rehan; Sahl, Robert; Ogden, Shawwna; Malik, Salma

2016-05-01

The aim of this article is to review related literature on management of hyperphagia and impulsive behaviors in Prader-Willi syndrome (PWS) that includes either naltrexone or bupropion. In this article we also discuss a case of a 13-year-old female with PWS struggling with some behavioral and psychiatric symptoms.

Face Discrimination Skills in Prader-Willi Syndrome and Autism Spectrum Disorder

ERIC Educational Resources Information Center

Feldman, Benjamin H.; Dimitropoulos, Anastasia

2014-01-01

Individuals with Prader-Willi Syndrome (PWS) are at risk for autism spectrum disorder (ASD), including socialization problems. The PWS chromosome 15q11-13 maternal uniparental disomy (mUPD) subtype displays greater ASD symptoms than the paternal deletion (DEL) subtype. Since interpreting faces leads to successful socialization, we compared face…

Self Concept in People with Williams Syndrome and Prader-Willi Syndrome

ERIC Educational Resources Information Center

Plesa-Skwerer, Daniela; Sullivan, Kate; Joffre, Kristen; Tager-Flusberg, Helen

2004-01-01

This study explored self concepts in matched groups of adolescents and adults with Williams syndrome (WS) and Prader-Willi syndrome (PWS), using Damon and Hart's [Self-understanding in Childhood and Adolescence, Cambridge University Press, New York, 1988] semi-structured interview. The main findings were that the WS participants were more…

Prader-Willi Syndrome: Intellectual Abilities and Behavioural Features by Genetic Subtype

ERIC Educational Resources Information Center

Milner, Katja M.; Craig, Ellen E.; Thompson, Russell J.; Veltman, Marijcke W. M.; Simon Thomas, N.; Roberts, Sian; Bellamy, Margaret; Curran, Sarah R.; Sporikou, Caroline M. J.; Bolton, Patrick F.

2005-01-01

Background: Studies of chromosome 15 abnormality have implicated over-expression of paternally imprinted genes in the 15q11-13 region in the aetiology of autism. To test this hypothesis we compared individuals with Prader-Willi syndrome (PWS) due to uniparental disomy (UPD--where paternally imprinted genes are over-expressed) to individuals with…

Excessive appetitive arousal in Prader-Willi syndrome.

PubMed

Hinton, E C; Isles, A R; Williams, N M; Parkinson, J A

2010-02-01

This study focused on genetic and behavioural aspects of one important component of the motivation to eat - how appetitive arousal is elicited through the presentation of food-associated stimuli. Individuals with Prader-Willi syndrome, a genetic disorder associated with hyperphagia, and control participants completed a computerised response task in the presence of motivational stimuli. In controls, appetitive arousal was specific to particular stimuli. In contrast, individuals with PWS showed a non-specific pattern of arousal. Over-activation of the anticipatory motivation system may be one consequence of the genetic disorder in PWS. 2009 Elsevier Ltd. All rights reserved.

Prader-Willi syndrome in a child with XYY.

PubMed

Honma, A; Ishii, R; Ito, A; Kato, M; Saitoh, S; Hayasaka, K

1999-01-01

We report a 26-month-old boy with XYY syndrome, with the complication of Prader-Willi syndrome (PWS) due to uniparental maternal disomy of chromosome 15. To our knowledge, this is the first case of XYY syndrome and PWS. Clinical findings were fully compatible with the diagnostic criteria for PWS. Molecular analysis revealed a maternal heterodisomy of chromosome 15, indicating that non-disjunction of chromosome 15 had occurred at maternal meiosis I, and that the non-disjunction of chromosome Y and of chromosome 15 had occurred independently.

Exploring patterns of unwanted behaviours in adults with Prader-Willi syndrome.

PubMed

Pignatti, Riccardo; Mori, Ileana; Bertella, Laura; Grugni, Graziano; Giardino, Daniela; Molinari, Enrico

2013-11-01

Obsessive-compulsive (O-C) traits, and excessive food intake are well known behavioural manifestations among individuals with Prader-Willi Syndrome (PWS). Other unwanted behaviours are also frequently observed, but they need a more specific investigation, especially in the adult population. The behaviour of 31 PWS adults was investigated via the Symptom Checklist-90-Revised (SCL-90-R), the Yale-Brown Obsessive Compulsive Scale Symptom Checklist (Y-BOCS-SC), and the Prader-Willi Behavioural Checklist (PBC). The PBC is a quick screening questionnaire prompted specifically for the investigation on adults with PWS. Statistical clustering revealed two patterns of unwanted behaviours from the PBC. Behaviours belonging to the first cluster (e.g., Excessive food intake, Skin picking) appear to be linked to the usual phenotypic manifestation of PWS. By contrast, many other behaviours (e.g., some O-C symptoms and aggressive actions) could show a relationship also to individual psychopathologies. Both internal (Anxiety and Depression) and external (Hostility) difficulties in managing impulses should account for individually distinct behaviours in adults with PWS. © 2013 John Wiley & Sons Ltd.

A Mindfulness-Based Health Wellness Program for Individuals with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Singh, Nirbhay N.; Lancioni, Giulio E.; Singh, Ashvind N. A.; Winton, Alan S. W.; Singh, Angela D. A.; Singh, Judy

2011-01-01

Individuals with Prader-Willi syndrome (PWS) are often overweight or obese because of their delayed satiety response. Three individuals with PWS participated in a long-term, multicomponent mindfulness-based health wellness program to reduce their obesity by changing their lifestyles. The components included (a) physical exercise, (b) food…

The Relationship between Specific Cognitive Impairment and Behaviour in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Woodcock, K. A.; Oliver, C.; Humphreys, G. W.

2011-01-01

Background: Individuals with Prader-Willi syndrome (PWS) have been shown to demonstrate a particular cognitive deficit in attention switching and high levels of preference for routine and temper outbursts. This study assesses whether a specific pathway between a cognitive deficit and behaviour via environmental interaction can exist in individuals…

Behavioral and Emotional Symptoms of Children and Adolescents with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Reddy, Linda A.; Pfeiffer, Steven I.

2007-01-01

To examine the behavioral and emotional difficulties of 73 children and adolescents with Prader-Willi Syndrome (PWS), mental retardation-only, and dual diagnosis (i.e., mental retardation and psychiatrically disordered) on the Devereux Scales of Mental Disorders (DSMD: Naglieri, LeBuffe, & Pfeiffer, "Devereux Scales of Mental Disorders" (DSMD) San…

The Effect of Vision on Postural Strategies in Prader-Willi Patients

ERIC Educational Resources Information Center

Cimolin, Veronica; Galli, Manuela; Vismara, Luca; Grugni, Graziano; Priano, Lorenzo; Capodaglio, Paolo

2011-01-01

The aim of this study was to quantify the role of visual contribution in patients with Prader-Willi syndrome (PWS) on balance maintenance using a force platform. We enrolled 14 individuals with PWS free from conditions associated with impaired balance, 44 obese (OG) and 20 healthy controls (CG). Postural sway was measured for 60 s while standing…

Sex and Genes, Part 1: Sexuality and down, Prader-Willi, and Williams Syndromes

ERIC Educational Resources Information Center

Watson, Shelley Lynn; Richards, Deborah A.; Miodrag, Nancy; Fedoroff, J. Paul

2012-01-01

Specific genetic syndromes affect individuals' sexual development, experiences, and fertility. Individuals with specific syndromes can also display inappropriate sexual behavior resulting from vulnerabilities presented by their genetic makeup. Using clinical case studies, we discuss the specific impact that Down, Prader-Willi, and Williams…

The Relationship between Components of the Behavioural Phenotype in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Oliver, Chris; Woodcock, Kate A.; Humphreys, Glyn W.

2009-01-01

Background: Repetitive questions and temper outbursts form part of the behavioural phenotype of Prader-Willi syndrome (PWS). We investigated the phenomenology of temper outbursts in PWS and their relationship with other PWS behavioural characteristics. Method: Four individuals with PWS were observed (5-10 h), during a number of experimental and…

Physical health problems in adults with Prader-Willi syndrome.

PubMed

Sinnema, Margje; Maaskant, Marian A; van Schrojenstein Lantman-de Valk, Henny M J; van Nieuwpoort, I Caroline; Drent, Madeleine L; Curfs, Leopold M G; Schrander-Stumpel, Constance T R M

2011-09-01

Prader-Willi syndrome (PWS) is a genetic disorder which is characterized by severe hypotonia and feeding problems in early infancy. In later childhood and adolescence, this is followed by hyperphagia and extreme obesity if the diet is not strictly controlled. Data on physical health problems in adults with PWS are scarce. We report on the prevalence of physical health problems in a Dutch cohort of adults with PWS in relation to age, BMI, and genetic subtype. Participants (n = 102) were retrieved via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with intellectual disabilities (ID). Details regarding physical health problem spanning the participants' lifespan were collected from caretakers through semi-structured interviews. Cardiovascular problems included diabetes mellitus, hypertension, and cerebrovascular accidents. Respiratory infections were frequent in adulthood. In males, cryptorchidism was almost universal, for which 28/48 males had a history of surgery, mostly orchidopexy. None of the women had a regular menstrual cycle. Sixteen individuals had a diagnosis of osteoporosis. Spinal deformation, hip dysplasia, and foot abnormalities were common. Skinpicking, leg edema, and erysipelas were frequent dermatological problems. The findings in our group support the notion that the prevalence of physical health problems is underestimated. This underscores the importance of developing monitoring programs which would help to recognize physical health problems at an early stage. Copyright © 2011 Wiley-Liss, Inc.

Recognition of Emotion in Facial Expression by People with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Whittington, J.; Holland, T.

2011-01-01

Background: People with Prader-Willi syndrome (PWS) may have mild intellectual impairments but less is known about their social cognition. Most parents/carers report that people with PWS do not have normal peer relationships, although some have older or younger friends. Two specific aspects of social cognition are being able to recognise other…

Language Development in a 3-Year-Old Boy with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Atkin, Keith; Lorch, Marjorie Perlman

2007-01-01

Prader-Willi syndrome (PWS) is a genetic disorder which has widespread developmental consequences including motor, cognitive and language delay. Previous research on PWS children has focused primarily on phonological development and dysfluency. In the present study, the lexical development of a boy with PWS was investigated in a series of 18 play…

Specific treatment of Prader-Willi syndrome through cyclical rehabilitation programmes.

PubMed

Grolla, Emanuele; Andrighetto, Gilberto; Parmigiani, Pietro; Hladnik, Uros; Ferrari, Gabriela; Bernardelle, Roberta; Lago, Martina Dal; Albarello, Anna; Baschirotto, Giuseppe; Filippi, Giuseppe; Lovato, Roberto; Dolcetta, Diego

2011-01-01

 To evaluate retrospectively the efficiency of our rehabilitation programme for patients with Prader-Willi Syndrome. In total, 49 patients were examined, 21 female and 28 male, the youngest in their late teens. Prader-Willi syndrome is generally characterised by cognitive impairment, behavioural abnormalities, and hyperphagia. Patients are usually considerably adverse to any form of physical exercise, and despite hormonal therapy, weight control in adult patients can be difficult.  Four times a year, disease-specific residential programmes were organised, each lasting 4 weeks. The patients were restricted to a 1500 Kcal diet. In addition, they were required to do 6.5 h of physical exercise daily, stamina being built up by using music therapy, psychomotor therapy, education and entertainment activities. BMI decreased by 2.1 average points in every residential session. For three patients who attended our treatments regularly, a reduction of 8.9 points over 6 years was recorded. An attendance of at least three sessions per year seemed to be necessary to substantially reduce weight. A multidisciplinary approach and a daily calorie-counted diet can lead to significant weight loss in teenage and adult PWS patients. This approach would also be suitable in treating patients with other obesity syndromes with mental retardation.

Perceptions of Body Image by Persons with Prader-Willi Syndrome and Their Parents

ERIC Educational Resources Information Center

Napolitano, Deborah A.; Zarcone, Jennifer; Nielsen, Sarah; Wang, Hongyue; Caliendo, Jillian Maynard

2010-01-01

Prader-Willi syndrome is a genetic disorder characterized by obesity. The Figure Rating Scale (Stunkard, Sorensen, & Schulsinger, 1983) was completed by 43 individuals with this syndrome to determine their level of dissatisfaction with their body. Their parents also completed this scale regarding their child to determine whether they were…

"Hungry Eyes": Visual Processing of Food Images in Adults with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Key, A. P. F.; Dykens, E. M.

2008-01-01

Background: Prader-Willi syndrome (PWS) is a genetic disorder associated with intellectual disabilities, compulsivity, hyperphagia and increased risks of life-threatening obesity. Food preferences in people with PWS are well documented, but research has yet to focus on other properties of food in PWS, including composition and suitability for…

Assessment of Executive Functions in Prader-Willi Syndrome and Relationship with Intellectual Level

ERIC Educational Resources Information Center

Chevalere, J.; Postal, V.; Jauregui, J.; Copet, P.; Laurier, V.; Thuilleaux, D.

2013-01-01

Introduction: The aim of the present study was to determine whether individuals with Prader--Willi syndrome (PWS) have impaired global executive functioning and whether this deficit is linked with intellectual disability. Another objective focussed on the variability in performance of intellectual quotient (IQ) and executive functions (EF)…

A Mindfulness-Based Health Wellness Program for an Adolescent with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Singh, Nirbhay N.; Lancioni, Giulio E.; Singh, Ashvind N.; Winton, Alan S. W.; Singh, Judy; McAleavey, Kristen M.; Adkins, Angela D.

2008-01-01

Individuals with Prader-Willi syndrome have hyperphagia, a characteristic eating disorder defined by a marked delay in the satiety response when compared to controls. This eating disorder has been particularly difficult to control. The authors taught and evaluated effectiveness of regular exercise alone, regular exercise plus healthy eating, and…

Effectiveness of a 6-Month Home-Based Training Program in Prader-Willi Patients

ERIC Educational Resources Information Center

Vismara, Luca; Cimolin, Veronica; Grugni, Graziano; Galli, Manuela; Parisio, Cinzia; Sibilia, Olivia; Capodaglio, Paolo

2010-01-01

In addition to hypotonia and relative sarcopenia, patients with Prader-Willi syndrome (PWS) show reduced spontaneous physical activity and gait disorders. Scant evidence exists that daily muscle training increases their lean mass and physical activity levels. Whether adequate long-term physical training is feasible and effective in improving…

Genetics of Prader-Willi syndrome and Prader-Will-Like syndrome

PubMed Central

2016-01-01

The Prader-Willi syndrome (PWS) is a human imprinting disorder resulting from genomic alterations that inactivate imprinted, paternally expressed genes in human chromosome region 15q11-q13. This genetic condition appears to be a contiguous gene syndrome caused by the loss of at least 2 of a number of genes expressed exclusively from the paternal allele, including SNRPN, MKRN3, MAGEL2, NDN and several snoRNAs, but it is not yet well known which specific genes in this region are associated with this syndrome. Prader-Will-Like syndrome (PWLS) share features of the PWS phenotype and the gene functions disrupted in PWLS are likely to lie in genetic pathways that are important for the development of PWS phenotype. However, the genetic basis of these rare disorders differs and the absence of a correct diagnosis may worsen the prognosis of these individuals due to the endocrine-metabolic malfunctioning associated with the PWS. Therefore, clinicians face a challenge in determining when to request the specific molecular test used to identify patients with classical PWS because the signs and symptoms of PWS are common to other syndromes such as PWLS. This review aims to provide an overview of current knowledge relating to the genetics of PWS and PWLS, with an emphasis on identification of patients that may benefit from further investigation and genetic screening. PMID:27777904

Genetics of Prader-Willi syndrome and Prader-Will-Like syndrome.

PubMed

Cheon, Chong Kun

2016-09-01

The Prader-Willi syndrome (PWS) is a human imprinting disorder resulting from genomic alterations that inactivate imprinted, paternally expressed genes in human chromosome region 15q11-q13. This genetic condition appears to be a contiguous gene syndrome caused by the loss of at least 2 of a number of genes expressed exclusively from the paternal allele, including SNRPN , MKRN3 , MAGEL2 , NDN and several snoRNAs , but it is not yet well known which specific genes in this region are associated with this syndrome. Prader-Will-Like syndrome (PWLS) share features of the PWS phenotype and the gene functions disrupted in PWLS are likely to lie in genetic pathways that are important for the development of PWS phenotype. However, the genetic basis of these rare disorders differs and the absence of a correct diagnosis may worsen the prognosis of these individuals due to the endocrine-metabolic malfunctioning associated with the PWS. Therefore, clinicians face a challenge in determining when to request the specific molecular test used to identify patients with classical PWS because the signs and symptoms of PWS are common to other syndromes such as PWLS. This review aims to provide an overview of current knowledge relating to the genetics of PWS and PWLS, with an emphasis on identification of patients that may benefit from further investigation and genetic screening.

Cognitive and Adaptive Advantages of Growth Hormone Treatment in Children with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Dykens, Elisabeth M.; Roof, Elizabeth; Hunt-Hawkins, Hailee

2017-01-01

Background: People with Prader-Willi syndrome (PWS) typically have mild to moderate intellectual deficits, compulsivity, hyperphagia, obesity, and growth hormone deficiencies. Growth hormone treatment (GHT) in PWS has well-established salutatory effects on linear growth and body composition, yet cognitive benefits of GHT, seen in other patient…

Obesity management in Prader-Willi syndrome.

PubMed

Salehi, Parisa; Leavitt, Anne; Beck, Anita E; Chen, Maida L; Roth, Christian L

2015-03-01

Prader-Willi Syndrome (PWS) is one of the most common genetic causes of obesity. The phenotype of obesity in PWS is unique and characterized by hyperphagia, earlier meal initiation, delayed meal termination, reduced energy expenditure, abnormal gut hormone profiles, as well as irregular responses to food in areas of the brain associated with satiety and reward. Management of obesity is necessary to avoid major morbidity. The relentless food-seeking behavior associated with PWS such as stealing, hoarding food, eating inedibles, and lying about eating, can cause turmoil both inside and outside of the home. Management is challenging for both patients and caretakers, but at this time there are limited medical therapies available besides dietary restriction and behavior management. However, current research shows promise for discovery of additional treatment options for hyperphagia and obesity management in PWS.

Social Responsiveness and Competence in Prader-Willi Syndrome: Direct Comparison to Autism Spectrum Disorder

ERIC Educational Resources Information Center

Dimitropoulos, Anastasia; Ho, Alan; Feldman, Benjamin

2013-01-01

Prader-Willi syndrome (PWS), a neurodevelopmental disorder primarily characterized by hyperphagia and food preoccupations, is caused by the absence of expression of the paternally active genes in the proximal arm of chromosome 15. Although maladaptive behavior and the cognitive profile in PWS have been well characterized, social functioning has…

Repetitive and Ritualistic Behaviour in Children with Prader-Willi Syndrome and Children with Autism

ERIC Educational Resources Information Center

Greaves, N.; Prince, E.; Evans, D. W.; Charman, T.

2006-01-01

Background: Recent research has shown that the range of repetitive behaviour seen in individuals with Prader-Willi syndrome (PWS) extends beyond food-related behaviour. Methods: The presence and intensity of repetitive, rigid and routinized behaviour in children with PWS was compared with that seen in children with another neurodevelopmental…

Expressive and Receptive Language in Prader-Willi Syndrome: Report on Genetic Subtype Differences

ERIC Educational Resources Information Center

Dimitropoulos, Anastasia; Ferranti, Angela; Lemler, Maria

2013-01-01

Prader-Willi syndrome (PWS), most recognized for the hallmark hyperphagia and food preoccupations, is caused by the absence of expression of the paternally active genes in the q11-13 region of chromosome 15. Since the recognition of PWS as a genetic disorder, most research has focused primarily on the medical, genetic, and behavioral aspects of…

A Preliminary Analysis of the Phenomenology of Skin-Picking in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Morgan, Jessica R.; Storch, Eric A.; Woods, Douglas W.; Bodzin, Danielle; Lewin, Adam B.; Murphy, Tanya K.

2010-01-01

To examine the nature and psychosocial correlates of skin-picking behavior in youth with Prader-Willi Syndrome (PWS). Parents of 67 youth (aged 5-19 years) with PWS were recruited to complete an internet-based survey that included measures of: skin-picking behaviors, the automatic and/or focused nature of skin-picking, severity of skin-picking…

Families of Children with Prader-Willi Syndrome: Stress-Support and Relations to Child Characteristics.

ERIC Educational Resources Information Center

Hodapp, Robert M.; And Others

1997-01-01

This study examined stress-support in 42 families of 3- to 18-year-old children with Prader-Willi Syndrome. While children's age, intelligence quotient, and degree of obesity were not related to familial stress, families experienced greater stress when children showed more behavior problems overall, more externalizing and internalizing problems,…

The Transition between the Phenotypes of Prader-Willi Syndrome during Infancy and Early Childhood

ERIC Educational Resources Information Center

Butler, Jill V.; Whittington, Joyce E.; Holland, Anthony J.; McAllister, Catherine J.; Goldstone, Anthony P

2010-01-01

Aim: Prader-Willi syndrome (PWS) is a genetic disorder historically characterized by two phenotypic stages. The early phenotype in infants is associated with hypotonia, poor suck, and failure to thrive. In later childhood, PWS is associated with intellectual disability, hyperphagia, as well as growth and sex hormone deficiency. Little is known…

Cognitive Abilities and Genotype in a Population-Based Sample of People with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Whittington, J.; Holland, A.; Webb, T.; Butler, J.; Clarke, D.; Boer, H.

2004-01-01

Prader-Willi syndrome (PWS) is characterized by extreme floppiness at birth, impaired sexual development, short stature, severe over-eating, characteristic physical features and learning disabilities (LD). Impaired social cognition, literal mindedness and cognitive inflexibility are also present. The syndrome has two main genetic subtypes that…

A complete YAC contig of the Prader-Willi/Angelman chromosome region (15q11-q13) and refined localization of the SNRPN gene

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mutirangura, A.; Jayakumar, A.; Sutcliffe, J.S.

1993-12-01

Since a previous report of a partial YAC contig of the Prader-Willi/Angelman chromosome region (15q11-q13), a complete contig spanning approximately 3.5 Mb has been developed. YACs were isolated from two human genomic libraries by PCR and hybridization screening methods. Twenty-three sequence-tagged sites (STSs) were mapped within the contig, a density of [approximately]1 per 200 kb. Overlaps between YAC clones were identified by Alu-PCR dot-blot analysis and confirmed by STS mapping or hybridization with ends of YAC inserts. The gene encoding small nuclear ribonucleoprotein-associated peptide N (SNRPN), recently identified as a candidate gene for Prader-Willi syndrome, was localized within this contigmore » between markers PW71 and TD3-21. Loci mapped within and immediately flanking the Prader-Willi/Angelman chromosome region contig are ordered as follows: cen-IR39-ML34-IR4-3R-TD189-1-PW71-SNRPN-TD3-21-LS6-1-GABRB3,D15S97-GABRA5-IR10-1-CMW1-tel. This YAC contig will be a useful resource for more detailed physical mapping of the region, for generation of new DNA markers, and for mapping or cloning candidate genes for the Prader-Willi and Angelman syndromes. 36 refs., 2 figs., 2 tabs.« less

Brief Report: Repetitive Behaviour Profiles in Williams syndrome: Cross Syndrome Comparisons with Prader-Willi and Down syndromes.

PubMed

Royston, R; Oliver, C; Moss, J; Adams, D; Berg, K; Burbidge, C; Howlin, P; Nelson, L; Stinton, C; Waite, J

2018-01-01

This study describes the profile of repetitive behaviour in individuals with Williams syndrome, utilising cross-syndrome comparisons with people with Prader-Willi and Down syndromes. The Repetitive Behaviour Questionnaire was administered to caregivers of adults with Williams (n = 96), Prader-Willi (n = 103) and Down (n = 78) syndromes. There were few group differences, although participants with Williams syndrome were more likely to show body stereotypies. Individuals with Williams syndrome also showed more hoarding and less tidying behaviours than those with Down syndrome. IQ and adaptive ability were negatively associated with repetitive questioning in people with Williams syndrome. The profile of repetitive behaviour amongst individuals with Williams syndrome was similar to the comparison syndromes. The cognitive mechanisms underlying these behaviours in genetic syndromes warrant further investigation.

Neurobehavioral phenotype in Prader-Willi syndrome.

PubMed

Whittington, Joyce; Holland, Anthony

2010-11-15

The focus of this article is on the lifetime development of people with Prader-Willi syndrome (PWS) and specifically on the neurobehavioral phenotype. We consider studies of this aspect of the phenotype (the "behavioral phenotype" of the syndrome) that have confirmed that there are specific behaviors and psychiatric disorders, the propensities to which are increased in those with PWS, and cannot be accounted for by other variables such as IQ or adaptive behavior. Beginning with a description of what is observed in people with PWS, we review the evolving PWS phenotype and consider how some aspects of the phenotype might be best explained, and how this complex phenotype may relate to the equally complex genotype. We then consider in more detail some of the neurobehavioral aspects of the phenotype listed above that raise the greatest management problems for parents and carers. © 2010 Wiley-Liss, Inc.

The Neuroanatomy of Genetic Subtype Differences in Prader-Willi Syndrome

PubMed Central

Honea, Robyn A.; Holsen, Laura M.; Lepping, Rebecca J.; Perea, Rodrigo; Butler, Merlin G.; Brooks, William M.; Savage, Cary R.

2012-01-01

Objective Despite behavioral differences between genetic subtypes of Prader-Willi syndrome, no studies have been published characterizing brain structure in these subgroups. Our goal was to examine differences in the brain structure phenotype of common subtypes of Prader-Willi syndrome (PWS) [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)]. Methods Fifteen individuals with PWS due to a typical deletion ((DEL) Type I; n=5, Type II; n=10), 8 with PWS due to UPD, and 25 age-matched healthy-weight individuals (HWC) participated in structural magnetic resonance imaging (MRI) scans. A custom voxel-based morphometry processing stream was used to examine regional differences in gray and white matter volume between groups, covarying for age, sex, and body mass index (BMI). Results Overall, compared to HWC, PWS individuals had lower gray matter volumes that encompassed the prefrontal, orbitofrontal and temporal cortices, hippocampus and parahippocampal gyrus, and lower white matter volumes in the brain stem, cerebellum, medial temporal and frontal cortex. Compared to UPD, the DEL subtypes had lower gray matter volume primarily in the prefrontal and temporal cortices, and lower white matter in the parietal cortex. The UPD subtype had more extensive lower gray and white matter volumes in the orbitofrontal and limbic cortices compared to HWC. Conclusions These preliminary findings are the first structural neuroimaging findings to support potentially separate neural mechanisms mediating the behavioral differences seen in these genetic subtypes. PMID:22241551

Beneficial Effects of GH in Young Adults With Prader-Willi Syndrome: A 2-Year Crossover Trial.

PubMed

Kuppens, Renske J; Bakker, Nienke E; Siemensma, Elbrich P C; Tummers-de Lind van Wijngaarden, Roderick F A; Donze, Stephany H; Festen, Dederieke A M; van Alfen-van der Velden, Janielle A E M; Stijnen, Theo; Hokken-Koelega, Anita C S

2016-11-01

Patients with Prader-Willi syndrome (PWS) are severely at risk to develop morbid obesity, diabetes mellitus type 2, and cardiovascular disease, leading to high mortality. They have an increased fat mass (FM) and decreased lean body mass (LBM). During childhood, GH treatment counteracts the natural course of increasing obesity. Discontinuation of GH treatment at attainment of adult height (AH) might deteriorate their improved clinical condition, whereas continuation might benefit them. To investigate the effects of GH versus placebo on body composition in young adults with PWS who were GH treated for many years during childhood and had attained AH. Two-year, randomized, double-blind, placebo-controlled crossover study with stratification for gender and body mass index in 27 young adults with PWS. PWS Reference Center in The Netherlands. Crossover intervention with GH (0.67 mg/m 2 · d) and placebo, both during 1 year. Body composition, measured by dual-energy x-ray absorptiometry. During placebo, FM increased (relative change +21.5%; P < .001). Compared with placebo, GH treatment resulted in lower FM (-2.9 kg; P = .004) and higher LBM (+1.5 kg; P = .005), representing relative changes of -17.3% FM and +3.5% LBM. Both limb and trunk FM percentage were lower during GH versus placebo (relative change +17.3% and +15.6%; P < .001 and P = .007, respectively). No GH-related adverse events occurred. GH-treated young adults with PWS who have attained AH benefit from continuation of GH treatment. FM increases during placebo, whereas GH versus placebo results in lower FM and higher LBM. Thus, GH treatment maintains the improved body composition without safety concerns.

Successful treatment of heart failure in an adult patient with Prader-Willi syndrome.

PubMed

Kawano, Hiroaki; Ikeda, Tooru; Shimazaki, Koichi; Arakawa, Shuji; Matsumoto, Yuji; Hayano, Motonobu; Maemura, Koji

2013-01-01

Prader-Willi Syndrome (PWS) is a rare genetic disorder characterized by physical, psychological and physiological abnormalities. Obesity and related cardiovascular diseases are a common problem in adult patients with PWS. This report describes a case of adult PWS with heart failure associated with marked obesity and sleep-disordered breathing that was successfully treated with oxygen therapy, adaptive servoventilation, medications, diet therapy and rehabilitation.

Review of Prader-Willi syndrome: the endocrine approach

PubMed Central

Heksch, Ryan; Kamboj, Manmohan; Anglin, Kathryn

2017-01-01

Prader-Willi syndrome (PWS) is a complex genetic disorder with implications on the endocrine and neurologic systems, metabolism, and behavior. Early in life, PWS is characterized by hypotonia and failure to thrive, followed by obesity and hyperphagia. Patients with PWS develop hypothalamic dysfunction which may lead growth hormone deficiency (GHD), hypogonadism, hypothyroidism, adrenal insufficiency, and poor bone mineral density (BMD). In addition to hypothalamic dysfunction, individuals with PWS have increased risk for obesity which may be complicated by metabolic syndrome and type 2 diabetes mellitus (T2DM). In this paper, we will review the current literature pertaining to the endocrine concerns of PWS and current recommendations for screening and management of these conditions. PMID:29184809

Prader-Willi syndrome: atypical psychoses and motor dysfunctions.

PubMed

Verhoeven, Willem M A; Tuinier, Siegfried

2006-01-01

Prader-Willi syndrome (PWS) is the result of a lack of expression of genes on the paternally derived chromosome 15q11-q13 and can be considered as a hypothalamic disorder. Its behavioral phenotype is characterized by ritualistic, stereotyped, and compulsive behaviors as well as motor abnormalities. After adolescence, recurrent affective psychoses are relatively frequent, especially in patients with uniparental disomy. These psychotic states have a subacute onset with complete recovery and comprise an increase of psychomotor symptoms that show resemblance with catatonia. Some evidence has emerged that gamma-aminobutyric acid (GABA) dysfunctionality is involved in both PWS and catatonia. Treatment of these atypical psychoses should preferably include GABA mimetic compounds like lorazepam, valproic acid, and possibly topiramate.

Prader-Willi syndrome: a case report with atypical developmental features.

PubMed

Sewaybricker, Letícia E; Guaragna-Filho, Guilherme; Paula, Georgette B; Andrade, Juliana G R; Tincani, Bruna J; D'Souza-Li, Lília; Lemos-Marini, Sofia H V; Maciel-Guerra, Andréa T; Guerra-Júnior, Gil

2014-09-01

To describe the case of a male Prader-Willi syndrome (PWS) patient with atypical development features. We report the case of a male adolescent with confirmed diagnosis of PWS which presents atypical phenotype. The patient progressed with spontaneous and complete pubertal development, stature in the normal range, and weight control without any pharmacological treatment, except metformin. PWS is an imprinting paternally inherited disorder of 15q11-13 characterized by hypotonia in infant age, hyperphagia, varied degrees of mental retardation, behavior problems, hypogonadism, short stature, and other less common findings.

Analysis of N- and O-Linked Protein Glycosylation in Children with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Munce, T.; Heussler, H. S.; Bowling, F. G.

2010-01-01

Background: Current genotype-phenotype correlations in Prader-Willi syndrome (PWS) are struggling to give an explanation of the diversity in phenotype and there is a need to move towards a molecular understanding of PWS. A range of functions related to glycoproteins are involved in the pathophysiology of PWS and it may be that abnormal…

The effects of Bifidobacterium animalis ssp. lactis B94 on gastrointestinal wellness in adults with Prader-Willi syndrome: study protocol for a randomized controlled trial.

PubMed

Alyousif, Zainab; Miller, Jennifer L; Sandoval, Mariana Y; MacPherson, Chad W; Nagulesapillai, Varuni; Dahl, Wendy J

2018-04-27

Constipation is a frequent problem in adults with Prader-Willi syndrome. Certain probiotics have been shown to improve transit and gastrointestinal symptoms of adults with functional constipation. The aim of this study is to determine the effect of daily consumption of Bifidobacterium animalis ssp. lactis B94 (B. lactis B94) on stool frequency, stool form, and gastrointestinal symptoms in adults with Prader-Willi syndrome. Adults with Prader-Willi syndrome (18-75 years old, n = 36) will be recruited and enrolled in a 20-week, randomized, double-blind, placebo-controlled, crossover study. Study subjects will be randomized to B. lactis B94 or placebo each for a 4-week period, preceded by a 4-week baseline and followed by 4-week washouts. Subjects will complete daily records of stool frequency and stool form (a proxy of transit time). Dietary intake data also will be collected. Stools, one in each period, will be collected for exploratory microbiota analyses. To our knowledge, this is the first randomized controlled trial evaluating the effectiveness of B. lactis in adults with Prader-Willi syndrome. The results of this study will provide evidence of efficacy for future clinical trials in patient populations with constipation. ClinicalTrials.gov ( NCT03277157 ). Registered on 08 September 2017.

Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome

PubMed Central

Polex-Wolf, Joseph; Lam, Brian Y.H.; Larder, Rachel; Rimmington, Debra; Bosch, Fàtima; Cenzano, Verónica Jiménez; Ayuso, Eduard; Ma, Marcella K.L.; Coll, Anthony P.; O’Rahilly, Stephen; Yeo, Giles S.H.

2018-01-01

Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116+/–P mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116fl mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS. PMID:29376887

Hypothalamic loss of Snord116 recapitulates the hyperphagia of Prader-Willi syndrome.

PubMed

Polex-Wolf, Joseph; Lam, Brian Yh; Larder, Rachel; Tadross, John; Rimmington, Debra; Bosch, Fàtima; Cenzano, Verónica Jiménez; Ayuso, Eduard; Ma, Marcella Kl; Rainbow, Kara; Coll, Anthony P; O'Rahilly, Stephen; Yeo, Giles Sh

2018-03-01

Profound hyperphagia is a major disabling feature of Prader-Willi syndrome (PWS). Characterization of the mechanisms that underlie PWS-associated hyperphagia has been slowed by the paucity of animal models with increased food intake or obesity. Mice with a microdeletion encompassing the Snord116 cluster of noncoding RNAs encoded within the Prader-Willi minimal deletion critical region have previously been reported to show growth retardation and hyperphagia. Here, consistent with previous reports, we observed growth retardation in Snord116+/-P mice with a congenital paternal Snord116 deletion. However, these mice neither displayed increased food intake nor had reduced hypothalamic expression of the proprotein convertase 1 gene PCSK1 or its upstream regulator NHLH2, which have recently been suggested to be key mediators of PWS pathogenesis. Specifically, we disrupted Snord116 expression in the mediobasal hypothalamus in Snord116fl mice via bilateral stereotaxic injections of a Cre-expressing adeno-associated virus (AAV). While the Cre-injected mice had no change in measured energy expenditure, they became hyperphagic between 9 and 10 weeks after injection, with a subset of animals developing marked obesity. In conclusion, we show that selective disruption of Snord116 expression in the mediobasal hypothalamus models the hyperphagia of PWS.

A Characterization of Movement Skills in Obese Children with and without Prader-Willi Syndrome

ERIC Educational Resources Information Center

Lam, Melanie Y.; Rubin, Daniela A.; Duran, Andrea T.; Chavoya, Frank A.; White, Elizabeth; Rose, Debra J.

2016-01-01

Purpose: The aim of this study was twofold: (a) to measure and compare motor proficiency in obese children with Prader-Willi syndrome (OB-PWS) to that in obese children without PWS (OB), and (b) to compare motor proficiency in OB-PWS and OB to normative data. Method: Motor proficiency was measured using the Bruininks-Oseretsky Test of Motor…

Excessive Picking in Prader-Willi Syndrome: A Pilot Study of Phenomenological Aspects and Comorbid Symptoms.

ERIC Educational Resources Information Center

Wigren, Margareta; Heimann, Mikael

2001-01-01

Interviews with parents of 37 individuals (ages 12-30) with Prader-Willi syndrome revealed two-thirds displayed skin picking with a frequency ranging from chronic to transient, episodic symptoms. Many individuals with skin picking also exhibited comorbid picking behaviors And individuals with excessive skin picking also had frequent tantrums and…

Food-Related Neural Circuitry in Prader-Willi Syndrome: Response to High- versus Low-Calorie Foods

ERIC Educational Resources Information Center

Dimitropoulos, Anastasia; Schultz, Robert T.

2008-01-01

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by hyperphagia and food preoccupations. Although dysfunction of the hypothalamus likely has a critical role in hyperphagia, it is only one of several regions involved in the regulation of eating. The purpose of this research was to examine food-related neural circuitry…

Cognitive Profile in a Large French Cohort of Adults with Prader-Willi Syndrome: Differences between Genotypes

ERIC Educational Resources Information Center

Copet, P.; Jauregi, J.; Laurier, V.; Ehlinger, V.; Arnaud, C.; Cobo, A. -M.; Molinas, C.; Tauber, M.; Thuilleaux, D.

2010-01-01

Background: Prader-Willi syndrome (PWS) is a rare genetic disorder characterised by developmental abnormalities leading to somatic and psychological symptoms. These include dysmorphic features, impaired growth and sexual maturation, hyperphagia, intellectual delay, learning disabilities and maladaptive behaviours. PWS is caused by a lack of…

The dilemma of diagnostic testing for Prader-Willi syndrome

PubMed Central

Hung, Dorothy

2017-01-01

Although Prader-Willi syndrome (PWS) is a well-described clinical dysmorphic syndrome, DNA testing is required for a definitive diagnosis. A definitive diagnosis can be made in approximately 99% of cases using DNA testing; there are a number of DNA tests that can be used for this purpose, although there is no set standard algorithm of testing. The dilemma arises because of the complex genetic mechanisms at the basis of PWS, which need to be elucidated. To establish the molecular mechanism with a complete work up, involves at least 2 tests. Here we discuss the commonly used tests currently available and suggest a cost—effective approach to diagnostic testing. PMID:28164030

Expressive and receptive language in Prader-Willi syndrome: report on genetic subtype differences.

PubMed

Dimitropoulos, Anastasia; Ferranti, Angela; Lemler, Maria

2013-01-01

Prader-Willi syndrome (PWS), most recognized for the hallmark hyperphagia and food preoccupations, is caused by the absence of expression of the paternally active genes in the q11-13 region of chromosome 15. Since the recognition of PWS as a genetic disorder, most research has focused primarily on the medical, genetic, and behavioral aspects of the syndrome. Extensive research has not been conducted on the cognitive, speech, and language abilities in PWS. In addition, language differences with regard to genetic mechanism of PWS have not been well investigated. To date, research indicates overall language ability is markedly below chronological age with expressive language more impaired than receptive language in people with PWS. Thus, the aim of the present study was to further characterize expressive and receptive language ability in 35 participants with PWS and compare functioning by genetic subtype using the Clinical Evaluation of Language Fundamentals-4 (CELF-IV). Results indicate that core language ability is significantly impaired in PWS and both expressive and receptive abilities are significantly lower than verbal intelligence. In addition, participants with the maternal uniparental disomy (mUPD) genetic subtype exhibit discrepant language functioning with higher expressive vs. receptive language abilities. Future research is needed to further examine language functioning in larger genetic subtype participant samples using additional descriptive measures. Further work should also delineate findings with respect to size of the paternal deletion (Type 1 and Type 2 deletions) and explore how overexpression of maternally expressed genes in the 15q11-13 region may relate to verbal ability. After reading this article, the reader will be able to: (1) summarize primary characteristics of Prader-Willi syndrome (PWS), (2) describe differentiating characteristics for the PWS genetic subtypes, (3) recall limited research regarding language functioning in PWS to date

Prader-Willi Critical Region, a Non-Translated, Imprinted Central Regulator of Bone Mass: Possible Role in Skeletal Abnormalities in Prader-Willi Syndrome.

PubMed

Khor, Ee-Cheng; Fanshawe, Bruce; Qi, Yue; Zolotukhin, Sergei; Kulkarni, Rishikesh N; Enriquez, Ronaldo F; Purtell, Louise; Lee, Nicola J; Wee, Natalie K; Croucher, Peter I; Campbell, Lesley; Herzog, Herbert; Baldock, Paul A

2016-01-01

Prader-Willi Syndrome (PWS), a maternally imprinted disorder and leading cause of obesity, is characterised by insatiable appetite, poor muscle development, cognitive impairment, endocrine disturbance, short stature and osteoporosis. A number of causative loci have been located within the imprinted Prader-Willi Critical Region (PWCR), including a set of small non-translated nucleolar RNA's (snoRNA). Recently, micro-deletions in humans identified the snoRNA Snord116 as a critical contributor to the development of PWS exhibiting many of the classical symptoms of PWS. Here we show that loss of the PWCR which includes Snord116 in mice leads to a reduced bone mass phenotype, similar to that observed in humans. Consistent with reduced stature in PWS, PWCR KO mice showed delayed skeletal development, with shorter femurs and vertebrae, reduced bone size and mass in both sexes. The reduction in bone mass in PWCR KO mice was associated with deficiencies in cortical bone volume and cortical mineral apposition rate, with no change in cancellous bone. Importantly, while the length difference was corrected in aged mice, consistent with continued growth in rodents, reduced cortical bone formation was still evident, indicating continued osteoblastic suppression by loss of PWCR expression in skeletally mature mice. Interestingly, deletion of this region included deletion of the exclusively brain expressed Snord116 cluster and resulted in an upregulation in expression of both NPY and POMC mRNA in the arcuate nucleus. Importantly, the selective deletion of the PWCR only in NPY expressing neurons replicated the bone phenotype of PWCR KO mice. Taken together, PWCR deletion in mice, and specifically in NPY neurons, recapitulates the short stature and low BMD and aspects of the hormonal imbalance of PWS individuals. Moreover, it demonstrates for the first time, that a region encoding non-translated RNAs, expressed solely within the brain, can regulate bone mass in health and disease.

TPH2 G/T Polymorphism Is Associated with Hyperphagia, IQ, and Internalizing Problems in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Dykens, Elisabeth M.; Roof, Elizabeth; Bittel, Douglas; Butler, Merlin G.

2011-01-01

Background: Prader-Willi syndrome (PWS) is a genetic, neurodevelopmental disorder characterized by intellectual disabilities, growth hormone dysregulation, hyperphagia, increased risks of morbid obesity, compulsive behaviors, and irritability. As aberrant serotonergic functioning is strongly implicated in PWS, we examined associations between the…

Assessment of Pretend Play in Prader-Willi Syndrome: A Direct Comparison to Autism Spectrum Disorder

ERIC Educational Resources Information Center

Zyga, Olena; Russ, Sandra; Ievers-Landis, Carolyn E.; Dimitropoulos, Anastasia

2015-01-01

Children with Prader-Willi syndrome (PWS) are at risk for autism spectrum disorder (ASD), including pervasive social deficits. While play impairments in ASD are well documented, play abilities in PWS have not been evaluated. Fourteen children with PWS and ten children with ASD were administered the Autism Diagnostic Observation Schedule (ADOS)…

Behavioral treatment of obesity in patients with Prader-Willi syndrome.

PubMed

Altman, K; Bondy, A; Hirsch, G

1978-12-01

Self-monitoring combined with contingency contracting resulted in weight loss, modification of dysfunctional eating habits, and increased or sustained exercise rates for two obese, mentally retarded adolescent females with Prader-Willi syndrome. Contingency contracting between clients and their parents/caregivers was used to specify consequences for daily self-monitoring, reduced caloric intake, weight loss, and exercise. Punishment for food stealing was also employed. Results suggest that contingency contracting is an effective technique for producing long-term weight loss in obese mentally retarded adolescents. Further, these techniques offer an alternative to the clinician considering solely dietary restriction or surgical intervention.

Evaluating the Feasibility of a Play-Based Telehealth Intervention Program for Children with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Dimitropoulos, Anastasia; Zyga, Olena; Russ, Sandra

2017-01-01

Here we report the feasibility and acceptability of telehealth for direct intervention in children with Prader-Willi syndrome (PWS). Children with PWS have social-cognitive challenges that are similar to children with ASD. However, developing behavioral interventions for individuals with PWS is faced with the significant challenge of enrolling…

Cognitive, Emotional, Physical and Social Effects of Growth Hormone Treatment in Adults with Prader-Willi Syndrome

ERIC Educational Resources Information Center

Hoybye, C; Thoren, M.; Bohm, B.

2005-01-01

Prader-Willi syndrome (PWS) is a multisystem genetic disorder characterized by short stature, muscular hypotonia, hyperphagia, obesity, maladaptive behaviour, hypogonadism and partial growth hormone (GH) deficiency (GHD). Severe GHD of other aetiologies has been shown to affect mood and quality of life negatively, and there are reports of…

Klinefelter's syndrome and Prader-Willi syndrome: a rare combination.

PubMed

Verhoeven, W M A; de Vries, B B A; Duffels, S J H; Egger, J I M; Noordam, C; Tuinier, S

2007-01-01

In this paper a review is presented of the rare combination of Klinefelter's syndrome and Prader-Willi syndrome (PWS) and a second case of this combination with a uniparental disomy (UPD) etiology of PWS is described. Patients outlined in all other 8 reports and the present case have a PWS phenotype. Virtually no information is available on the behavioral and psychopathological phenotype in this combination. The latter may be explained by the observation that psychiatric syndromes are especially prevalent in PWS patients with a UPD. It is concluded that instability in mood and behavior in this and other syndromes should be preferentially treated with mood stabilizing agents. Copyright (c) 2007 S. Karger AG, Basel.

Behavioral phenotype in adults with Prader-Willi syndrome.

PubMed

Sinnema, Margje; Einfeld, Stewart L; Schrander-Stumpel, Constance T R M; Maaskant, Marian A; Boer, Harm; Curfs, Leopold M G

2011-01-01

Prader-Willi syndrome (PWS) is characterized by temper tantrums, impulsivity, mood fluctuations, difficulty with change in routine, skinpicking, stubbornness and aggression. Many studies on behavior in PWS are limited by sample size, age range, a lack of genetically confirmed diagnosis of PWS and inconsistent assessment of behavior. The aim of this study was to explore systematically the relation between behavioral problems and age groups, genetic subtypes and BMI categories in an adult PWS population. Participants were contacted via the Dutch Prader-Willi Parent Association and through physicians specialized in persons with ID. Behaviors were studied using the Developmental Behavior Checklist for Adults (DBC-A). The forms were completed by the main caregivers of 98 adults with a genetically confirmed diagnosis of PWS. Differences between age groups were statistically significant (ANOVA, p=0.03). DBC-A total scores were higher in the consecutive age groups, with the most behavioral problems in the oldest age groups. Differences between genetic subtypes were also statistically significant (ANOVA, p<0.01). Persons with mUPD had higher total scores on the DBC-A than persons with a deletion. Those with a Type I deletion showed higher total DBC-A scores than persons with a Type II deletion. There were no statistically significant differences in DBC-A total scores between the different BMI categories. Individuals with a BMI<25 had higher scores on the self-absorbed subscale compared to persons with a BMI between 25 and 30. Unlike previous descriptions of the behavioral phenotype in adults with PWS, we did not find a reduction in behavioral problems in older adults. Therefore, special attention should be paid to behavioral problems as part of general management of adults with PWS. Longitudinal studies are warranted to gain more insight into the natural history and course of behavioral problems in adults and older people with PWS over the long term and possible risk and

Clinical Management of a Child with Prader-Willi Syndrome from Maternal Uniparental Disomy (UPD) Genetic Inheritance

ERIC Educational Resources Information Center

Bellon-Harn, Monica L.

2005-01-01

Prader-Willi Syndrome (PWS) is reported in 1 in 10,000-15,000 individuals. Unfortunately, many cases are missed due to clinicians' lack of familiarity with the syndrome as well as clinical and laboratory diagnostic criteria. Although common clinical characteristics are reported, variety exists in the nature and severity of dysfunction associated…

Life Satisfaction Among Mothers of Individuals with Prader-Willi Syndrome.

PubMed

Shivers, Carolyn M; Leonczyk, Caroline L; Dykens, Elisabeth M

2016-06-01

Mothers of individuals with Prader-Willi syndrome (PWS) often experience numerous stressors, even when compared to mothers of children with other intellectual and developmental disabilities. Despite this, these mothers show great variability in self-reported life satisfaction. Using data from a longitudinal study of individuals with PWS and their families, the present study analyzed factors related to maternal life satisfaction, both cross-sectionally and over time. Results show that both child factors (e.g., behavior problems, hyperphagia) and maternal factors (e.g., stress, coping style) were significantly related to maternal life satisfaction. However, none of the tested variables predicted change in life satisfaction over time. Research and practice implications are discussed.

Executive Functions and Prader-Willi Syndrome: Global Deficit Linked with Intellectual Level and Syndrome-Specific Associations

ERIC Educational Resources Information Center

Chevalère, Johann; Postal, Virginie; Jauregui, Joseba; Copet, Pierre; Laurier, Virginie; Thuilleaux, Denise

2015-01-01

The aim of this study was to support the growing evidence suggesting that Prader-Willi Syndrome (PWS) might present with an impairment of executive functions (EFs) and to investigate whether this impairment is specific to patients with PWS or due to their intellectual disability (ID). Six tasks were administered to assess EFs (inhibition,…

A Long-Term Population-Based Clinical and Morbidity Review of Prader-Willi Syndrome in Western Australia

ERIC Educational Resources Information Center

Thomson, A. K.; Glasson, E. J.; Bittles, A. H.

2006-01-01

Background: 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. Methods: All persons with a diagnosis of PWS were identified from the…

Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings.

PubMed

Angulo, M A; Butler, M G; Cataletto, M E

2015-12-01

Prader-Willi syndrome (PWS) is a multisystemic complex genetic disorder caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13 region. There are three main genetic subtypes in PWS: paternal 15q11-q13 deletion (65-75 % of cases), maternal uniparental disomy 15 (20-30 % of cases), and imprinting defect (1-3 %). DNA methylation analysis is the only technique that will diagnose PWS in all three molecular genetic classes and differentiate PWS from Angelman syndrome. Clinical manifestations change with age with hypotonia and a poor suck resulting in failure to thrive during infancy. As the individual ages, other features such as short stature, food seeking with excessive weight gain, developmental delay, cognitive disability and behavioral problems become evident. The phenotype is likely due to hypothalamic dysfunction, which is responsible for hyperphagia, temperature instability, high pain threshold, hypersomnia and multiple endocrine abnormalities including growth hormone and thyroid-stimulating hormone deficiencies, hypogonadism and central adrenal insufficiency. Obesity and its complications are the major causes of morbidity and mortality in PWS. An extensive review of the literature was performed and interpreted within the context of clinical practice and frequently asked questions from referring physicians and families to include the current status of the cause and diagnosis of the clinical, genetics and endocrine findings in PWS. Updated information regarding the early diagnosis and management of individuals with Prader-Willi syndrome is important for all physicians and will be helpful in anticipating and managing or modifying complications associated with this rare obesity-related disorder.

Behavioral phenotype in a child with Prader-Willi syndrome and comorbid 47, XYY.

PubMed

Palkar, Pooja; Kabasakalian, Anahid; Taylor, Bonnie; Doernberg, Ellen; Ferretti, Casara Jean; Uzunova, Genoveva; Hollander, Eric

2016-08-01

We report a 12-year-old male with Prader-Willi syndrome (PWS) and 47, XYY syndrome. Genetic work up revealed 47, XYY karyotype. PWS diagnosis was made by polymerase chain reaction methylation and maternal uniparental disomy (mUPD) was determined to be the etiology. Review of distinct behavioral features, possible interplay between the two syndromes and considerations for diagnoses are presented. To our knowledge, this is the first report of behavioral features in PWS with comorbid 47, XYY.

[The reproductive system in Prader-Willi syndrome].

PubMed

Eldar-Geva, Talia; Hirsch, Harry J; Gross-Tsur, Varda

2015-03-01

Prader-Willi syndrome (PWS) is a genetic syndrome caused by the lack of expression of imprinted genes located on paternal chromosome 15q11-q13, characterized by endocrine defects, an insatiable appetite, short stature, cognitive and behavioral difficulties and dysmorphic features. Nearly all PWS males and most PWS women show clinical and/or laboratory evidence of hypogonadism, affecting their habitus, health and quality of life. Until recently, hypogonadism in PWS was generally considered to be of centrall, hypothalamic origin. However, recent studies have shown that primary gonadal dysfunction is the major contributor to hypogonadism in this condition, while severe gonadotropin deficiency is rare. Despite clinical and laboratory evidence of hypogonadism, young adult PWS men and women have sexual and romantic interests and aspirations. Pregnancies have been reported in a few women with genetically documented PWS. Fertility has not been reported in PWS men. Recognition of these interests is essential for physicians and caregivers in order to offer proper anticipatory guidance, psychological and sex education and counseling. Individual variations in pubertal development, reproductive hormone profiles, bone-mineral density and individual appeal need to be considered when recommending sex hormone replacement in this population. Testosterone should be considered in most hypogonadal PWS males, considering possible side effects. Hormone replacement may be indicated in PWS women with decreasing bone mineral density or in PWS women who wish to have regular menses. Contraception should be considered in women with normal inhibin B levels. Hormone replacement is likely to improve bone density, quality of life and body image.

Cerebrospinal fluid monoamines in Prader-Willi syndrome.

PubMed

Akefeldt, A; Ekman, R; Gillberg, C; Månsson, J E

1998-12-15

The behavioral phenotype of Prader-Willi syndrome (PWS) suggests hypothalamic dysfunction and altered neurotransmitter regulation. The purpose of this study was to examine whether there was any difference in the concentrations of monoamine metabolites in the cerebrospinal fluid (CSF) in PWS and non-PWS comparison cases. The concentration of monoamine metabolites in CSF was determined in 13 children and adolescents with PWS diagnosed on clinical and genetic criteria. The concentrations were compared with those from 56 comparison cases in healthy and other contrast groups. The concentrations of dopamine and particularly serotonin metabolites were increased in the PWS group. The differences were most prominent for 5-hydroxyindoleacetic acid. The increased concentrations were found in all PWS cases independently of age, body mass index, and level of mental retardation. The findings implicate dysfunction of the serotonergic system and possibly also of the dopamine system in PWS individuals, and might help inform future psychopharmacologic studies.

Gait Pattern in Two Rare Genetic Conditions Characterized by Muscular Hypotonia: Ehlers-Danlos and Prader-Willi Syndrome

ERIC Educational Resources Information Center

Cimolin, Veronica; Galli, Manuela; Vismara, Luca; Grugni, Graziano; Camerota, Filippo; Celletti, Claudia; Albertini, Giorgio; Rigoldi, Chiara; Capodaglio, Paolo

2011-01-01

This study aimed to quantify and compare the gait pattern in Ehlers-Danlos (EDS) and Prader-Willi syndrome (PWS) patients to provide data for developing evidence-based rehabilitation strategies. Twenty EDS and 19 PWS adult patients were evaluated with an optoelectronic system and force platforms for measuring kinematic and kinetic parameters…

The Relationship between Compulsive Behaviour and Academic Achievement across the Three Genetic Subtypes of Prader-Willi Syndrome

ERIC Educational Resources Information Center

Zarcone, J.; Napolitano, D.; Peterson, C.; Breidbord, J.; Ferraioli, S.; Caruso-Anderson, M.; Holsen, L.; Butler, M. G.; Thompson, T.

2007-01-01

Background: Prader-Willi syndrome (PWS) is a genetic syndrome associated with several physical, cognitive and behavioural characteristics. For many individuals with this syndrome, compulsive behaviour is often noted in both food and non-food situations. The focus of this paper is on the non-food-related compulsions in individuals with PWS and…

Ghrelin concentrations in Prader-Willi syndrome (PWS) infants and children: changes during development.

PubMed

Haqq, Andrea M; Grambow, Steven C; Muehlbauer, Michael; Newgard, Christopher B; Svetkey, Laura P; Carrel, Aaron L; Yanovski, Jack A; Purnell, Jonathan Q; Freemark, Michael

2008-12-01

Prader-Willi syndrome (PWS) is associated with failure to thrive in infancy and progressive hyperphagia and obesity in childhood. This progressive weight gain is associated with hyperghrelinaemia and increased insulin sensitivity. The role of ghrelin excess in the pathogenesis of obesity is unclear. To determine if high ghrelin levels precede the onset of obesity in young PWS children. A cross-sectional study of 33 infants with PWS and 28 healthy control subjects (C). Fasting ghrelin and other satiety hormones were measured. Median total serum ghrelin in young children with PWS trended higher, but did not differ significantly from those in C of similar age, weight-for-age z-score and sex. However, there was more variability in ghrelin concentrations of young PWS. Eleven of 33 PWS subjects had ghrelin levels greater than the 95th percentile for ghrelin values in the C subjects (> 2871 pg/ml). Six of the PWS subjects with high ghrelin levels had weight-for-age z-scores < 0. Ghrelin concentrations in PWS and C infants exceeded those in older children. In youngsters with PWS, leptin was higher, suggesting a relative excess of fat to lean body mass and plasma adiponectin was increased. Young infants with PWS who have not yet developed hyperphagia or obesity have median fasting ghrelin levels similar to controls. However, a subset (33%) of young PWS is hyperghrelinaemic; approximately one-half of those with hyperghrelinaemia have BMI z-score < 0. The age-related decline in ghrelin is blunted in PWS.

Associations between Repetitive Questioning, Resistance to Change, Temper Outbursts and Anxiety in Prader-Willi and Fragile-X Syndromes

ERIC Educational Resources Information Center

Woodcock, K.; Oliver, C.; Humphreys, G.

2009-01-01

Background: The behavioural phenotypes of Prader-Willi (PWS) and Fragile-X (FraX) syndromes both comprise repetitive behaviours with differences between the profiles. In this study we investigated the context and antecedents to the repetitive behaviours and the association with other behavioural phenotypic characteristics in order to generate…

Prader-Willi Syndrome: Clinical Genetics and Diagnostic Aspects with Treatment Approaches.

PubMed

Butler, Merlin G; Manzardo, Ann M; Forster, Janice L

2016-01-01

Prader-Willi syndrome (PWS) is a neuro-developmental genetic disorder due to lack of expression of genes inherited from the paternal chromosome 15q11-q13 region with three main genetic subtypes. These include paternal 15q11-q13 deletion (about 70% of cases), maternal uniparental disomy 15 or both 15s from the mother (20-30% of cases), and defects in the imprinting center (1-3%) which controls the expression of imprinted genes in this chromosome region. Clinical manifestations include infantile hypotonia with a poor suck resulting in failure to thrive, short stature, small hands/feet and hypogonadism/hypogenitalism due to growth and other hormone deficiencies, hyperphagia and excessive weight gain with obesity and cognitive and behavioral problems including obsessive compulsions, tantrums and self-injury. The phenotype is likely related to hypothalamic dysfunction. Hyperphagia and obesity with related complications are major causes of morbidity and mortality in PWS requiring accurate diagnosis, appropriate medical management and treatment; the major objective of our report. An extensive review of the literature was undertaken including genetics, clinical and behavioral aspects, and updated health-related information addressing the importance of early diagnosis and treatment of individuals with Prader-Willi syndrome. A searchable, bulleted and formatted list of topics related to this obesity syndrome was provided utilizing a Table of Contents approach for the clinical practitioner. Physicians and other health care providers can use this review with clinical, genetic and treatment summaries divided into sections that are pertinent in the context of clinical practice. Finally, frequently asked questions by clinicians, families and other interested participants will be addressed.

Behavior and emotional disturbance in Prader-Willi syndrome.

PubMed

Einfeld, S L; Smith, A; Durvasula, S; Florio, T; Tonge, B J

1999-01-15

To determine if persons with the Prader-Willi syndrome (PWS) have increased psychopathology when compared with matched controls, and whether there is a specific behavior phenotype in PWS, the behavior of 46 persons with PWS was compared with that of control individuals derived from a community sample (N = 454) of persons with mental retardation (MR). Behaviors were studied using the Developmental Behaviour Checklist, an instrument of established validity in the evaluation of behavioral disturbance in individuals with MR. PWS subjects were found to be more behaviorally disturbed than controls overall, and especially in antisocial behavior. In addition, some individual behaviors were more common in PWS subjects than controls. When these behaviors are considered together with findings from other studies using acceptably rigorous methods, a consensus behavior phenotype for PWS can be formulated. This will provide a valid foundation for studies of the mechanism of genetic pathogenesis of behavior in PWS.

Mathematical skills in Prader-Willi Syndrome.

PubMed

Bertella, L; Girelli, L; Grugni, G; Marchi, S; Molinari, E; Semenza, C

2005-02-01

This paper investigates mathematical skills in Prader-Willi Syndrome (PWS), a pathological condition because of congenital alterations of chromosome pair 15. The following questions were addressed: (1) Are mathematical skills in PWS relatively more impaired with respect to other cognitive functions (as has been repeatedly but anecdotally reported)?; and (2) What is the nature of the mathematical impairment? The first study employed the Wechsler Adult Intelligence Scale (WAIS) and an extensive battery of cognitive tasks for which norms are known. Both batteries include a mathematical section. The second study used a theoretically motivated series of mathematical tasks specifically designed to individually assess the different cognitive components underlying mathematical skills. Mathematical skills were found to be the most impaired cognitive abilities together with short-term memory capacity. No specific mathematical domain was seen to be unaffected in PWS participants. The clearest deficits observed concern 'syntactic' processes in number transcoding, multiplication, number facts retrieval and calculation procedures. Failure of mathematical skills is the most distinctive feature in the cognitive profile of PWS. However, to determine whether this is indeed a specific pattern of performance related to PWS, results must be compared with those obtained with patients manifesting other genetic disorders.

The Course and Outcome of Psychiatric Illness in People with Prader-Willi Syndrome: Implications for Management and Treatment

ERIC Educational Resources Information Center

Soni, S.; Whittington, J.; Holland, A. J.; Webb, T.; Maina, E.; Boer, H.; Clarke, D.

2007-01-01

Background: This study is part of a larger UK-wide study investigating psychiatric illness in people with Prader-Willi syndrome (PWS), and describes the longitudinal aspect of psychiatric illness, in particular psychotic illness, and examines the use and role of psychotropic medication. Method: A total of 119 individuals with genetically confirmed…

The Need for Control/Comparison Studies in Establishing Diagnostic Indicators: Prader-Willi Syndrome as a Case in Point.

ERIC Educational Resources Information Center

Taylor, Ronald L.; Caldwell, Mary Lou

1990-01-01

The psychometric characteristics of 12 adults with Prader-Willi syndrome (PWS) and a group without PWS but with other similar traits were compared. Results found cognitive, behavioral and educational traits often associated with PWS to be present in both groups, illustrating the importance of control/comparison groups in research establishing…

Fractal dimension approach in postural control of subjects with Prader-Willi Syndrome

PubMed Central

2011-01-01

Background Static posturography is user-friendly technique suitable for the study of the centre of pressure (CoP) trajectory. However, the utility of static posturography in clinical practice is somehow limited and there is a need for reliable approaches to extract physiologically meaningful information from stabilograms. The aim of this study was to quantify the postural strategy of Prader-Willi patients with the fractal dimension technique in addition to the CoP trajectory analysis in time and frequency domain. Methods 11 adult patients affected by Prader-Willi Syndrome (PWS) and 20 age-matched individuals (Control group: CG) were included in this study. Postural acquisitions were conducted by means of a force platform and the participants were required to stand barefoot on the platform with eyes open and heels at standardized distance and position for 30 seconds. Platform data were analysed in time and frequency domain. Fractal Dimension (FD) was also computed. Results The analysis of CoP vs. time showed that in PWS participants all the parameters were statistically different from CG, with greater displacements along both the antero-posterior and medio-lateral direction and longer CoP tracks. As for frequency analysis, our data showed no significant differences between PWS and CG. FD evidenced that PWS individuals were characterized by greater value in comparison with CG. Conclusions Our data showed that while the analysis in the frequency domain did not seem to explain the postural deficit in PWS, the FD method appears to provide a more informative description of it and to complement and integrate the time domain analysis. PMID:21854639

Trajectory and outcomes of speech language therapy in the Prader-Willi syndrome (PWS): case report.

PubMed

Misquiatti, Andréa Regina Nunes; Cristovão, Melina Pavini; Brito, Maria Claudia

2011-03-01

The aim of this study was to describe the trajectory and the outcomes of speech-language therapy in Prader-Willi syndrome through a longitudinal study of the case of an 8 year-old boy, along four years of speech-language therapy follow-up. The therapy sessions were filmed and documental analysis of information from the child's records regarding anamnesis, evaluation and speech-language therapy reports and multidisciplinary evaluations were carried out. The child presented typical characteristics of Prader-Willi syndrome, such as obesity, hyperfagia, anxiety, behavioral problems and self aggression episodes. Speech-language pathology evaluation showed orofacial hypotony, sialorrhea, hypernasal voice, cognitive deficits, oral comprehension difficulties, communication using gestures and unintelligible isolated words. Initially, speech-language therapy had the aim to promote the language development emphasizing social interaction through recreational activities. With the evolution of the case, the main focus became the development of conversation and narrative abilities. It were observed improvements in attention, symbolic play, social contact and behavior. Moreover, there was an increase in vocabulary, and evolution in oral comprehension and the development of narrative abilities. Hence, speech-language pathology intervention in the case described was effective in different linguistic levels, regarding phonological, syntactic, lexical and pragmatic abilities.

Analysis of N- and O-linked protein glycosylation in children with Prader-Willi syndrome.

PubMed

Munce, T; Heussler, H S; Bowling, F G

2010-10-01

Current genotype-phenotype correlations in Prader-Willi syndrome (PWS) are struggling to give an explanation of the diversity in phenotype and there is a need to move towards a molecular understanding of PWS. A range of functions related to glycoproteins are involved in the pathophysiology of PWS and it may be that abnormal glycosylation is contributing to the biological phenotype. The objective of this study was to investigate the state of N- and O-linked glycosylation in children with Prader-Willi syndrome. Twenty-three children with PWS and 20 non-PWS controls were included in the study. Protein N-linked glycosylation was assessed by analysing serum transferrin through mass spectrometry and protein O-linked through isoelectric focusing (IEF) of serum apolipoprotein C-III (apoC-III), confirmed by mass spectrometry. The results of this analysis indicated that the N-linked glycosylation pathway in PWS is normal. A subgroup of PWS individuals was found to have a hyposialylated pattern of apoC-III isoforms. This was independent of the underlying genetic mechanism and is the first report of an apoC-III IEF abnormality in PWS. This is the first report of apoC-III hyposialylation in PWS. As this field is in its infancy, additional study is required before these findings may be used in clinical settings. © 2010 The Authors. Journal of Intellectual Disability Research © 2010 Blackwell Publishing Ltd.

Causes of Death in Prader-Willi Syndrome: Prader-Willi Syndrome Association (USA) 40-Year Mortality Survey

PubMed Central

Butler, Merlin G.; Manzardo, Ann M.; Heinemann, Janalee; Loker, Carolyn; Loker, James

2016-01-01

Background Prader-Willi syndrome (PWS) is a rare complex neurodevelopmental genetic disorder that is associated with hyperphagia and morbid obesity in humans leading to a shortened life expectancy. This report summarizes the primary causes of death and evaluates mortality trends in a large cohort of individuals with PWS. Methods PWSA (USA) mortality syndrome-specific database of death reports was collected through a cursory bereavement program for PWSA(USA) families using a brief survey created in 1999. Causes of death were descriptively characterized and statistically examined using Cox Proportional Hazards. Results A total of 486 deaths were reported (263 males, 217 females, 6 unknown) between 1973 and 2015 with mean age of 29.5 ± 16 years (2mo–67yrs), 70% occurring in adulthood. Respiratory failure was the most common cause accounting for 31% of all deaths. Males were at increased risk for presumed hyperphagia-related accidents/injuries compared to females and cardiopulmonary factors. PWS maternal disomy 15 genetic subtype showed an increased risk of death from cardiopulmonary factors compared to the deletion subtype. Conclusions These findings highlight the heightened vulnerability towards obesity and hyperphagia-related mortality in PWS. Future research is needed to address critical vulnerabilities such as gender and genetic subtype in the cause of death in PWS. PMID:27854358

Prader-Willi syndrome: genetic tests and clinical findings.

PubMed

Fridman, C; Varela, M C; Kok, F; Setian, N; Koiffmann, C P

2000-01-01

Here we describe the genetic studies performed in 53 patients with the suspected diagnosis of Prader-Willi syndrome (PWS). PWS is characterized by neonatal hypotonia, hypogonadism, delayed psychomotor development, hyperphagia, obesity, short stature, small hands and feet, learning disabilities, and obsessive-compulsive behavior. Through the methylation analysis of the SNRPN gene, microsatellite studies of loci mapped within and outside the PWS/AS region, and fluorescence in situ hybridization (FISH) study, we confirmed the diagnosis in 35 patients: 27 with a paternal deletion, and 8 with maternal uniparental disomy (UPD). The clinical comparisons between deleted and UPD patients indicated that there were no major phenotype differences, except for a lower birth length observed in the UPD children. Our sample was composed of more girls than boys; UPD patients were diagnosed earlier than the deleted cohort (2(10/12) s. 7(9/12) years); and, in the deleted group, the boys were diagnosed earlier than the girls (5(2/12) vs. 7(8/12) years, respectively).

[Neuropsychiatric aspects of Prader-Willi syndrome – a review].

PubMed

Briegel, Wolfgang

2018-05-01

Prader-Willi Syndrome (PWS) is caused by the absence of paternal expression of imprinted genes in the region at 15q11–q13. With an estimated birth incidence of 1/15 000 – 1/30 000, PWS is one of the more frequent genetic syndromes among humans. Typical physical features include neonatal hypotonia and feeding problems, hypogonadism, hyperphagia in later childhood with consecutive obesity, and short stature. Most people with PWS show a mild to moderate intellectual disability. Furthermore, lability of mood, temper tantrums, skin-picking, and compulsive behaviors are quite typical for subjects with PWS. Psychotic disorders have also been found to be quite common in adulthood. This manuscript reviews current knowledge about the etiology, physical features, developmental aspects, behavioral phenotype, and psychiatric disorders that occur as well as existing psychopharmacological and psychotherapeutic interventions.

Clinical management of behavioral characteristics of Prader-Willi syndrome.

PubMed

Ho, Alan Y; Dimitropoulos, Anastasia

2010-05-06

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder caused by an abnormality on the long arm of chromosome 15 (q11-q13) that results in a host of phenotypic characteristics, dominated primarily by hyperphagia and insatiable appetite. Characteristic behavioral disturbances in PWS include excessive interest in food, skin picking, difficulty with a change in routine, temper tantrums, obsessive and compulsive behaviors, and mood fluctuations. Individuals with PWS typically have intellectual disabilities (borderline to mild/moderate mental retardation) and exhibit a higher overall behavior disturbance compared to individuals with similar intellectual disability. Due to its multisystem disorder, family members, caregivers, physicians, dieticians, and speech-language pathologists all play an important role in the management and treatment of symptoms in an individual with PWS. This article reviews current research on behavior and cognition in PWS and discusses management guidelines for this disorder.

An Investigation into Food Preferences and the Neural Basis of Food-Related Incentive Motivation in Prader-Willi Syndrome

ERIC Educational Resources Information Center

Hinton, E. C.; Holland, A. J.; Gellatly, M. S. N.; Soni, S.; Owen, A. M.

2006-01-01

Background: Research into the excessive eating behaviour associated with Prader-Willi syndrome (PWS) to date has focused on homeostatic and behavioural investigations. The aim of this study was to examine the role of the reward system in such eating behaviour, in terms of both the pattern of food preferences and the neural substrates of incentive…

The Effects of Muscle Hypotonia and Weakness on Balance: A Study on Prader-Willi and Ehlers-Danlos Syndrome Patients

ERIC Educational Resources Information Center

Galli, Manuela; Cimolin, Veronica; Vismara, Luca; Grugni, Graziano; Camerota, Filippo; Celletti, Claudia; Albertini, Giorgio; Rigoldi, Chiara; Capodaglio, Paolo

2011-01-01

Prader-Willi syndrome (PWS) and Ehlers-Danlos syndrome (EDS) are two different genetical disorders both characterized, among other features, by muscular hypotonia. Postural control seems to be impaired in both conditions. The aim of the present study was to quantitatively compare postural control in adult PWS and EDS using stabilometric platform…

Parental Ratings of Children and Adolescents with Prader-Willi Syndrome on the Behavior Rating Inventory of Executive Function (BRIEF)

ERIC Educational Resources Information Center

Hutchison, Marnie; Pei, Jacqueline; Leung, Wing Sze Wence; Mackenzie, Michelle; Hicks, Melanie D.; Thurm, Audrey E.; Han, Joan C.; Haqq, Andrea M.

2015-01-01

We investigated executive functioning in 25 children and adolescents with Prader-Willi syndrome (PWS) on the Behavior Rating Inventory of Executive Function (BRIEF). Significant deficits emerged, with mean scores on all but two scales reaching levels of clinical significance (T score = 65). Older children tended to have higher scores than younger…

Compulsive behavior in Prader-Willi syndrome: examining severity in early childhood.

PubMed

Dimitropoulos, A; Blackford, J; Walden, T; Thompson, T

2006-01-01

Prader-Willi syndrome (PWS) is a genetic disorder characterized by hyperphagia and food preoccupations. Researchers indicate that individuals with PWS, including young children, exhibit food and non-food-related compulsions. Normative rituals are also often present among typically developing preschoolers. However, it is unclear how these behaviors affect the child. Although preschoolers with PWS exhibit more types of rituals than other populations, it is uncertain if the severity of these behaviors differs from the rituals experienced during normative development. Thus, the purpose of this research was to determine whether the ritualistic behaviors exhibited by preschoolers with PWS differ in severity from those exhibited during normative development. We also sought to identify whether non-food ritualistic behavior was related to the hyperphagia in PWS. Parents of 68 children with PWS, 86 typically developing children, and 57 children with developmental delays completed questionnaires on rituals and eating behavior. Children with PWS exhibited more severe ritualistic behavior than typically developing children but not other children with developmental delays. However, the severity of non-food-related rituals was related to the severity of eating behavior in PWS. We hypothesize that this link between hyperphagia and non-food-related compulsivity may share a common underlying neurobiological mechanism.

Examination of Global Methylation and Targeted Imprinted Genes in Prader-Willi Syndrome.

PubMed

Manzardo, A M; Butler, M G

2016-01-01

Methylation changes observed in Prader-Willi syndrome (PWS) may impact global methylation as well as regional methylation status of imprinted genes on chromosome 15 (in cis) or other imprinted obesity-related genes on other chromosomes (in trans) leading to differential effects on gene expression impacting obesity phenotype unique to (PWS). Characterize the global methylation profiles and methylation status for select imprinted genes associated with obesity phenotype in a well-characterized imprinted, obesity-related syndrome (PWS) relative to a cohort of obese and non-obese individuals. Global methylation was assayed using two methodologies: 1) enriched LINE-1 repeat sequences by EpigenDx and 2) ELISA-based immunoassay method sensitive to genomic 5-methylcytosine by Epigentek. Target gene methylation patterns at selected candidate obesity gene loci were determined using methylation-specific PCR. Study participants were recruited as part of an ongoing research program on obesity-related genomics and Prader-Willi syndrome. Individuals with non-syndromic obesity (N=26), leanness (N=26) and PWS (N=39). A detailed characterization of the imprinting status of select target genes within the critical PWS 15q11-q13 genomic region showed enhanced cis but not trans methylation of imprinted genes. No significant differences in global methylation were found between non-syndromic obese, PWS or non-obese controls. None. Percentage methylation and the methylation index. The methylation abnormality in PWS due to errors of genomic imprinting effects both upstream and downstream effectors in the 15q11-q13 region showing enhanced cis but not trans methylation of imprinted genes. Obesity in our subject cohorts did not appear to impact global methylation levels using the described methodology.

Language development in a 3-year-old boy with Prader-Willi syndrome.

PubMed

Atkin, Keith; Lorch, Marjorie Perlman

2007-04-01

Prader-Willi syndrome (PWS) is a genetic disorder which has widespread developmental consequences including motor, cognitive and language delay. Previous research on PWS children has focused primarily on phonological development and dysfluency. In the present study, the lexical development of a boy with PWS was investigated in a series of 18 play sessions recorded over a 4 month period from the ages 3;7 to 3;11. In comparison to the language development of children with Down syndrome this child with PWS appears to display a distinct developmental pattern. The possibility of detailing a behavioural phenotype of genetic disorders affecting language development is discussed.

Prader-Willi Syndrome: Parent Perceptions of School, Professional, Social, and Informational Support, and Relations between Support, Child Behavior, and Stress

ERIC Educational Resources Information Center

Lowe-Greenlee, Barbara

2010-01-01

Prader-Willi syndrome (PWS) is a rare genetic disorder that adversely impacts child development and health conditions, and is often associated with significant behavioral challenges. In particular, children with PWS typically exhibit extremely high levels of maladaptive behavior (e.g., excessive food seeking, hording, and binging; temper tantrums;…

Grey matter volume and cortical structure in Prader-Willi syndrome compared to typically developing young adults.

PubMed

Manning, Katherine E; Tait, Roger; Suckling, John; Holland, Anthony J

2018-01-01

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder of genomic imprinting, presenting with a characteristic overeating disorder, mild to moderate intellectual disability, and a variable range of social and behavioral difficulties. Consequently, widespread alterations in neural structure and developmental and maturational trajectory would be expected. To date, there have been few quantitative and systematic studies of brain morphology in PWS, although alterations of volume and of cortical organisation have been reported. This study aimed to investigate, in detail, the structure of grey matter and cortex in the brain in a sample of young adults with PWS in a well-matched case-controlled analysis. 20 young adults with PWS, aged 19-27 years, underwent multiparameter mapping magnetic resonance imaging sequences, from which measures of grey matter volume, cortical thickness and magnetisation transfer saturation, as a proxy measure of myelination, were examined. These variables were investigated in comparison to a control group of 40 typically developing young adults, matched for age and sex. A voxel-based morphometry analysis identified large and widespread bilateral clusters of both increased and decreased grey matter volume in the brain in PWS. In particular, widespread areas of increased volume encompassed parts of the prefrontal cortex, especially medially, the majority of the cingulate cortices, from anterior to posterior aspects, insula cortices, and areas of the parietal and temporal cortices. Increased volume was also reported in the caudate, putamen and thalamus. The most ventromedial prefrontal areas, in contrast, showed reduced volume, as did the parts of the medial temporal lobe, bilateral temporal poles, and a small cluster in the right lateral prefrontal cortex. Analysis of cortical structure revealed that areas of increased volume in the PWS group were largely driven by greater cortical thickness. Conversely, analysis of myelin content using

Growth Hormone Therapy in Adults with Prader-Willi Syndrome.

PubMed

Vogt, Karen S; Emerick, Jill E

2015-04-16

Prader-Willi syndrome (PWS) is characterized by hyperphagia, obesity if food intake is not strictly controlled, abnormal body composition with decreased lean body mass and increased fat mass, decreased basal metabolic rate, short stature, low muscle tone, cognitive disability, and hypogonadism. In addition to improvements in linear growth, the benefits of growth hormone therapy on body composition and motor function in children with PWS are well established. Evidence is now emerging on the benefits of growth hormone therapy in adults with PWS. This review summarizes the current literature on growth hormone status and the use of growth hormone therapy in adults with PWS. The benefits of growth hormone therapy on body composition, muscle strength, exercise capacity, certain measures of sleep-disordered breathing, metabolic parameters, quality of life, and cognition are covered in detail along with potential adverse effects and guidelines for initiating and monitoring therapy.

Prader-Willi syndrome: is there a recognizable fetal phenotype?

PubMed

Bigi, Nicole; Faure, Jean-Michel; Coubes, Christine; Puechberty, Jacques; Lefort, Geneviève; Sarda, Pierre; Blanchet, Patricia

2008-09-01

To determine fetal features, which could lead to the diagnosis of Prader-Willi syndrome (PWS) during pregnancy. We analyze the ultrasound features, genetic studies and pathologic findings in two cases of PWS diagnosed during pregnancy. In the first case, diminished fetal movement, polyhydramnios and oddly positioned hands and feet suggested PWS. Methylation studies confirmed diagnosis and a deletion was detected in the 15q11-q13 region. In the second case, similar ultrasound findings led to prenatal diagnosis of PWS with an abnormal methylation pattern compatible with uniparental disomy. Both fetuses had a characteristic appearance at 28 and 30 weeks' gestation, which included a peculiar position of hands with flexed wrists and dorsi-extended feet with flexed toes. The peculiar position of the extremities combined with diminished fetal movement and polyhydramnios seems to be characteristic and should suggest PWS. Copyright (c) 2008 John Wiley & Sons, Ltd.

Congenital hepatic fibrosis in a child with Prader-Willi syndrome: a novel association.

PubMed

Al Sarkhy, Ahmed; Hassan, Saeed; Alasmi, Mona; Assiri, Asaad Muhammed; Alkuraya, Fowzan S

2014-01-01

Prader-Willi syndrome (PWS) is a rare genetic disorder caused by deletion or unexpression of the chromosome 15 (q 11-13). Symptomatologies include hypotonia, hyperphagia, cognitive impairment, and characteristic dysmorphic profile. Here, we report a 4-year-old boy with PWS who presented with complications of congenital hepatic fibrosis. The uniparental heterodisomy makes it unlikely that the hepatic fibrosis was caused by unmasking of a recessive mutation on the maternal chromosome 15 although we cannot exclude the possibility of a recessively inherited mutation elsewhere given the parental consanguinity. This is the first report of congenital hepatic fibrosis in PWS.

Relationship between the IQ of People with Prader-Willi Syndrome and that of Their Siblings: Evidence for Imprinted Gene Effects

ERIC Educational Resources Information Center

Whittington, J.; Holland, A.; Webb, T.

2009-01-01

Background: Genetic disorders occasionally provide the means to uncover potential mechanisms linking gene expression and physical or cognitive characteristics or behaviour. Prader-Willi syndrome (PWS) is one such genetic disorder in which differences between the two main genetic subtypes have been documented (e.g. higher verbal IQ in one vs.…

Behavioral and psychiatric disorders in Prader-Willi syndrome: a population study in Japan.

PubMed

Hiraiwa, Rika; Maegaki, Yoshihiro; Oka, Akira; Ohno, Kousaku

2007-10-01

Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder characterized by mental retardation and distinct physical, behavioral, and psychiatric features. Based on parents' questionnaires, we examined the prevalence of behavioral and psychiatric disorders of 165 persons with PWS aged 2-31 years in Japan. The data were analyzed comparing four different age groups with PWS: group 1, 2-5 years (n=34); group 2, 6-11 years (n=57); group 3, 12-17 years (n=45); and group 4, 18-31 years (n=29). Further, we compared the results of our PWS group 4 with those of 42 age-, gender-, and intelligence level-matched intellectual disability (ID) individuals without PWS. Our results showed that repetitive speech and stubbornness were prominent from early childhood and other behavioral problems such as hyperphagia, stealing food, temper tantrums, lying, and emotional lability tended to be more frequent with age among persons with PWS. Moreover, young adults with PWS have significantly higher rates of behavioral and psychiatric disorders than IDs without PWS, such as stubbornness, hyperphagia, temper tantrums, self-injurious behavior (skin picking), hypersomnia, inactivity, and delusion. Degree of obesity was not necessarily related to behavioral and psychiatric features associated with PWS. Our findings revealed that persons with PWS are more vulnerable to behavioral and psychiatric disorders particularly in young adulthood compared to those with ID from other etiologies in Japan.

Central adrenal insufficiency in young adults with Prader-Willi syndrome.

PubMed

Grugni, Graziano; Beccaria, Luciano; Corrias, Andrea; Crinò, Antonino; Cappa, Marco; De Medici, Clotilde; Di Candia, Stefania; Gargantini, Luigi; Ragusa, Letizia; Salvatoni, Alessandro; Sartorio, Alessandro; Spera, Sabrina; Andrulli, Simeone; Chiumello, Giuseppe; Mussa, Alessandro

2013-09-01

A high prevalence (60%) of central adrenal insufficiency (CAI) has been reported in Prader-Willi syndrome (PWS) using the metyrapone test. We have assessed CAI in adults with PWS using the low-dose short synacthen test (LDSST). Basal cortisol and ACTH, and 30-min cortisol after the administration of 1 μg synacthen, were determined in 53 PWS adults (33 females). A peak cortisol value of ≥500 nmol/l was taken as normal. Hormonal profiles were analysed in relation to gender, genotype and phenotype. Deficient patients were retested by high-dose short synachten test (HDSST) or a repeat LDSST. Mean ± SD basal cortisol and ACTH were 336·6 ± 140·7 nmol/l and 4·4 ± 3·7 pmol/l respectively. Cortisol rose to 615·4 ± 135·0 nmol/l after LDSST. Eight (15·1%) patients had a peak cortisol response <500 nmol/l, with a lower mean ± SD (range) basal cortisol of 184·9 ± 32·0 (138·0-231·7) compared with 364·1 ± 136·6 (149·0-744·5) in normal responders (P < 0·001). Seven of the eight patients underwent retesting, with 4 (7·5%) showing persistent suboptimal responses. Basal and peak cortisol correlated in females (r = 0·781, P < 0·001). Logistic regression revealed that only female gender and baseline cortisol were predictors of cortisol peaks (adjusted R square 0·505). Although CAI can be part of the adult PWS phenotype, it has a lower prevalence (7·5%) than previously reported. Clinicians are advised to test PWS patient for CAI. Our study also shows that basal cortisol is closely correlated with adrenal response to stimulation, indicating that its measurement may be helpful in selecting patients for LDSST. © 2013 John Wiley & Sons Ltd.

Truncating mutations of MAGEL2 cause Prader-Willi phenotypes and autism.

PubMed

Schaaf, Christian P; Gonzalez-Garay, Manuel L; Xia, Fan; Potocki, Lorraine; Gripp, Karen W; Zhang, Baili; Peters, Brock A; McElwain, Mark A; Drmanac, Radoje; Beaudet, Arthur L; Caskey, C Thomas; Yang, Yaping

2013-11-01

Prader-Willi syndrome (PWS) is caused by the absence of paternally expressed, maternally silenced genes at 15q11-q13. We report four individuals with truncating mutations on the paternal allele of MAGEL2, a gene within the PWS domain. The first subject was ascertained by whole-genome sequencing analysis for PWS features. Three additional subjects were identified by reviewing the results of exome sequencing of 1,248 cases in a clinical laboratory. All four subjects had autism spectrum disorder (ASD), intellectual disability and a varying degree of clinical and behavioral features of PWS. These findings suggest that MAGEL2 is a new gene causing complex ASD and that MAGEL2 loss of function can contribute to several aspects of the PWS phenotype.

The developmental trajectory of disruptive behavior in Down syndrome, fragile X syndrome, Prader-Willi syndrome and Williams syndrome.

PubMed

Rice, Lauren J; Gray, Kylie M; Howlin, Patricia; Taffe, John; Tonge, Bruce J; Einfeld, Stewart L

2015-06-01

The aim of this study was to investigate the developmental trajectories of verbal aggression, physical aggression, and temper tantrums in four genetic syndrome groups. Participants were part of the Australian Child to Adult Development Study (ACAD), which collected information from a cohort of individuals with an intellectual disability at five time points over 18 years. Data were examined from a total of 248 people with one of the four following syndromes: Down syndrome, Fragile X syndrome, Prader-Willi syndrome, or Williams syndrome. Changes in behaviors were measured using validated items from the Developmental Behavior Checklist (DBC). The results indicate that, while verbal aggression shows no evidence of diminishing with age, physical aggression, and temper tantrums decline with age before 19 years for people with Down syndrome, Fragile X syndrome, and William syndrome; and after 19 years for people with Prader-Willi syndrome. These findings offer a somewhat more optimistic outlook for people with an intellectual disability than has previously been suggested. Research is needed to investigate the mechanisms predisposing people with PWS to persistence of temper tantrums and physical aggression into adulthood. © 2015 Wiley Periodicals, Inc.

Examination of Global Methylation and Targeted Imprinted Genes in Prader-Willi Syndrome

PubMed Central

Manzardo, AM; Butler, MG

2016-01-01

Context Methylation changes observed in Prader-Willi syndrome (PWS) may impact global methylation as well as regional methylation status of imprinted genes on chromosome 15 (in cis) or other imprinted obesity-related genes on other chromosomes (in trans) leading to differential effects on gene expression impacting obesity phenotype unique to (PWS). Objective Characterize the global methylation profiles and methylation status for select imprinted genes associated with obesity phenotype in a well-characterized imprinted, obesity-related syndrome (PWS) relative to a cohort of obese and non-obese individuals. Design Global methylation was assayed using two methodologies: 1) enriched LINE-1 repeat sequences by EpigenDx and 2) ELISA-based immunoassay method sensitive to genomic 5-methylcytosine by Epigentek. Target gene methylation patterns at selected candidate obesity gene loci were determined using methylation-specific PCR. Setting Study participants were recruited as part of an ongoing research program on obesity-related genomics and Prader-Willi syndrome. Participants Individuals with non-syndromic obesity (N=26), leanness (N=26) and PWS (N=39). Results A detailed characterization of the imprinting status of select target genes within the critical PWS 15q11-q13 genomic region showed enhanced cis but not trans methylation of imprinted genes. No significant differences in global methylation were found between non-syndromic obese, PWS or non-obese controls. Intervention None. Main outcome measures Percentage methylation and the methylation index. Conclusion The methylation abnormality in PWS due to errors of genomic imprinting effects both upstream and downstream effectors in the 15q11-q13 region showing enhanced cis but not trans methylation of imprinted genes. Obesity in our subject cohorts did not appear to impact global methylation levels using the described methodology. PMID:28111641

Psychotropic treatments in Prader-Willi syndrome: a critical review of published literature.

PubMed

Bonnot, O; Cohen, D; Thuilleaux, D; Consoli, A; Cabal, S; Tauber, M

2016-01-01

Prader-Willi syndrome (PWS) is a rare genetic syndrome. The phenotype includes moderate to intellectual disability, dysmorphia, obesity, and behavioral disturbances (e.g., hetero and self-injurious behaviors, hyperphagia, psychosis). Psychotropic medications are widely prescribed in PWS for symptomatic control. We conducted a systematic review of published literature to examine psychotropic medications used in PWS. MEDLINE was searched to identify articles published between January 1967 and December 2014 using key words related to pharmacological treatments and PWS. Articles with original data were included based on a standardized four-step selection process. The identification of studies led to 241 records. All selected articles were evaluated for case descriptions (PWS and behavioral signs) and treatment (type, titration, efficiency, and side effects). Overall, 102 patients were included in these studies. Treatment involved risperidone (three reports, n = 11 patients), fluoxetine (five/n = 6), naltrexone (two/n = 2), topiramate (two/n = 16), fluvoxamine (one/n = 1), mazindol (one/n = 2), N-acetyl cysteine (one/n = 35), rimonabant (one/n = 15), and fenfluramine (one/n = 15). We identified promising treatment effects with topiramate for self-injury and impulsive/aggressive behaviors, risperidone for psychotic symptoms associated with uniparental disomy (UPD), and N-acetyl cysteine for skin picking. The pharmacological approach of behavioral impairment in PWS has been poorly investigated to date. Further randomized controlled studies are warranted. Behavioral disturbances in Prader-Willi syndrome including aggressive reactions, skin picking, and hyperphagia might be very difficult to manage. Antipsychotic drugs are widely prescribed, but weight gain and increased appetite are their major side effects. Topiramate might be efficient for self-injury and impulsive/aggressive behaviors, N-acetyl cysteine is apromising treatment for

Skin-Picking in Individuals with Prader-Willi Syndrome: Prevalence, Functional Assessment, and Its Comorbidity with Compulsive and Self-Injurious Behaviours

ERIC Educational Resources Information Center

Didden, Robert; Korzilius, Hubert; Curfs, Leopold M. G.

2007-01-01

Background: Individuals with Prader-Willi syndrome (PWS) are at increased risk for mental health and behaviour problems, such as skin-picking and compulsive behaviours. Prevalence and functional assessment of skin-picking, and its association with compulsive behaviour and self-injury, were investigated in a large group of individuals with PWS (n =…

Cognitive and behavioural aspects of Prader-Willi syndrome.

PubMed

Rice, Lauren J; Einfeld, Stewart L

2015-03-01

To provide a review of the recent advances in the diagnosis and treatment of psychiatric disorders in Prader-Willi syndrome (PWS). Research in the last 12 months has provided a descriptive prognosis of psychosis in PWS and highlighted the possible genes associated with the increased risk of psychosis for those with maternal uniparental disomy (mUPD). Several studies investigating social and communication skills have shown people with PWS to have difficulty with core, receptive and expressive language skills, interpreting emotional valence in faces, playing with children of their own age, understanding personal space and a developmental delay in the theory of mind. These social and communication deficits are often more pronounced in those with mUPD. Two recent clinical trials of oxytocin provide mixed results and highlight the need for an improved understanding of the neurobiological characteristics of the PWS brain. A recent pilot study suggests N-acetylcysteine may be a viable treatment for skin picking. Recent advances have contributed to our understanding of the emotional and behavioural problems associated with PWS, and provided directions for further research.

Prader-Willi syndrome with elevated follicle stimulating hormone levels and diabetes mellitus.

PubMed

Nagai, T; Mimura, N; Tomizawa, T; Monden, T; Mori, M

1998-12-01

A 21 -year-old man with Prader-Willi syndrome (PWS) was hospitalized due to hyperglycemia. After diet therapy and transient insulin administration, his blood glucose levels improved. Based on the fact that his urinary C-peptide levels increased, the diabetes mellitus may have been due to insulin resistance with obesity. In addition, his testes had become atrophied. Testosterone levels remained low even after human chorionic gonadotropin (HCG) administration. Luteinizing hormone (LH) levels were also low after LH releasing hormone (LHRH) administration. The LH response increased slightly after daily LHRH administration, indicating hypothalamic hypogonadism. Follicle stimulating hormone (FSH) levels were, however, high and increased after LHRH administration. The selective FSH elevation may have been due to the accompanying idiopathic oligospermia.

Everyday physical activity and adiposity in Prader-Willi syndrome.

PubMed

van den Berg-Emons, Rita; Festen, Dederieke; Hokken-Koelega, Anita; Bussmann, Johannes; Stam, Henk

2008-11-01

The aim of this study was to assess the impact of Prader-Willi syndrome (PWS) on the level of everyday physical activity and to explore whether the activity level is related to adiposity. Measurements were performed with an accelerometry-based Activity Monitor during two consecutive schooldays in 12 children with PWS (7-16 years of age) and in 12 age- and gender-matched, healthy children. Adiposity was assessed by body mass index standard deviation scores and by percentage body fat (dual energy X-ray absorptiometry). Mean duration of dynamic activities (expressed as percentage of 24 h) was lower in children with PWS than in the comparison group (8.7 [2.5]% and 12.0 [3.1]%, respectively; p = 0.01). Six children with PWS had normal activity levels. Physical activity level was not related to adiposity. The results indicate that, as a group, children with PWS have an inactive lifestyle. However, children with PWS cannot be stereotyped as inactive since half of them had normal activity levels.

The European Prader-Willi Syndrome Clinical Research Database: An Aid in the Investigation of a Rare Genetically Determined Neurodevelopmental Disorder

ERIC Educational Resources Information Center

Holland, A.; Whittington, J.; Cohen, O.; Curfs, L.; Delahaye, F.; Dudley, O.; Horsthemke, B.; Lindgren, A. -C.; Nourissier, C.; Sharma, N.; Vogels, A.

2009-01-01

Background: Prader-Willi Syndrome (PWS) is a rare genetically determined neurodevelopmental disorder with a complex phenotype that changes with age. The rarity of the syndrome and the need to control for different variables such as genetic sub-type, age and gender limits clinical studies of sufficient size in any one country. A clinical research…

Prader-Willi syndrome: intellectual abilities and behavioural features by genetic subtype.

PubMed

Milner, Katja M; Craig, Ellen E; Thompson, Russell J; Veltman, Marijcke W M; Thomas, N Simon; Roberts, Sian; Bellamy, Margaret; Curran, Sarah R; Sporikou, Caroline M J; Bolton, Patrick F

2005-10-01

Studies of chromosome 15 abnormality have implicated over-expression of paternally imprinted genes in the 15q11-13 region in the aetiology of autism. To test this hypothesis we compared individuals with Prader-Willi syndrome (PWS) due to uniparental disomy (UPD--where paternally imprinted genes are over-expressed) to individuals with the 15q11-13 deletion form of the syndrome (where paternally imprinted genes are not over-expressed). We also tested reports that PWS cases due to the larger type I (TI) form of deletion show differences to cases with the smaller type II (TII) deletion. Ninety-six individuals with PWS were recruited from genetic centres and the PWS association. Forty-nine individuals were confirmed as having maternal UPD of chromosome 15 and were age and sex matched to 47 individuals with a deletion involving 15q11-13 (32 had the shorter (T II) deletion, and 14 had the longer (TI) deletion). Behavioural assessments were carried out blind to genetic status, using the Autism Diagnostic Observation Schedule (ADOS), the Autism Diagnostic Interview (ADI), the Autism Screening Questionnaire (ASQ), the Children's Yale-Brown Obsessive-Compulsive Scale (CY-BOCS), the Vineland Adaptive Behaviour Scales (VABS), and measurements of intellectual ability, including the Wechsler and Mullen Scales and Raven's Matrices. UPD cases exhibited significantly more autistic-like impairments in reciprocal social interaction on questionnaire, interview and standardised observational measures. Comparison of TI and TII deletion cases revealed few differences, but ability levels tended to be lower in the TI deletion cases. Findings from a large study comparing deletion and UPD forms of Prader-Willi syndrome were consistent with other evidence in indicating that paternally imprinted genes in the 15q11-13 region constitute a genetic risk factor for aspects of autistic symptomatology. These genes may therefore play a role in the aetiology of autism. By contrast with another report

Stress, Locus of Control, and Family Cohesion and Adaptability in Parents of Children with Down, Williams, Fragile X, and Prader-Willi Syndromes

ERIC Educational Resources Information Center

Lanfranchi, Silvia; Vianello, Renzo

2012-01-01

The present study analyzes differences in parental stress in families of children with Down, Williams, Fragile X, and Prader-Willi syndromes, exploring factors that influence parental stress, such as child's characteristics, parental locus of control, and family cohesion and adaptability. Differences between mothers and fathers are also…

Behavioural and cognitive profiles of mouse models for Prader-Willi syndrome.

PubMed

Relkovic, Dinko; Isles, Anthony R

2013-03-01

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder with aspects of psychiatric illness caused by genetic mutations at chromosome 15q11-q13. In addition to causing PWS, this interval is also thought to be of importance more generally in the development of autism and psychotic illness. The PWS genetic interval is conserved in mammals, and consequently mice carrying genetic manipulations affecting one or all of the genes in the region of conserved synteny have been generated and used in neurobehavioural studies. Here we give an overview of these models and describe the behavioural and neurobiological analyses that have been performed, many of which have provide new insights into the molecular and neural processes influenced by genes within the PWS interval. Copyright © 2011 Elsevier Inc. All rights reserved.

Scatter Plot Analysis of Excessive Daytime Sleepiness and Severe Disruptive Behavior in Adults with Prader-Willi Syndrome: A Pilot Study

ERIC Educational Resources Information Center

Maas, Anneke P. H. M.; Didden, Robert; Bouts, Lex; Smits, Marcel G.; Curfs, Leopold M. G.

2009-01-01

Individuals with Prader-Willi syndrome (PWS) are at risk for excessive daytime sleepiness (EDS) and disruptive behavior. This pilot study explores temporal characteristics of EDS and severe disruptive behavior across time of day and day of week in seven individuals with PWS (aged between 33 and 49 years) of whom five were matched to controls.…

Gastro-oesophageal reflux - an important causative factor of severe tooth wear in Prader-Willi syndrome?

PubMed

Saeves, Ronnaug; Strøm, Finn; Sandvik, Leiv; Nordgarden, Hilde

2018-04-23

GORD and acidic drinks, and both may be important aetiological factors underlying the extreme tooth wear in this group. Our data suggest a need for routine screening for GORD and dental wear in young individuals with Prader-Willi syndrome.

Growth Charts for Prader-Willi Syndrome During Growth Hormone Treatment

PubMed Central

Butler, Merlin G.; Lee, Jaehoon; Cox, Devin M.; Manzardo, Ann M.; Gold, June-Anne; Miller, Jennifer L.; Roof, Elizabeth; Dykens, Elisabeth; Kimonis, Virginia; Driscoll, Daniel J.

2018-01-01

The purpose of the current study was to develop syndrome-specific standardized growth curves for growth hormone–treated Prader-Willi syndrome (PWS) individuals aged 0 to 18 years. Anthropometric growth-related measures were obtained on 171 subjects with PWS who were treated with growth hormone for at least 40% of their lifespan. They had no history of scoliosis. PWS standardized growth curves were developed for 7 percentile ranges using the LMS method for weight, height, head circumference, weight/length, and BMI along with normative 3rd, 50th, and 97th percentiles plotted using control data from the literature and growth databases. Percentiles were plotted on growth charts for comparison purposes. Growth hormone treatment appears to normalize stature and markedly improves weight in PWS compared with standardized curves for non–growth hormone–treated PWS individuals. Growth chart implications and recommended usage are discussed. PMID:26842920

Diagnosis and treatment of GH deficiency in Prader-Willi syndrome.

PubMed

Grugni, Graziano; Marzullo, Paolo

2016-12-01

Prader-Willi syndrome (PWS) results from under-expression of the paternally-derived chromosomal region 15q11-13. Growth failure is a recognized feature of PWS, and both quantitative and qualitative defects of the GH/IGF-I axis revealing GH deficiency (GHD) have been demonstrated in most children with PWS. In PWS adults, criteria for GHD are biochemically fulfilled in 8-38% of the studied cohorts. Published data support benefits of early institution of GH therapy (GHT) in PWS children, with positive effects on statural growth, body composition, metabolic homeostasis, and neurocognitive function. Like in pediatric PWS, GHT also yields beneficial effects on lean and body fat, exercise capacity, and quality of life of PWS adults. Although GHT has been generally administered safely in PWS children and adults, careful surveillance of risks is mandatory during prolonged GH replacement for all PWS individuals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Prader-Willi syndrome and autism spectrum disorders: an evolving story.

PubMed

Dykens, Elisabeth M; Lee, Evon; Roof, Elizabeth

2011-09-01

Prader-Willi syndrome (PWS) is well-known for its genetic and phenotypic complexities. Caused by a lack of paternally derived imprinted material on chromosome 15q11-q13, individuals with PWS have mild to moderate intellectual disabilities, repetitive and compulsive behaviors, skin picking, tantrums, irritability, hyperphagia, and increased risks of obesity. Many individuals also have co-occurring autism spectrum disorders (ASDs), psychosis, and mood disorders. Although the PWS 15q11-q13 region confers risks for autism, relatively few studies have assessed autism symptoms in PWS or directly compared social, behavioral, and cognitive functioning across groups with autism or PWS. This article identifies areas of phenotypic overlap and difference between PWS and ASD in core autism symptoms and in such comorbidities as psychiatric disorders, and dysregulated sleep and eating. Though future studies are needed, PWS provides a promising alternative lens into specific symptoms and comorbidities of autism.

Mechanisms of obesity in Prader-Willi syndrome.

PubMed

Khan, M J; Gerasimidis, K; Edwards, C A; Shaikh, M G

2018-01-01

Obesity is the most common cause of metabolic complications and poor quality of life in Prader-Willi syndrome (PWS). Hyperphagia and obesity develop after an initial phase of poor feeding and failure to thrive. Several mechanisms for the aetiology of obesity in PWS are proposed, which include disruption in hypothalamic pathways of satiety control resulting in hyperphagia, aberration in hormones regulating food intake, reduced energy expenditure because of hypotonia and altered behaviour with features of autism spectrum disorder. Profound muscular hypotonia prevents PWS patients from becoming physically active, causing reduced muscle movements and hence reduced energy expenditure. In a quest for the aetiology of obesity, recent evidence has focused on several appetite-regulating hormones, growth hormone, thyroid hormones and plasma adipocytokines. However, despite advancement in understanding of the genetic basis of PWS, there are contradictory data on the role of satiety hormones in hyperphagia and data regarding dietary intake are limited. Mechanistic studies on the aetiology of obesity and its relationship with disease pathogenesis in PWS are required. . In this review, we focused on the available evidence regarding mechanisms of obesity and potential new areas that could be explored to help unravel obesity pathogenesis in PWS. © 2016 World Obesity Federation.

Elimination disorders in persons with Prader-Willi and Fragile-X syndromes.

PubMed

Equit, Monika; Piro-Hussong, Aline; Niemczyk, Justine; Curfs, Leopold; von Gontard, Alexander

2013-09-01

Elimination disorders are common in typically developing children. Only few studies have addressed elimination disorders in persons with intellectual disability (ID)-and even fewer studies in those with specific syndromes. The aim of the study was to investigate the rates of elimination disorders and behavioral symptoms in persons with Prader-Willi (PWS) and Fragile-X syndromes (FXS) in a large sample. Three hundred fifty-seven persons with PWS or FXS were recruited through parent self-help groups. A questionnaire regarding elimination symptoms, as well as the child behavior checklist (CBCL)/young adult behavior checklist (YABCL) were filled out by parents or caregivers. The sample included 191 persons with PWS (54.5% male) with a mean age of 20.0 years and 166 persons with FXS (92.2% male) with a mean age of 15.4 years. Persons with FXS were significantly more often affected by elimination disorders. 29.3% of persons with PWS and 48.8% of persons with FXS had at least one elimination disorder. Persons with FXS also had more often DUI (29.5% vs. 12.0%) and FI (28.9% vs. 12.6%). Rates of NE were similar in both groups (22.0% in PWS vs. 28.9% in FXS). Young adults with PWS had more behavioral symptoms in the clinical range (70.8% vs. 48.3%). Incontinence and behavioral symptoms were significantly associated in persons with FXS. NE, DUI, and FI are very common in persons with FXS and PWS and are associated with other behavioral symptoms in persons with FXS. They persist into adulthood. Early assessment and treatment are recommended. Copyright © 2012 Wiley Periodicals, Inc.

Near demise of a child with Prader-Willi syndrome during elective orchidopexy.

PubMed

Mantadakis, Elpis; Spanaki, Anna-Maria; Geromarkaki, Elsa; Vassilaki, Efrosini; Briassoulis, George

2006-07-01

The case of a morbidly obese 3.5-year-old boy, with Prader-Willi syndrome (PWS), who experienced a life-threatening episode of pulmonary edema soon after induction of general anesthesia with sevoflurane and intubation for orchidopexy is presented. The patient who had history of sleep apnea and who had an uneventful laparoscopy under general anesthesia 6 months previously was supported with mechanical ventilation with positive end expiratory pressure but developed hyperthermia, pneumonia, sepsis, and Acute Respiratory Distress Syndrome in the intensive care unit. He recovered fully 11 days after surgery. The possible contributing factors for the development of pulmonary edema are discussed. Arrangements for monitoring in an intensive care setting after surgery are highly recommended for patients with PWS.

Rehabilitation priorities for individuals with Prader-Willi Syndrome.

PubMed

Pituch, Keenan A; Green, Vanessa A; Didden, Robert; Lang, Russell; O'Reilly, Mark F; Lancioni, Giulio E; Whittle, Lisa; Hodis, Flaviu; Sigafoos, Jeff

2010-01-01

To identify rehabilitation priorities that parents have for their children, including their adult-aged children, with Prader-Willi Syndrome (PWS) and to determine the relation between these priorities and the child's levels of adaptive behaviour functioning. Parents involved in organisations related to PWS were invited to complete an online survey. The survey listed 54 skills/behaviours (e.g. toileting, expresses wants and needs and tantrums) representing 10 adaptive functioning domains (e.g. self-care, communication and problem behaviour). Parents rated their child's current level of ability/performance with respect to each skill/behaviour and indicated the extent to which training/treatment was a priority. Fifty-eight surveys were completed during the 4-month data collection period. Parents identified nine high-priority skills/behaviours from five different adaptive functioning domains. For most domains, parent priorities showed a significant linear relation to the children's adaptive behaviour deficits, in that priorities reflected areas where the child had the greatest deficits and the most problematic behaviours. Rehabilitation professionals should focus on the eating issues that arise in PWS and identify the adaptive functioning deficits of these individuals because such deficits are high-priority areas for parents.

Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi Syndrome

USDA-ARS?s Scientific Manuscript database

Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms ...

Treatment with growth hormone in the prader-willi syndrome.

PubMed

Moix Gil, Eugènia; Giménez-Palop, Olga; Caixàs, Assumpta

2018-04-01

The Prader-Willi syndrome (PWS) is a rare genetic disorder caused by absence of expression of the paternal alleles in región 15q11.2-q13. Obesity and hormonal deficiencies, especially of growth hormone (GH), are the most important signs from the therapeutic viewpoint. Recombinant GH (rGH) is effective in children and represents the mainstay in treatment; by contrast, little evidence in available in adult patients. To review the reported evidence on the beneficial and adverse effects of treatment with rGH in children and adults. A review was made of 62 original articles published between 2000 and 2017 using the PubMed database. In pediatric and adult PWS, rGH improves body morphology and composition, physical performance, cognition, psychomotor development, respiratory function, and quality of life with few adverse effects. Treatment with rGH is effective and safe and improves quality of life in both children and adults with PWS. Copyright © 2018 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

Appetitive behavior, compulsivity, and neurochemistry in Prader-Willi syndrome.

PubMed

Dimitropoulos, A; Feurer, I D; Roof, E; Stone, W; Butler, M G; Sutcliffe, J; Thompson, T

2000-01-01

Advances in genetic research have led to an increased understanding of genotype-phenotype relationships. Excessive eating and weight gain characteristic of Prader-Willi syndrome (PWS) have been the understandable focus of much of the research. The intense preoccupation with food, lack of satiation, and incessant food seeking are among the most striking features of PWS. It has become increasingly clear that the behavioral phenotype of PWS also includes symptoms similar to obsessive compulsive disorder, which in all probability interact with the incessant hunger and lack of satiation to engender the intense preoccupation and food seeking behavior that is characteristic of this disorder. Several lines of evidence suggest that genetic material on chromosome 15 may alter synthesis, release, metabolism, binding, intrinsic activity, or reuptake of specific neurotransmitters, or alter the receptor numbers and/or distribution involved in modulating feeding. Among the likely candidates are GABAnergic, serotonergic, and neuropeptidergic mechanisms. This review summarizes what is known about the appetitive behavior and compulsivity in PWS and discusses the possible mechanisms underlying these behaviors. MRDD Research Reviews 2000;6:125-130. Copyright 2000 Wiley-Liss, Inc.

ADHD symptoms and insistence on sameness in Prader-Willi syndrome.

PubMed

Wigren, M; Hansen, S

2005-06-01

Apart from a pervasive eating disorder, the Prader-Willi (PWS) syndrome is characterized by a distinct behavioural profile comprising maladaptive behaviours, obsessive-compulsive traits and skin picking, all included in the PWS behavioural phenotype. In this study, we present a further delineation of this characteristic behavioural profile by screening for indices of executive dysfunctions related to attention-deficit/hyperactivity disorder (ADHD), immature compulsive-like adherence to sameness and skin picking, and how these features aggregate into symptom constellations in children and adolescents with PWS. Parents of 58 individuals with PWS (aged 5-18 years) participated by completing Childhood Routines Inventory (CRI) and Conners' Parent Rating Scale (CPRS-48). Results showed that indices of ADHD and excessive insistence on sameness were common, comorbid and of early onset. They were both associated with conduct problems. Skin picking, appearing as a single and comorbid symptom, was less associated with childlike compulsions and ADHD-related problems. Findings are discussed in terms of further research in executive dysfunctions in PWS.

Rituals and compulsivity in Prader-Willi syndrome: profile and stability.

PubMed

Wigren, M; Hansen, S

2003-09-01

Prader-Willi syndrome (PWS) is characterized by an increased risk for obsessive-compulsive disorder. This study investigated the nature of compulsive-like behaviours in the PWS. Parents of 50 individuals with PWS (aged 5-18 years) and 50 typically developing 4-year-old children completed the Childhood Routines Inventory. This instrument measures compulsive-like behaviours in normative childhood. Many childhood compulsive behaviours are prevalent among older children and adolescents with PWS. Group differences were observed in that the PWS group, independent of age, gender and cognitive dysfunctions, exhibited more intense compulsive behaviours related to insistence on sameness in many daily activities and social contexts. Findings also revealed an age-independent low-prevalent pattern of PWS compulsivity, probably related to other features in the PWS symptomatology. Compulsions of childhood do not subside with age in adolescents with PWS. The findings indicate that the differentiation between delayed childhood rituals and pathological manifestations of compulsive features is complex in PWS populations.

The Prevalence and Treatment of Hip Dysplasia in Prader-Willi Syndrome (PWS).

PubMed

Trizno, Anastasiya A; Jones, Alexander S; Carry, Patrick M; Georgopoulos, Gaia

2018-03-01

Prader-Willi syndrome (PWS) is a genetic disorder with multisystem involvement. There are a number of associated orthopaedic manifestations, the most recognized of which is scoliosis. The aim of this study was to assess the prevalence of hip dysplasia and to investigate its treatment in patients with PWS. Following IRB approval, all patients seen at our institution's Prader-Willi multidisciplinary clinic were retrospectively reviewed. Only patients with an ultrasound, anteroposterior (AP) spine, AP abdomen, AP hip radiograph, and/or skeletal survey were included in the study. The presence of hip dysplasia was determined based on ultrasonographic and/or radiographic measurements performed by a single fellowship trained pediatric orthopaedic surgeon. A multivariable logistic regression analysis was used to test the association between patient demographics and the prevalence of hip dysplasia. Age at diagnosis, treatment type, and outcomes were recorded for patients that underwent treatment for hip dysplasia. Hip dysplasia was identified in 30% (27/90) of the patient population. Two of the 27 patients (7.4%) had normal films but had a history of resolved hip dysplasia. Prevalence was not associated with sex (P=0.7072), genetic subtype (P=0.5504), race (P=0.8537), ethnicity (P=0.2191), or duration of follow-up (P=0.4421). Eight of the 27 patients (30%) underwent hip treatment by Pavlik harness (2/8), Pavlik harness and closed reduction (1/8), closed reduction (3/8), open reduction (1/8), and unspecified hip surgery (1/8). The mean age at diagnosis was 2 months for the patients that were successfully treated for hip dysplasia (3/8) and 12 months for those who had residual dysplasia following the treatment (5/8). Our study demonstrates a higher prevalence of hip dysplasia in patients with PWS than previously documented. The age at which hip dysplasia develops remains unknown; therefore, we recommend an ultrasound screening for all infants with PWS at 6 weeks of age and

Frontal behavioral syndromes in Prader-Willi syndrome.

PubMed

Ogura, Kaeko; Shinohara, Mayumi; Ohno, Kousaku; Mori, Etsuro

2008-08-01

Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder presenting with behavioral problems including hyperphagia, emotional aberration, and compulsion-like behaviors. This combination of behavioral problems is likely to be caused by damage to the orbitofrontal cortices and anterior temporal lobes or to circuits involving them. To investigate the prevalence of eating and non-eating behavioral disturbances in PWS by using assessment tools developed originally for patients with frontotemporal dementia and with frontal lobe injury. The questionnaire consisted of 35 questions related to three categories of behavior: eating behaviors (including four domains: appetite, food preference, eating habits, and other oral behaviors), stereotypy (including four domains: roaming, speaking, movements, and daily rhythm), and collecting behaviors. It was administered in Japan to the parents of 250 individuals aged 1-42 years with a clinical diagnosis of PWS. The prevalence rates of symptoms in all categories were high. Each domain involved in eating behaviors was significantly correlated with stereotypy and collecting behaviors. The prevalence rates and severity scores of some eating and non-eating behaviors were higher in the older groups. Abnormal eating behaviors, stereotyped behaviors, and collecting behaviors were common in the PWS subjects. There was also a potential link between abnormal eating and non-eating behaviors related to frontal behavioral syndromes. It is likely that these behavioral abnormalities reflect dysfunction of the orbitofrontal cortices and anterior temporal lobes.

Dermatoglyphic features in Prader-Willi syndrome with respect to chromosomal findings

PubMed Central

Reed, Terry; Butler, Merlin G.

2017-01-01

Dermatoglyphic findings were compared in 38 Prader-Willi syndrome (PWS) patients and 270 normal controls. Twenty-one of the PWS patients had an interstitial deletion of the proximal long arm of chromosome 15 and seventeen PWS cases had normal chromosomes. Findings in PWS are not diagnostic but do show some consistent deviations that can be used in the clinical evaluation of PWS patients. These include a displacement of the axial triradius away from the normal proximal position, an excess of whorls primarily on the thumbs, radial termination of the palmar A mainline, and lack of arches on the big toe. Deletion PWS patients were much more homogeneous than non-deletion cases with respect to plantar patterns. The previously reported deficit of plantar pattern intensity was restricted only to deletion PWS and was characterized by a lack of plantar interdigital II–IV patterns with almost exclusively hallucal distal loops. PMID:6713710

Strengths and weaknesses in the cognitive profile of youngsters with Prader-Willi syndrome.

PubMed

Curfs, L M; Wiegers, A M; Sommers, J R; Borghgraef, M; Fryns, J P

1991-12-01

In this report we present the results of a study of the intellectual functioning and cognitive profile of 26 Prader-Willi syndrome (PWS) patients. The mean IQ score was 62.3 (range 39-96). In 13 patients a significant difference between verbal and performance IQ was found. In 10 of them the performance IQ was higher than the verbal. The results of subtest analysis indicate that cognitive strengths are more visible than cognitive weaknesses. Highest scores were noted especially in the performance scale, i.e. Block Design (9 children) and Coding or Mazes (5 children). Analysis of all available data indicates that PWS patients score better on visual motor discrimination skills than on auditory verbal processing skills. These results are promising for intervention programs and education strategies.

[Care continuity for patients with Prader-Willi syndrome during transition from childhood to adulthood].

PubMed

Saitoh, Shinji

2010-01-01

Prader-Willi syndrome(PWS) is a complex multisystem genetic disorder, of which characteristic phenotypes include neonatal hypotonia, hyperphagia resulting in obesity, mental retardation, hypogonadism, and behavioral and psychiatric problems. The diagnosis can be obtained as early as during neonatal period thanks to development of genetic testing. Clinical features of PWS will change depending on age, although core phenotypes of hyperphagia, obesity and psychiatric issues stay for lifetime. Therefore, integrated multidisciplinary approach starting from neonatal period is mandatory to ensure optimal management to improve lifelong quality of life. For successful transition from childhood to adulthood, multidisciplinary team need to share clinical information, and should keep the same policy about food, environment and psychiatric issues.

Genetics and mathematics: evidence from Prader-Willi syndrome.

PubMed

Semenza, Carlo; Pignatti, Riccardo; Bertella, Laura; Ceriani, Francesca; Mori, Ileana; Molinari, Enrico; Giardino, Daniela; Malvestiti, Francesca; Grugni, Graziano

2008-01-15

Mathematical abilities were tested in people with Prader-Willi syndrome (PWS), using a series of basic mathematical tasks for which normative data are available. The difference between the deletion and the disomy variants of this condition was explored. While a wide phenotypic variation was found, some basic findings emerge clearly. As expected from previous literature, deletion and disomy participants were found to differ in their degree of impairment, with disomy being overall the most spared condition. However, the tasks selectively spared in the disomy condition are not necessarily the easiest ones and those that discriminate less the PWS group from controls. It rather seems that disomy patients are spared, with respect to deletion, in tasks entailing transcoding and comparison of numbers in the Arabic code. Overall a particular difficulty was detected in reliably performing parity judgments. This task has been shown to be very frequently spared after a brain injury, even in severe aphasic conditions. The most interesting result is the sparing in analog number scale, whereby PWS seem, overall, to outperform controls. This finding may help in understanding previously reported, surprising results about cognitive skills in PWS. Elevated performances in PWS may result from life-long hyper-reliance on one visuo-spatial system in presence of underdevelopment of the other.

Corticospinal physiology in patients with Prader-Willi syndrome: a transcranial magnetic stimulation study.

PubMed

Civardi, Carlo; Vicentini, Roberta; Grugni, Graziano; Cantello, Roberto

2004-10-01

Prader-Willi syndrome (PWS) is a genetic developmental disorder, mostly caused by a deletion on the paternal chromosome 15 or by a maternal uniparental disomy 15. Some PWS clinical and neurochemical features suggest an involvement of the corticospinal motor structures. To explore the corticospinal physiology of PWS by transcranial magnetic stimulation. A community-based hospital. We studied motor evoked potentials in the first dorsal interosseous muscle of 21 young-adult patients with PWS. Thirteen patients had a deletion at chromosome 15; 8 had a uniparental disomy. We measured the following variables: relaxed motor threshold, central motor conduction time, duration of the central silent period, and short-interval intracortical inhibition and facilitation. We also recorded F waves in the first dorsal interosseous muscle. We had 11 normal controls. In the whole PWS group, motor threshold was higher as compared with controls (P<.05). The central motor conduction time, central silent period, and F waves were normal. Intracortical facilitation was reduced significantly (P<.001). Patients with PWS and a deletion had a weaker intracortical inhibition as compared with patients with PWS and a uniparental disomy (P<.05). Transcranial magnetic stimulation changes in patients with PWS suggested a hypo-excitability of the motor cortical areas. Defective neurogenesis of the cortical tissue and multiple transmitter alterations are the putative causes. Impaired intracortical inhibition might represent an electrical marker for a deletion defect.

Maladaptive behaviour in Prader-Willi syndrome in adult life.

PubMed

Clarke, D J; Boer, H; Chung, M C; Sturmey, P; Webb, T

1996-04-01

Thirty adults with Prader-Willi syndrome (PWS) were compared with 30 adults with non-specific learning disability matched for age, sex and severity of mental retardation. Maladaptive behaviour was assessed with the Aberrant Behavior Checklist (ABC), a 58-item structured interview which rates behaviours from 0 (not a problem) to 3 (severe problem) and which yields five factors (I) irritability, agitation; (II) lethargy, withdrawal; (III) stereotypic behavior; (IV) hyperactivity, non-compliance; and (V) inappropriate speech). The PWS sample had significantly higher factor I (P < 0.001) and factor V (P < 0.05) scores. The PWS sample had mean scores above 1 for 17 ABC items; the contrast subjects had no mean scores above 1. The factor I scores for the PWS sample were similar to those of inpatients in hospital facilities for adults with mental retardation and mental illness or severely challenging behaviour. The results support previous work, and extend it by suggesting that temper tantrums, self-injury, impulsiveness, lability of mood, inactivity and repetitive speech are characteristic behaviours in PWS in adult life. Studies of the reasons for heterogeneity in behaviour are now needed.

Mental Health Problems in Children with Prader-Willi Syndrome

PubMed Central

Skokauskas, Norbert; Sweeny, Eileen; Meehan, Judith; Gallagher, Louise

2012-01-01

Background: Prader-Willi Syndrome (PWS) is a genetically determined neurodevelopmental disorder, which occurs in approximately one in 22000 births. Aims: This study aimed to investigate psychiatric characteristics of children diagnosed with PWS compared with an age-, gender- and IQ-matched control group. The parents of children with PWS were assessed for psychological distress in comparison to the parents of the control group. Methodological limitations identified in previous studies were addressed in the present study. Methods: Psychiatric problems were evaluated in a sample of children with genetically confirmed PWS and an age- and IQ-matched control group using the Child Behaviour Checklist 6–18. Parental psychological distress for both groups was evaluated with the Brief Symptom Inventory. Results: Children with PWS had more severe somatic, social, and thought problems, and were more withdrawn-depressed in comparison to controls. Borderline difficulties were detected for the affective, somatic, and attention deficit-hyperactivity CBCL DSM-orientated subscales in the PWS group. Parents of PWS children, in comparison to controls, had more somatization, phobic anxiety, obsessive-compulsive, and anxiety problems. Conclusions: PWS represents a complex psychological disorder with multiple areas of disturbances. PMID:22876265

Movement characteristics of persons with prader-willi syndrome rising from supine.

PubMed

Belt, A B; Hertel, T A; Mante, J R; Marks, T; Rockett, V L; Wade, C; Clayton-Krasinski, D

2001-01-01

The purposes of this study were to: 1) determine if previously published descriptors of the supine to stand rising task in healthy individuals could be applied to the movements of persons with Prader-Willi Syndrome (PWS); and 2) assess upper extremity (UE), axial region (AX), and lower extremity (LE) movements among subjects with PWS compared with controls. Nine subjects with PWS (seven-36 years of age) and matched controls were videotaped performing 10 rising trials. The UE, AX, and LE movements were classified using published descriptors. Occurrence frequencies of movement patterns, duration of movement, and the relationships among body region movement score, BMI, and age were determined. Subjects with PWS utilized developmentally less advanced asymmetrical rising patterns, took longer to rise, and demonstrated less within subject variability than controls. Categorical descriptors, with minor modifications, can be used to describe rising movements in persons with PWS. Knowledge of successful rising patterns may assist PTs when examining or planning intervention strategies for teaching the rising task.

Maternal uniparental disomy 14 syndrome demonstrates prader-willi syndrome-like phenotype.

PubMed

Hosoki, Kana; Kagami, Masayo; Tanaka, Touju; Kubota, Masaya; Kurosawa, Kenji; Kato, Mitsuhiro; Uetake, Kimiaki; Tohyama, Jun; Ogata, Tsutomu; Saitoh, Shinji

2009-12-01

To delineate the significance of maternal uniparental disomy 14 (upd(14)mat) and related disorders in patients with a Prader-Willi syndrome (PWS)-like phenotype. We examined 78 patients with PWS-like phenotype who lacked molecular defects for PWS. The MEG3 methylation test followed by microsatellite polymorphism analysis of chromosome 14 was performed to detect upd(14)mat or other related abnormalities affecting the 14q32.2-imprinted region. We identified 4 patients with upd(14)mat and 1 patient with an epimutation in the 14q32.2 imprinted region. Of the 4 patients with upd(14)mat, 3 had full upd(14)mat and 1 was mosaic. Upd(14)mat and epimutation of 14q32.2 represent clinically discernible phenotypes and should be designated "upd(14)mat syndrome." This syndrome demonstrates a PWS-like phenotype particularly during infancy. The MEG3 methylation test can detect upd(14)mat syndrome defects and should therefore be performed for all undiagnosed infants with hypotonia.

What is the value of growth hormone therapy in Prader Willi syndrome?

PubMed

Bridges, Nicola

2014-02-01

Prader Willi syndrome (PWS) is a genetic condition caused by loss of the paternal copy of a region of imprinted genes on chromosome 15. There is severe muscular hypotonia in the neonatal period, with the onset of hyperphagia and food-seeking behaviour in childhood. All individuals with PWS have developmental delay. Without careful control of food intake and the food environment, individuals with PWS become morbidly obese and are likely to die as young adults from the complications of obesity. The aims of growth hormone (GH) treatment in PWS are distinct from the use of GH in other conditions-although GH does increase final height in PWS, the main benefits of treatment are improved body composition and better exercise capacity, which can help with the aim of preventing obesity. GH trials in PWS have demonstrated improved muscle bulk, reduced fat mass and increased levels of physical activity. GH has also been demonstrated to improve attainment of developmental and cognitive milestones in children with PWS. GH treatment appears to change respiratory status in PWS, possibly because of growth of lymphoid tissue at the start of treatment. Respiratory assessment is recommended prior to, and just after starting GH treatment. Ideal age for starting GH is not clear, although there has been a trend towards starting at younger ages. It may be that GH treatment in childhood confers benefits into adult life. There are less data to support continuing GH treatment into adult life.

Prader-Willi syndrome: clinical picture, psychosocial support and current management.

PubMed

Wigren, M; Hansen, S

2003-11-01

Prader-Willi syndrome (PWS) is a rare, genetically based disorder that occurs in about 1 of 15 000 live-born children. To raise a child with PWS is challenging for parents and requires support from multiprofessional habilitation services. This paper maps the need for psychosocial support and current management of children and adolescents with PWS. Parents to 58 children with PWS (aged 5-18 years) completed questionnaires covering clinical, diagnostic and psychosocial issues. The children received their diagnosis at a mean age of 2.5 year. Growth hormone treatment was given to 72%. Sixty-three per cent of the sample was not overweight. Neuropsychiatric symptoms were common from early age and some were related to obesity. Most parents wanted information as to availability of external resources and future child needs. Few parents needed family-directed support. The overall impression is that the eating disorder is managed relatively well. Even so PWS symptoms typically exacerbate over time and consequently parents need continuous support throughout childhood and adolescence. Greater attention should be paid to idiosyncrasies in cognitive functioning and to clinical markers of neuropsychiatric problems.

Working-for-Food Behaviors: A Preclinical Study in Prader-Willi Mutant Mice.

PubMed

Lassi, Glenda; Maggi, Silvia; Balzani, Edoardo; Cosentini, Ilaria; Garcia-Garcia, Celina; Tucci, Valter

2016-11-01

Abnormal feeding behavior is one of the main symptoms of Prader-Willi syndrome (PWS). By studying a PWS mouse mutant line, which carries a paternally inherited deletion of the small nucleolar RNA 116 (Snord116), we observed significant changes in working-for-food behavioral responses at various timescales. In particular, we report that PWS mutant mice show a significant delay compared to wild-type littermate controls in responding to both hour-scale and seconds-to-minutes-scale time intervals. This timing shift in mutant mice is associated with better performance in the working-for-food task, and results in better decision making in these mutant mice. The results of our study reveal a novel aspect of the organization of feeding behavior, and advance the understanding of the interplay between the metabolic functions and cognitive mechanisms of PWS. Copyright © 2016 by the Genetics Society of America.

Endocrine manifestations and management of Prader-Willi syndrome.

PubMed

Emerick, Jill E; Vogt, Karen S

2013-08-21

Prader-Willi syndrome (PWS) is a complex genetic disorder, caused by lack of expression of genes on the paternally inherited chromosome 15q11.2-q13. In infancy it is characterized by hypotonia with poor suck resulting in failure to thrive. As the child ages, other manifestations such as developmental delay, cognitive disability, and behavior problems become evident. Hypothalamic dysfunction has been implicated in many manifestations of this syndrome including hyperphagia, temperature instability, high pain threshold, sleep disordered breathing, and multiple endocrine abnormalities. These include growth hormone deficiency, central adrenal insufficiency, hypogonadism, hypothyroidism, and complications of obesity such as type 2 diabetes mellitus. This review summarizes the recent literature investigating optimal screening and treatment of endocrine abnormalities associated with PWS, and provides an update on nutrition and food-related behavioral intervention. The standard of care regarding growth hormone therapy and surveillance for potential side effects, the potential for central adrenal insufficiency, evaluation for and treatment of hypogonadism in males and females, and the prevalence and screening recommendations for hypothyroidism and diabetes are covered in detail. PWS is a genetic syndrome in which early diagnosis and careful attention to detail regarding all the potential endocrine and behavioral manifestations can lead to a significant improvement in health and developmental outcomes. Thus, the important role of the provider caring for the child with PWS cannot be overstated.

Urinary incontinence in persons with Prader-Willi Syndrome.

PubMed

Von Gontard, Alexander; Didden, Robert; Sinnema, Margje; Curfs, Leopold

2010-12-01

To assess and identify the frequency and type of urinary incontinence (UI), as well as associated symptoms in persons with Prader-Willi syndrome (PWS). PWS is characterized by mental retardation, short stature, obesity and hypogonadism. The behavioural phenotype includes eating problems, temper outbursts, affective disorders, stereotypies and speech abnormalities. UI is common in children with mental retardation in general, but has not been reported systematically in children with PWS so far. The Dutch version of the 'Parental Questionnaire: Enuresis/Urinary Incontinence' was completed by 118 parents of children with PWS. This questionnaire includes items referring to day- and night-time wetting, toilet habits, observable voiding behaviours and reactions, urinary tract infections, stool habits and behavioural symptoms. The rate of nocturnal enuresis in persons with PWS was 13.6% (16) at a mean age of 15.1 years. 3.8% (5) had additional daytime urinary incontinence, and 3.3% (4) had faecal incontinence. Lower urinary tract symptoms were commonly indicative of overactive bladder, dysfunctional voiding and postponement. Also, the rate of internalizing and externalizing behavioural problems was high. Urinary incontinence is more common in persons with PWS than in typically developing children, adolescents and adults. As lower urinary tract symptoms are common, detailed assessment and specific treatment of UI should be part of the care of all persons with PWS. © 2010 THE AUTHORS. JOURNAL COMPILATION © 2010 BJU INTERNATIONAL.

[Prader Willi syndrome patients: study of 77 patients].

PubMed

Poyatos, David; Camprubí, Cristina; Gabau, Elisabeth; Nosas, Ramón; Villatoro, Sergi; Coll, María Dolores; Guitart, Miriam

2009-11-07

The Prader-Willi syndrome (PWS) is a disease of genetic origin. It is characterized by neonatal hypotonia, hypogonadism, hiperfagia leading to obesity, low stature, developmental delay, moderate mental retardation, abnormal behavior and characteristic facial appearance. It is caused by the loss or the inactivation of paternal genes of the imprinted region 15q11-13. There are different genetic causes: paternal 15q11-q13 deletion in 70% of patients, maternal uniparental disomy in the 20-25% and less than 5% have an imprinting defect. We present the results obtained in the transverse clinical - genetic study of 77 PWS patients. There has been realized the study of 374 suspected PWS patients. Cytogenetics studies of bands G and hybridization in situ fluorescent (FISH) and molecular genetics analysis of microsatellites, Southern blot, MS-PCR and sequenciation were carried out. Holm's criteria use for the correlation phenotype - genotype in 48 patients. PWS was confirmed in 77 patients, 46 deletion, 16 uniparental disomy, two imprinting defect and 13 only PWS methylation pattern. Significant differences do not observe in the correlation phenotype - genotype. The frequencies of the molecular alterations, 71.87 % deletion, 25 % UPD and 3.12 % DI, they are similar to described in the literature. It presents the algorithm of diagnosis used with the MS-PCR as rapid technology to confirm PWS.

Hyperghrelinemia in Prader-Willi Syndrome Begins in Early Infancy Long Before the Onset of Hyperphagia

PubMed Central

Kweh, Frederick A.; Miller, Jennifer L.; Sulsona, Carlos R; Wasserfall, Clive; Atkinson, Mark; Shuster, Jonathan J.; Goldstone, Anthony P.; Driscoll, Daniel J.

2015-01-01

Circulating total ghrelin levels are elevated in older children and adults with Prader-Willi syndrome (PWS). However, the presence or absence of hyperghrelinemia in young children with PWS remains controversial. We hypothesized that a more robust way to analyze appetite-regulating hormones in PWS would be by nutritional phases rather than age alone. Our objectives were to compare total serum ghrelin levels in children with PWS by nutritional phase as well as to compare total ghrelin levels in PWS (5 weeks to 21 years of age) to normal weight controls and individuals with early-onset morbid obesity (EMO) without PWS. Fasting serum total ghrelin levels were measured in 60 subjects with PWS, 39 subjects with EMO of unknown etiology, and in 95 normal non-obese sibling controls of PWS or EMO subjects (SibC) in this 12 year longitudinal study. Within PWS, total ghrelin levels were significantly (P<0.001) higher in earlier nutritional phases: phase 1a (7,906 ± 5,887); 1b (5,057 ± 2,624); 2a (2,905 ± 1,521); 2b (2,615 ± 1,370) and 3 (2,423 ± 1,350). Young infants with PWS also had significantly (P=0.009) higher total ghrelin levels than did the sibling controls. Nutritional phase is an important independent prognostic factor of total ghrelin levels in individuals with PWS. Circulating ghrelin levels are elevated in young children with PWS long before the onset of hyperphagia, especially during the early phase of poor appetite and feeding. Therefore, it seems unlikely that high ghrelin levels are directly responsible for the switch to the hyperphagic nutritional phases in PWS. PMID:25355237

Prader-Willi syndrome and the evolution of human childhood.

PubMed

Haig, David; Wharton, Robert

2003-01-01

The kinship theory of genomic imprinting predicts that imprinted genes have effects on asymmetric kin (relatives with different degrees of matrilineal and patrilineal relatedness). The most important interaction with such a relative is a child's interaction with its mother. Therefore, the study of imprinted genes and their phenotypic effects promises to provide insights into the evolution of mother-child relations. Prader-Willi syndrome (PWS) is caused by the absence of expression of genes at 15q11-q13 that are normally expressed only when paternally derived. The kinship theory predicts that children with PWS will fail to express behaviors that have increased mothers' costs of child-rearing. Our analysis focuses on aspects of the PWS phenotype that affect appetite and feeding. Immediately after birth, children with PWS have little appetite and are usually unable to suckle, but at some stage (usually within the first 2 years) they develop a voracious appetite and an obsession with food. We conjecture that this change in appetite reflects evolutionary forces associated with weaning. Immediately after birth, when a child is completely dependent on the breast, poor appetite reduced maternal costs. However, once a child was able to consume supplemental foods, maternal costs would have been reduced by children with increased, nonfastidious appetites. Copyright 2003 Wiley-Liss, Inc.

Prader-Willi syndrome as a model of human hyperphagia.

PubMed

Tauber, Maithe; Diene, Gwenaelle; Mimoun, Emmanuelle; Çabal-Berthoumieu, Sophie; Mantoulan, Carine; Molinas, Catherine; Muscatelli, F; Salles, Jean Pierre

2014-01-01

Prader-Willi syndrome (PWS), first described in 1956, is considered as a paradigm of a neurodevelopmental disorder with severe and early obesity with hyperphagia and impaired satiety. The improved knowledge in the natural history and recent data on genetics offer new perspectives for understanding the metabolic and endocrine dysfunctions and possibly for treatment. Natural history of the disease has been described due to the early diagnosis performed in the first months of life and various nutritional phases have been described. In addition, there is clear evidence that the abnormal feeding behavior is included in the behavioral problems. Brain imaging studies have shown that some brain regions may be important in PWS. The role of SNORD116 gene cluster is detailed and its links with circadian rhythm and brain and hypothalamus development. Pathophysiology of the abnormal ghrelin levels and of OT dysfunction is documented. While no effect on appetite and weight regulation has been reported with ghrelin antagonists, OT has been shown to improve some of the behavioral problems in adults. We discuss our hypothesis of an abnormal ghrelin/OT/dopamine pathway which may explain the switch of nutritional phases and behavior. These new aspects offer an opportunity for therapeutic use and possible early intervention. © 2014 S. Karger AG, Basel.

Association between physical activity and bone in children with Prader-Willi syndrome.

PubMed

Duran, Andrea T; Wilson, Kathleen S; Castner, Diobel M; Tucker, Jared M; Rubin, Daniela A

2016-07-01

The aim of the study was to determine if physical activity (PA) is associated with bone health in children with Prader-Willi syndrome (PWS). Participants included 23 children with PWS (age: 11.0±2.0 years). PA, measured by accelerometry, was categorized into light, moderate, vigorous and moderate plus vigorous intensities. Hip, total body minus the head (body), bone mineral content (BMC), bone mineral density (BMD) and BMD z-score (BMDz) were measured by dual X-ray absorptiometry. Separate hierarchical regression models were completed for all bone parameters, PA intensity and select covariates. Moderate PA and select covariates explained the most variance in hip BMC (84.0%), BMD (61.3%) and BMDz (34.9%; p<0.05 for all). Likewise, for each body parameter, moderate PA and select covariates explained the most variance in body BMC (75.8%), BMD (74.4%) and BMDz (31.8%; p<0.05 for all). PA of at least moderate intensity appears important for BMC and BMD in children with PWS.

Copy number variations at the Prader-Willi syndrome region on chromosome 15 and associations with obesity in whites.

PubMed

Chen, Yuan; Liu, Yong-Jun; Pei, Yu-Fang; Yang, Tie-Lin; Deng, Fei-Yan; Liu, Xiao-Gang; Li, Ding-You; Deng, Hong-Wen

2011-06-01

Obesity is a serious health problem with strong genetic determination. Copy number variation (CNV) is a common type of genomic variant associated with some complex human diseases. However, it is not clear how CNVs contribute to the etiology of obesity. In this study, we examined 1,000 unrelated US whites to search for CNVs that may predispose to obesity. We focused our analyses on the Prader-Willi syndrome (PWS) critical region (chromosome 15q11-q13), because the PWS region is a hotspot for CNV generation and obesity is one of the major clinical manifestations for chromosome abnormalities at this region. We constructed a map containing 39 CNVs at the PWS critical region with CNV occurrence rates higher than 1%. Among them, three CNVs were significantly associated with body fat mass (P < 0.05), with a higher copy number (CN) associated with an increase of 5.08-9.77 kg in body fat mass. These three CNVs are close to two known PWS genes, NDN (necdin homolog) and C15orf2 (chromosome 15 open reading frame 2), and partially overlap with another obesity gene PWRN1 (Prader-Willi region nonprotein-coding RNA 1). Interestingly, our recently published whole genome association scan study using the same sample by examining single-nucleotide polymorphisms (SNPs) did not find any significant associations at these CNV regions, suggesting the importance of examining both CNVs and SNPs for better understanding of genetic basis of obesity. Further studies are warranted to validate these CNVs and their importance to obesity.

Puzzle Pieces: Neural Structure and Function in Prader-Willi Syndrome

PubMed Central

Manning, Katherine E.; Holland, Anthony J.

2015-01-01

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder of genomic imprinting, presenting with a behavioural phenotype encompassing hyperphagia, intellectual disability, social and behavioural difficulties, and propensity to psychiatric illness. Research has tended to focus on the cognitive and behavioural investigation of these features, and, with the exception of eating behaviour, the neural physiology is currently less well understood. A systematic review was undertaken to explore findings relating to neural structure and function in PWS, using search terms designed to encompass all published articles concerning both in vivo and post-mortem studies of neural structure and function in PWS. This supported the general paucity of research in this area, with many articles reporting case studies and qualitative descriptions or focusing solely on the overeating behaviour, although a number of systematic investigations were also identified. Research to date implicates a combination of subcortical and higher order structures in PWS, including those involved in processing reward, motivation, affect and higher order cognitive functions, with both anatomical and functional investigations indicating abnormalities. It appears likely that PWS involves aberrant activity across distributed neural networks. The characterisation of neural structure and function warrants both replication and further systematic study. PMID:28943631

Puzzle Pieces: Neural Structure and Function in Prader-Willi Syndrome.

PubMed

Manning, Katherine E; Holland, Anthony J

2015-12-17

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder of genomic imprinting, presenting with a behavioural phenotype encompassing hyperphagia, intellectual disability, social and behavioural difficulties, and propensity to psychiatric illness. Research has tended to focus on the cognitive and behavioural investigation of these features, and, with the exception of eating behaviour, the neural physiology is currently less well understood. A systematic review was undertaken to explore findings relating to neural structure and function in PWS, using search terms designed to encompass all published articles concerning both in vivo and post-mortem studies of neural structure and function in PWS. This supported the general paucity of research in this area, with many articles reporting case studies and qualitative descriptions or focusing solely on the overeating behaviour, although a number of systematic investigations were also identified. Research to date implicates a combination of subcortical and higher order structures in PWS, including those involved in processing reward, motivation, affect and higher order cognitive functions, with both anatomical and functional investigations indicating abnormalities. It appears likely that PWS involves aberrant activity across distributed neural networks. The characterisation of neural structure and function warrants both replication and further systematic study.

Gender Differences in the Behavioral Symptom Severity of Prader-Willi Syndrome.

PubMed

Gito, Masao; Ihara, Hiroshi; Ogata, Hiroyuki; Sayama, Masayuki; Murakami, Nobuyuki; Nagai, Toshiro; Ayabe, Tadayuki; Oto, Yuji; Shimoda, Kazutaka

2015-01-01

This study measured gender differences in Prader-Willi syndrome (PWS) in regard to the severity of behavioral symptoms. The Food Related Problem Questionnaire (FRPQ), the Aberrant Behavior Checklist Japanese Version, the Childhood Routines Inventory, the Pervasive Developmental Disorders Autism Society Japan Rating Scale, and Japanese ADHD-RS were administered to PWS patients (45 males aged 6 to 58 and 37 females aged 6 to 45). To examine the effects that gender and genotype have on the severity of each symptom, two-way ANOVAs were conducted. Significant interactions were found only in regard to FRPQ scores, such as FRPQ total score (F(1, 78) = 8.43, p < 0.01). The FRPQ of male deletion (DEL) individuals was higher than that of female DEL and male mUPD. The FRPQ of male maternal uniparental disomy (mUPD) was lower than that of female mUPD. In terms of problem behaviors, routines, autistic behaviors, and hyperactivity, no significant differences were found. Food-related behaviors in DEL were more severe in males, although those in mUPD were less severe in males.

Mosaicism for maternal uniparental disomy 15 in a boy with some clinical features of Prader-Willi syndrome.

PubMed

Zilina, Olga; Kahre, Tiina; Talvik, Inga; Oiglane-Shlik, Eve; Tillmann, Vallo; Ounap, Katrin

2014-01-01

Prader-Willi syndrome (PWS) is caused by the lack of paternal expression of imprinted genes in the human chromosomal region 15q11.2-q13.2, which can be due to an interstitial deletion at 15q11.2-q13 of paternal origin (65-75%), maternal uniparental disomy (matUPD) of chromosome 15 (20-30%), or an imprinting defect (1-3%). The majority of PWS-associated matUPD15 cases represent a complete heterodisomy of chromosome 15 or a mixture of hetero- and isodisomic regions across the chromosome 15. Pure maternal isodisomy is observed in only a few matUPD15 patients. Here we report a case of an 18-year-old boy with some clinical features of Prader-Willi syndrome, such as overweight, muscular hypotonia, facial dysmorphism and psychiatric problems, but there was no reason to suspect PWS in the patient based solely on the phenotype estimation. However, chromosomal microarray analysis (CMA) revealed mosaic loss of heterozygosity of the entire chromosome 15. Methylation-specific multiplex ligation-dependant probe amplification (MS-MLPA) analysis showed hypermethylation of the SNRPN and NDN genes in the PWS/AS critical region of chromosome 15 in this patient. Taking into consideration the MS-MLPA results and the presence of PWS features in the patient, we concluded that it was matUPD15, although the patient's parents were not enrolled in the study. According to CMA and karyotyping, no trisomic or monosomic cells were present. To the best of our knowledge, only two PWS cases with mosaic maternal isodisomy 15 and without trisomic/monosomic cell lines have been reported so far. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

A comprehensive team approach to the management of patients with Prader-Willi syndrome.

PubMed

Eiholzer, Urs; Whitman, Barbara Y

2004-09-01

Prader-Willi syndrome (PWS) is a genetic disorder characterized by extreme obesity accompanied by other, multisystem clinical manifestations encompassing both physical and behavioral/cognitive abnormalities. The multi-dimensional problems of patients with PWS cannot be treated with a single intervention and benefit from a team approach to management to optimize outcomes. Childhood stature below target height and reduced final height are some defining characteristics of PWS, and compelling evidence from growth hormone (GH) treatment trials suggests that hypothalamic GH deficiency exists. Treatment with GH has been shown to increase height velocity in children with PWS, decrease weight-for-height index values and body fat mass, and have a positive effect on lean body mass during at least the first year of therapy. In addition to medical concerns, the behavioral manifestations, including an uncorrectable deficit in appetite control, and cognitive limitations associated with PWS, require long-term multidisciplinary management.

Hyperghrelinemia in Prader-Willi syndrome begins in early infancy long before the onset of hyperphagia.

PubMed

Kweh, Frederick A; Miller, Jennifer L; Sulsona, Carlos R; Wasserfall, Clive; Atkinson, Mark; Shuster, Jonathan J; Goldstone, Anthony P; Driscoll, Daniel J

2015-01-01

Circulating total ghrelin levels are elevated in older children and adults with Prader-Willi syndrome (PWS). However, the presence or absence of hyperghrelinemia in young children with PWS remains controversial. We hypothesized that a more robust way to analyze appetite-regulating hormones in PWS would be by nutritional phases rather than age alone. Our objectives were to compare total serum ghrelin levels in children with PWS by nutritional phase as well as to compare total ghrelin levels in PWS (5 weeks to 21 years of age) to normal weight controls and individuals with early-onset morbid obesity (EMO) without PWS. Fasting serum total ghrelin levels were measured in 60 subjects with PWS, 39 subjects with EMO of unknown etiology, and in 95 normal non-obese sibling controls of PWS or EMO subjects (SibC) in this 12 year longitudinal study. Within PWS, total ghrelin levels were significantly (P < 0.001) higher in earlier nutritional phases: phase 1a (7,906  ±  5,887); 1b (5,057 ± 2,624); 2a (2,905 ± 1,521); 2b (2,615 ± 1,370) and 3 (2,423 ± 1,350). Young infants with PWS also had significantly (P = 0.009) higher total ghrelin levels than did the sibling controls. Nutritional phase is an important independent prognostic factor of total ghrelin levels in individuals with PWS. Circulating ghrelin levels are elevated in young children with PWS long before the onset of hyperphagia, especially during the early phase of poor appetite and feeding. Therefore, it seems unlikely that high ghrelin levels are directly responsible for the switch to the hyperphagic nutritional phases in PWS. © 2014 Wiley Periodicals, Inc.

Obesity and Prader-Willi Syndrome Affect Heart Rate Recovery from Dynamic Resistance Exercise in Youth

PubMed Central

Castner, Diobel M.; Clark, Susan J.; Judelson, Daniel A.; Rubin, Daniela A.

2016-01-01

Following exercise, heart rate decline is initially driven by parasympathetic reactivation and later by sympathetic withdrawal. Obesity delays endurance exercise heart rate recovery (HRR) in both children and adults. Young people with Prader-Willi Syndrome (PWS), a congenital cause for obesity, have shown a slower 60-s endurance exercise HRR compared to lean and obese children, suggesting compromised regulation. This study further evaluated effects of obesity and PWS on resistance exercise HRR at 30 and 60 s in children. PWS (8–18 years) and lean and obese controls (8–11 years) completed a weighted step-up protocol (six sets x 10 reps per leg, separated by one-minute rest), standardized using participant stature and lean body mass. HRR was evaluated by calculated HRR value (HRRV = difference between HR at test termination and 30 (HRRV30) and 60 (HRRV60) s post-exercise). PWS and obese had a smaller HRRV30 than lean (p < 0.01 for both). Additionally, PWS had a smaller HRRV60 than lean and obese (p = 0.01 for both). Obesity appears to delay early parasympathetic reactivation, which occurs within 30 s following resistance exercise. However, the continued HRR delay at 60 s in PWS may be explained by either blunted parasympathetic nervous system reactivation, delayed sympathetic withdrawal and/or poor cardiovascular fitness. PMID:28933384

Obesity and Prader-Willi Syndrome Affect Heart Rate Recovery from Dynamic Resistance Exercise in Youth.

PubMed

Castner, Diobel M; Clark, Susan J; Judelson, Daniel A; Rubin, Daniela A

2016-01-15

Following exercise, heart rate decline is initially driven by parasympathetic reactivation and later by sympathetic withdrawal. Obesity delays endurance exercise heart rate recovery (HRR) in both children and adults. Young people with Prader-Willi Syndrome (PWS), a congenital cause for obesity, have shown a slower 60-s endurance exercise HRR compared to lean and obese children, suggesting compromised regulation. This study further evaluated effects of obesity and PWS on resistance exercise HRR at 30 and 60 s in children. PWS (8-18 years) and lean and obese controls (8-11 years) completed a weighted step-up protocol (six sets x 10 reps per leg, separated by one-minute rest), standardized using participant stature and lean body mass. HRR was evaluated by calculated HRR value (HRRV = difference between HR at test termination and 30 (HRRV30) and 60 (HRRV60) s post-exercise). PWS and obese had a smaller HRRV30 than lean ( p < 0.01 for both). Additionally, PWS had a smaller HRRV60 than lean and obese ( p = 0.01 for both). Obesity appears to delay early parasympathetic reactivation, which occurs within 30 s following resistance exercise. However, the continued HRR delay at 60 s in PWS may be explained by either blunted parasympathetic nervous system reactivation, delayed sympathetic withdrawal and/or poor cardiovascular fitness.

Hormonal, metabolic and skeletal phenotype of Schaaf-Yang syndrome: a comparison to Prader-Willi syndrome.

PubMed

McCarthy, John M; McCann-Crosby, Bonnie M; Rech, Megan E; Yin, Jiani; Chen, Chun-An; Ali, May A; Nguyen, HaiThuy N; Miller, Jennifer L; Schaaf, Christian P

2018-05-01

Nonsense and frameshift mutations in the maternally imprinted, paternally expressed gene MAGEL2, located in the Prader-Willi critical region 15q11-15q13, have been reported to cause Schaaf-Yang syndrome (SYS), a genetic disorder that manifests as developmental delay/intellectual disability, hypotonia, feeding difficulties and autism spectrum disorder. Prader-Willi syndrome (PWS) is a genetic disorder characterised by severe infantile hypotonia, hypogonadotrophic hypogonadism, early childhood onset obesity/hyperphagia, developmental delay/intellectual disability and short stature. Scoliosis and growth hormone insufficiency are also prevalent in PWS.There is extensive documentation of the endocrine and metabolic phenotypes for PWS, but not for SYS. This study served to investigate the hormonal, metabolic and body composition phenotype of SYS and its potential overlap with PWS. In nine individuals with SYS (5 female/4 male; aged 5-17 years), we measured serum ghrelin, glucose, insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3, follicle-stimulating hormone, luteinising hormone, thyroid-stimulating hormone, free T4, uric acid and testosterone, and performed a comprehensive lipid panel. Patients also underwent X-ray and dual-energy X-ray absorptiometry analyses to assess for scoliosis and bone mineral density. Low IGF-1 levels despite normal weight/adequate nutrition were observed in six patients, suggesting growth hormone deficiency similar to PWS. Fasting ghrelin levels were elevated, as seen in individuals with PWS. X-rays revealed scoliosis >10° in three patients, and abnormal bone mineral density in six patients, indicated by Z-scores of below -2 SDs. This is the first analysis of the hormonal, metabolic and body composition phenotype of SYS. Our findings suggest that there is marked, but not complete overlap between PWS and SYS. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All

Postural strategies in Prader-Willi and Down syndrome patients.

PubMed

Cimolin, Veronica; Galli, Manuela; Grugni, Graziano; Vismara, Luca; Precilios, Helmer; Albertini, Giorgio; Rigoldi, Chiara; Capodaglio, Paolo

2011-01-01

Patients affected by Down (DS) and Prader-Willi syndrome (PWS) are characterised by some common clinical and functional features including gait disorders and reduced postural control. The aim of our study was to quantitatively compare postural control in adult PWS and DS. We studied 12 PWS and 19 DS adult patients matched for age, height, weight and body mass index. They were instructed to maintain an upright standing position on a force platform for 30s with open eyes (OE) and we calculated the range of center of pressure (CoP) displacement in the A/P direction (RANGE(AP)) and in the M/L direction (RANGE(ML)) and the total CoP trajectory length during quiet stance (Sway Path, SP). The range of oscillations in PWS and DS in both AP and ML direction were higher than in controls. PWS and DS were statistically different for RANGE(AP), with PWS showing higher mean values. Our results confirm a reduced capacity of both PWS and DS in maintaining postural stability. This appears to be in some respect different in PWS and DS, with PWS showing poorer control in AP. DS and, particularly, PWS should be encouraged to undergo specific balance training and strengthening of the ankle muscles as part of a comprehensive rehabilitation program to enhance daily functioning and quality of life. Copyright © 2010 Elsevier Ltd. All rights reserved.

Functional independence of Taiwanese children with Prader-Willi syndrome.

PubMed

Lee, Chung-Lin; Lin, Hsiang-Yu; Tsai, Li-Ping; Chiu, Huei-Ching; Tu, Ru-Yi; Huang, You-Hsin; Chien, Yin-Hsiu; Lee, Ni-Chung; Niu, Dau-Ming; Chao, Mei-Chyn; Tsai, Fuu-Jen; Chou, Yen-Yin; Chuang, Chih-Kuang; Lin, Shuan-Pei

2018-06-01

Prader-Willi syndrome (PWS) is a genetic disorder with obesity, developmental delay, short stature, and behavioral abnormalities. The study aimed to assess the functional independence in children with PWS. The Functional Independence Measure for Children (WeeFIM) was used to evaluate 81 children with PWS (44 boys and 37 girls) with a median age of 11 years 1 month (range 2 years 8 months to 20 years 2 months) were recruited between January 2013 and December 2016. The mean total WeeFIM score was 103.8 (maximum 126). Sixty-five patients (80%) had deletion type PWS, 16 (20.0%) had nondeletion type. The scores were 103.6 ± 18.5 for deletion and 104.8 ± 18.3 for nondeletion type (p = .405), 104.8 ± 19.3 in boys and 102.6 ± 17.3 in girls (p = .293). The mean self-care, mobility, and cognition scores were 47 (maximum 56), 33 (maximum 35), and 24 (maximum 35), respectively. All total scores and 18 subscores in the three functional domains were positively correlated with age (p < .05). Most children required assistance in problem-solving, comprehension, and expression. The WeeFIM identified the strengths and limitations of children with PWS and confirmed that support and supervision were needed in cognitive and self-care tasks. © 2018 Wiley Periodicals, Inc.

The usefulness of biliopancreatic diversion/Scopinaro operation in treatment of patients with Prader-Willi syndrome

PubMed Central

Michalik, Maciej; Frask, Agata; Zdrojewski, Michal; Doboszynska, Anna

2015-01-01

Prader-Willi syndrome (PWS) is the most common form of obesity with a genetic basis. The short expected survival time due to numerous accompanying diseases and their complications is the reason for research on the maximally efficient method of treatment of obesity in this syndrome. Undertaken attempts of conservative treatment, for example with somatostatin, are ineffective. It seems that the only effective treatment of obesity in this syndrome may be surgical. In this article we present 2 cases of patients with PWS who underwent surgery consisting of biliopancreatic diversion (BPD)/Scopinaro procedure. The BPD/Scopinaro operation in selected cases of disciplined patients with a co-operative family, which we find of key importance, can be considered as one option of treatment of this syndrome in patients with prior neglect of conservative treatment. PMID:26240637

Influence of the Prader-Willi syndrome imprinting center on the DNA methylation landscape in the mouse brain.

PubMed

Brant, Jason O; Riva, Alberto; Resnick, James L; Yang, Thomas P

2014-11-01

Reduced representation bisulfite sequencing (RRBS) was used to analyze DNA methylation patterns across the mouse brain genome in mice carrying a deletion of the Prader-Willi syndrome imprinting center (PWS-IC) on either the maternally- or paternally-inherited chromosome. Within the ~3.7 Mb imprinted Angelman/Prader-Willi syndrome (AS/PWS) domain, 254 CpG sites were interrogated for changes in methylation due to PWS-IC deletion. Paternally-inherited deletion of the PWS-IC increased methylation levels ~2-fold at each CpG site (compared to wild-type controls) at differentially methylated regions (DMRs) associated with 5' CpG island promoters of paternally-expressed genes; these methylation changes extended, to a variable degree, into the adjacent CpG island shores. Maternal PWS-IC deletion yielded little or no changes in methylation at these DMRs, and methylation of CpG sites outside of promoter DMRs also was unchanged upon maternal or paternal PWS-IC deletion. Using stringent ascertainment criteria, ~750,000 additional CpG sites were also interrogated across the entire mouse genome. This analysis identified 26 loci outside of the imprinted AS/PWS domain showing altered DNA methylation levels of ≥25% upon PWS-IC deletion. Curiously, altered methylation at 9 of these loci was a consequence of maternal PWS-IC deletion (maternal PWS-IC deletion by itself is not known to be associated with a phenotype in either humans or mice), and 10 of these loci exhibited the same changes in methylation irrespective of the parental origin of the PWS-IC deletion. These results suggest that the PWS-IC may affect DNA methylation at these loci by directly interacting with them, or may affect methylation at these loci through indirect downstream effects due to PWS-IC deletion. They further suggest the PWS-IC may have a previously uncharacterized function outside of the imprinted AS/PWS domain.

[Behavioral characteristics of children with Prader-Willi syndrome in preschool and school age: an exploratory study on ritualistic behavior].

PubMed

Sarimski, Klaus; Ebner, Sarah; Wördemann, Claudia

2012-01-01

Parents of 64 children and youths with Prader-Willi syndrome (PWS) describe their children's behaviour on the "Temperament and Atypical Behavior Scale" (TABS) and the German version of the "Developmental Behavior Checklist" (VFE). In the younger age group, there are no specific behavioural abnormalities which characterize a behavioral phenotype. In the older age group the data reveal elevated levels of abnormal behaviors (communication disturbance, social relations and disruptive behaviors). Parents stress ritualistic behaviors as especially challenging. The results concerning form and age-dependency of abnormal behaviors are discussed in the context of prevention and treatment options.

Cognition in people with Prader-Willi syndrome: Insights into genetic influences on cognitive and social development.

PubMed

Whittington, Joyce; Holland, Anthony

2017-01-01

We present a mini-review of cognition in Prader-Willi syndrome. Studies cited include findings on general ability (IQ), IQ correlates with family members, strengths and weaknesses in cognitive profiles in genetic subtypes, attainment in literacy and numeracy, language, comprehension, modality preferences, executive functions, and social cognition. The latter includes investigations of theory of mind, emotion recognition, face processing and knowledge of social norms. Results from research on mouse models and brain imaging studies relevant to cognition are briefly discussed. The importance of these studies to understanding and managing education and behaviour in PWS and the limitations of the studies in terms of small numbers, non-representativeness, and lack of replication is also touched upon. Copyright © 2016 Elsevier Ltd. All rights reserved.

Venovenous Extracorporeal Membrane Oxygenation in an Adult Patient With Prader-Willi Syndrome: A Nutrition Case Report.

PubMed

Pelekhaty, Stacy; Menaker, Jay

2018-03-12

Prader-Willi Syndrome (PWS) is a genetic condition that results in a constellation of symptoms and typically results in hyperphagia and obesity in adulthood. Critically ill adults with PWS present a unique challenge to the nutrition professional, particularly when they require support modalities such as extracorporeal membrane oxygenation (ECMO). The purpose of this case study is to review the nutrition care of a critically ill adult patient with PWS who required venovenous ECMO. The patient was successfully managed with a hypocaloric, high-protein approach, which did not result in the diagnosis of malnutrition during his hospitalization. The patient was ultimately transitioned off extracorporeal life support and discharged to a rehabilitation facility. © 2018 American Society for Parenteral and Enteral Nutrition.

Executive functions and Prader-Willi syndrome: global deficit linked with intellectual level and syndrome-specific associations.

PubMed

Chevalère, Johann; Postal, Virginie; Jauregui, Joseba; Copet, Pierre; Laurier, Virginie; Thuilleaux, Denise

2015-05-01

The aim of this study was to support the growing evidence suggesting that Prader-Willi Syndrome (PWS) might present with an impairment of executive functions (EFs) and to investigate whether this impairment is specific to patients with PWS or due to their intellectual disability (ID). Six tasks were administered to assess EFs (inhibition, switching, updating, cognitive estimation, and planning) to 17 patients with PWS and 17 age-matched healthy individuals. Performance was significantly impaired in the PWS group on all EFs and after controlling for IQ level, intergroup differences remained only for switching and cognitive estimation. In conclusion, PWS seems to be associated with a global impairment of EFs that appears to be closely linked with intellectual impairment but also with the PWS itself.

A further case of a Prader-Willi syndrome phenotype in a patient with Angelman syndrome molecular defect.

PubMed

De Molfetta, Greice Andreotti; Felix, Temis Maria; Riegel, Mariluce; Ferraz, Victor Evangelista de Faria; de Pina Neto, João Monteiro

2002-12-01

Angelman syndrome (AS) and Prader-Willi syndrome (PWS) are distinct human neurogenetic disorders; however, a clinical overlap between AS and PWS has been identified. We report on a further case of a patient showing the PWS phenotype with the AS molecular defect. Despite the PWS phenotype, the DNA methylation analysis of SNRPN revealed an AS pattern. Cytogenetic and FISH analysis showed normal chromosomes 15 and microsatellite analysis showed heterozygous loci inside and outside the 15q11-13 region. The presence of these atypical cases could be more frequent than previously expected and we reinforce that the DNA methylation analysis is important for the correct diagnosis of severe mental deficiency, congenital hypotonia and obesity.

Disorders of Sleep and Ventilatory Control in Prader-Willi Syndrome

PubMed Central

Gillett, Emily S.; Perez, Iris A.

2016-01-01

Prader-Willi syndrome (PWS) is an imprinted genetic disorder conferred by loss of paternal gene expression from chromosome 15q11.2-q13. Individuals with PWS have impairments in ventilatory control and are predisposed toward sleep disordered breathing due to a combination of characteristic craniofacial features, obesity, hypotonia, and hypothalamic dysfunction. Children with PWS progress from failure to thrive during infancy to hyperphagia and morbid obesity during later childhood and onward. Similarly, the phenotype of sleep disordered breathing in PWS patients also evolves over time from predominantly central sleep apnea in infants to obstructive sleep apnea (OSA) in older children. Behavioral difficulties are common and may make establishing effective therapy with continuous positive airway pressure (CPAP) more challenging when OSA persists after adenotonsillectomy. Excessive daytime sleepiness (EDS) is also common in patients with PWS and may continue after OSA is effectively treated. We describe here the characteristic ventilatory control deficits, sleep disordered breathing, and excessive daytime sleepiness seen in individuals with PWS. We review respiratory issues that may contribute to sudden death events in PWS patients during sleep and wakefulness. We also discuss therapeutic options for treating sleep disordered breathing including adenotonsillectomy, weight loss, and CPAP. Lastly, we discuss the benefits and safety considerations related to growth hormone therapy. PMID:28933403

Zebrafish Models of Prader-Willi Syndrome: Fast Track to Pharmacotherapeutics

PubMed Central

Spikol, Emma D.; Laverriere, Caroline E.; Robnett, Maya; Carter, Gabriela; Wolfe, Erin; Glasgow, Eric

2016-01-01

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder characterized by an insatiable appetite, leading to chronic overeating and obesity. Additional features include short stature, intellectual disability, behavioral problems and incomplete sexual development. Although significant progress has been made in understanding the genetic basis of PWS, the mechanisms underlying the pathogenesis of the disorder remain poorly understood. Treatment for PWS consists mainly of palliative therapies; curative therapies are sorely needed. Zebrafish, Danio rerio, represent a promising way forward for elucidating physiological problems such as obesity and identifying new pharmacotherapeutic options for PWS. Over the last decade, an increased appreciation for the highly conserved biology among vertebrates and the ability to perform high-throughput drug screening has seen an explosion in the use of zebrafish for disease modeling and drug discovery. Here, we review recent advances in developing zebrafish models of human disease. Aspects of zebrafish genetics and physiology that are relevant to PWS will be discussed, and the advantages and disadvantages of zebrafish models will be contrasted with current animal models for this syndrome. Finally, we will present a paradigm for drug screening in zebrafish that is potentially the fastest route for identifying and delivering curative pharmacotherapies to PWS patients. PMID:27857842

Disorders of Sleep and Ventilatory Control in Prader-Willi Syndrome.

PubMed

Gillett, Emily S; Perez, Iris A

2016-07-08

Prader-Willi syndrome (PWS) is an imprinted genetic disorder conferred by loss of paternal gene expression from chromosome 15q11.2-q13. Individuals with PWS have impairments in ventilatory control and are predisposed toward sleep disordered breathing due to a combination of characteristic craniofacial features, obesity, hypotonia, and hypothalamic dysfunction. Children with PWS progress from failure to thrive during infancy to hyperphagia and morbid obesity during later childhood and onward. Similarly, the phenotype of sleep disordered breathing in PWS patients also evolves over time from predominantly central sleep apnea in infants to obstructive sleep apnea (OSA) in older children. Behavioral difficulties are common and may make establishing effective therapy with continuous positive airway pressure (CPAP) more challenging when OSA persists after adenotonsillectomy. Excessive daytime sleepiness (EDS) is also common in patients with PWS and may continue after OSA is effectively treated. We describe here the characteristic ventilatory control deficits, sleep disordered breathing, and excessive daytime sleepiness seen in individuals with PWS. We review respiratory issues that may contribute to sudden death events in PWS patients during sleep and wakefulness. We also discuss therapeutic options for treating sleep disordered breathing including adenotonsillectomy, weight loss, and CPAP. Lastly, we discuss the benefits and safety considerations related to growth hormone therapy.

Good cognitive performances in a child with Prader-Willi syndrome.

PubMed

Nugnes, Rosa; Zito, Eugenio; Mozzillo, Enza; Camarca, Maria Erminia; Riccio, Maria Pia; Terrone, Gaetano; Melis, Daniela; Bravaccio, Carmela; Franzese, Adriana

2013-11-15

We report the case of a child affected by Prader-Willi syndrome (PWS) with good cognitive performances and without relevant behavioral abnormalities.The diagnosis of PWS, suspected on the basis of clinical features and past history, was confirmed by DNA methylation analysis. Additional genetic testing revealed a maternal uniparental disomy. Intellectual profile was analyzed by WISC-III and Raven's Progressive Matrices CPM, while the behavior was evaluated by K-SADS-PL and Child Behavior Checklist/4-18 to the parents.WISC-III test showed a Total Intelligence Quotient (T-IQ = 79) at the border level for age. The Verbal Intelligence Quotient (V-IQ) showed a lower score than the Performance Intelligence Quotient (P-IQ) (78 and 85, respectively). Raven's Matrices CPM showed an intelligence level at 75-90° percentile for age. Concerning behavioral evaluation, a difficulty in impulse control was observed, with persistent but controllable search for food, without a clear psychopathological meaning. Also according to K-SADS-PL no areas of psychopathological dimensions were detected. In conclusion, in presence of consisting clinical features of PWS and high diagnostic suspicion, the diagnosis of PWS should be considered even in presence of a borderline IQ and in absence of psychopathological abnormalities.

Autistic-like symptomatology in Prader-Willi syndrome: a review of recent findings.

PubMed

Dimitropoulos, Anastasia; Schultz, Robert T

2007-04-01

Prader-Willi syndrome (PWS) is caused by either the structural loss of material or the absence of gene expression from the paternally inherited copy of chromosome 15 in the q11-q13 region. In addition to a well-described behavioral phenotype that includes hyperphagia, obsessive-compulsive symptoms, disruptive behavior, and an increased risk for mood disorders, recent evidence also suggests that some individuals with PWS have repetitive behavior and social deficits reminiscent of autism spectrum disorders. In particular, it appears as if those with maternal uniparental disomy (UPD) as the cause of PWS are at greater risk for autistic symptomatology than those with paternal deletions of 15q11-q13. These findings are particularly intriguing in light of data implicating maternal duplications and triplications of the same chromosomal interval in idiopathic autism, as well as evidence that functional alterations of genes in this region are associated with social deficits found in a variety of neurodevelopmental disorders. This paper will review the recent evidence for phenotypic similarities between autism and PWS and the risk of symptomatology for the UPD subtype.

Relationship of sleep abnormalities to patient genotypes in Prader-Willi syndrome

DOE Office of Scientific and Technical Information (OSTI.GOV)

Vgontzas, A.N.; Kales, A.; Bixler, E.O.

To assess whether sleep abnormalities are related to the genetic abnormalities in Prader-Willi Syndrome (PWS), we performed polysomnographic studies (nighttime and daytime) and determined the chromosome 15 genotypes in eight patients with PWS. Four patients demonstrated sleep onset REM periods (SOREM), and five met the objective polysomnographic criteria for severe or moderate excessive daytime sleepiness (EDS). Three of the four patients with SOREM displayed a paternally derived deletion of chromosome 15q11-q13, whereas the fourth exhibited maternal uniparental heterodisomy in this chromosomal region (UPD). Two of the four patients that did not display SOREM carried paternally derived deletions; the remaining twomore » demonstrated UPD. Four of the five patients with EDS displayed paternal deletions, and the fifth exhibited UPD. One of three patients without evidence of EDS demonstrated paternal deletion; the remaining two showed UPD. Although neither EDS nor SOREM was not consistently associated with a specific genetic abnormality, these phenotypes may be more common in patients with paternal deletions than in those with UPD. Sleep abnormalities in PWS cannot be explained by a single genetic model. 32 refs., 1 tab.« less

The effect of vision on postural strategies in Prader-Willi patients.

PubMed

Cimolin, Veronica; Galli, Manuela; Vismara, Luca; Grugni, Graziano; Priano, Lorenzo; Capodaglio, Paolo

2011-01-01

The aim of this study was to quantify the role of visual contribution in patients with Prader-Willi syndrome (PWS) on balance maintenance using a force platform. We enrolled 14 individuals with PWS free from conditions associated with impaired balance, 44 obese (OG) and 20 healthy controls (CG). Postural sway was measured for 60s while standing on a force platform (Kistler, CH; acquisition frequency: 500 Hz) integrated with a video system. Patients maintained an upright standing position with Open Eyes (OE) and then with Closed Eyes (CE). The ratio between the value of the parameter under OE and CE conditions was measured. Under OE condition PWS and OG were characterized by higher postural instability than CG, with the PWS group showing poorer balance capacity than OG. The Romberg ratio showed that while OG and CG had lower balance without vision, PWS maintained the same performance changing from OE to CE. The integration of different sensory inputs appears similar in OG and CG with higher postural stability under OE than CE. Balance in PWS is not influenced by the elimination of visual input. Copyright © 2011 Elsevier Ltd. All rights reserved.

Genotype and phenotype in patients with Prader-Willi syndrome in Taiwan.

PubMed

Lin, Hsiang-Yu; Lin, Shuan-Pei; Chuang, Chih-Kuang; Chen, Ming-Ren; Yen, Jui-Lung; Lee, Yann-Jinn; Huang, Chi-Yu; Tsai, Li-Ping; Niu, Dau-Ming; Chao, Mei-Chyn; Kuo, Pao-Lin

2007-06-01

Several different genetic defects have been found to result in the characteristic phenotypic expression of Prader-Willi syndrome (PWS). We performed a retrospective analysis of 67 cases of molecularly confirmed PWS diagnosed from January 1980 through July 2006 in five medical centres in Taiwan. Clinical manifestations were compared between patients with deletion and those with maternal uniparental disomy (UPD). Deletion was present in 56 (84%), UPD in 10 (15%), and a probable imprinting centre deletion or imprinting defect in 1 (1%). PWS with deletion was more likely than that with UPD to be characterized by hypogonadism (p < 0.001), small hands and feet (p < 0.001), and hypopigmentation (p < 0.002). Both maternal (p = 0.015) and paternal age (p = 0.021) were higher in the UPD group. No other clinical features differed significantly different between the two groups. In contrast to most Western populations with a higher incidence of UPD, this study of PWS in Taiwan shows a higher incidence of deletion. There may be subtle phenotypic differences between the UPD and deletion genotypes, but its not clear that these are important clinically.

Eating behavior and gastric emptying in adults with Prader-Willi syndrome.

PubMed

Hoybye, Charlotte; Barkeling, Britta; Naslund, Erik; Thorén, Marja; Hellstrom, Per M

2007-01-01

Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by distinctive physical, behavioral and psychiatric features. One cardinal symptom is excessive eating, often leading to extreme obesity. The etiology of the hyperphagia is unknown, but eating behaviors and gastrointestinal motility could play a pivotal role. In this pilot study, we therefore sought to give a closer description of the two. 12 PWS adults, 6 men and 6 women, 17-37 years of age with a median BMI of 34.9 were evaluated. Computerized monitoring of eating behavior and assessment of gastric emptying using paracetamol absorption were analyzed. Gastric emptying rate was compared to the rate in normal and obese controls. Eating behavior pattern was nonhomogeneous in the PWS patients, but they experienced both hunger and satiation. In PWS gastric emptying was similar to lean subjects (p > 0.05), but longer than in obese subjects (p < 0.05). Despite obesity, this group of adults with PWS did not display overeating in the test situation and gastric emptying rate was normal. Numbers are small, but the results are important for the treatment of obesity in this special group of patients. Copyright 2007 S. Karger AG, Basel.

Subclinical dysphagia in persons with Prader-Willi syndrome.

PubMed

Gross, Roxann Diez; Gisser, Ronit; Cherpes, Gregory; Hartman, Katie; Maheshwary, Rishi

2017-02-01

Prader-Willi Syndrome (PWS) is caused by a genetic imprinting abnormality resulting from the lack of expression of the paternal genes at 15q11-q13. Intellectual disability, low muscle tone, and life-threatening hyperphagia are hallmarks of the phenotype. The need for the Heimlich maneuver, death from choking, and pulmonary infection occur in a disproportionally high number of persons with PWS. The widely held belief is that eating behaviors are responsible for choking and aspiration; yet, no investigation had sought to determine if swallowing impairments were present in persons with PWS. To address this research and clinical gap, simultaneous videofluoroscopy and nasal respiratory signals were used to record swallowing function and breathing/swallowing coordination in 30 participants with PWS. Subjects consumed thin liquid and barium cookies under two randomized conditions as follows: (i) controlled (cues to swallow and standardized bolus sizes); (ii) spontaneous (no cues or bolus size control). Under videofluoroscopy, the cohort showed disordered pharyngeal and esophageal swallowing in both conditions with disturbances in timing, clearance, and coordination of swallowing with the respiratory cycle. No participant showed a sensory response such as attempting to clear residue or coughing; thereby supporting the lack of overt symptoms. We conclude that the high death rate from choking and pulmonary infection in children and adults with PWS may be related, in part, to underlying, asymptomatic dysphagia. The combination of rapid eating and dysphagia would increase the risk of aspiration-related morbidity and mortality. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Mechanisms of activation of the paternally expressed genes by the Prader-Willi imprinting center in the Prader-Willi/Angelman syndromes domains

PubMed Central

Rabinovitz, Shiri; Kaufman, Yotam; Ludwig, Guy; Razin, Aharon; Shemer, Ruth

2012-01-01

The Prader-Willi syndrome/Angelman syndrome (PWS/AS) imprinted domain is regulated by a bipartite imprinting control center (IC) composed of a sequence around the SNRPN promoter (PWS-IC) and a 880-bp sequence located 35 kb upstream (AS-IC). The AS-IC imprint is established during gametogenesis and confers repression upon PWS-IC on the maternal allele. Mutation at PWS-IC on the paternal allele leads to gene silencing across the entire PWS/AS domain. This silencing implies that PWS-IC functions on the paternal allele as a bidirectional activator. Here we examine the mechanism by which PWS-IC activates the paternally expressed genes (PEGs) using transgenes that include the PWS-IC sequence in the presence or absence of AS-IC and NDN, an upstream PEG, as an experimental model. We demonstrate that PWS-IC is in fact an activator of NDN. This activation requires an unmethylated PWS-IC in the gametes and during early embryogenesis. PWS-IC is dispensable later in development. Interestingly, a similar activation of a nonimprinted gene (APOA1) was observed, implying that PWS-IC is a universal activator. To decipher the mechanism by which PWS-IC confers activation of remote genes, we performed methylated DNA immunoprecipitation (MeDIP) array analysis on lymphoblast cell lines that revealed dispersed, rather than continued differential methylation. However, chromatin conformation capture (3c) experiments revealed a physical interaction between PWS-IC and the PEGs, suggesting that activation of PEGs may require their proximity to PWS-IC. PMID:22529396

Evaluating the frequency and characteristics of seizures in 142 Japanese patients with Prader-Willi syndrome.

PubMed

Takeshita, Eri; Murakami, Nobuyuki; Sakuta, Ryoichi; Nagai, Toshiro

2013-08-01

Prader-Willi syndrome (PWS) has not been widely regarded as a disorder with a risk factor for seizures. We retrospectively investigated the frequency and characteristics of seizures and examined genotype-phenotype correlations with respect to seizures in PWS. We analyzed 142 patients with PWS and identified 31 (22%) with seizures. The most common seizure type was febrile convulsion (12%, 17/142). Epilepsy occurred in 6% of the patients in our cohort (9/142). The frequencies of febrile seizure and epilepsy in PWS were higher than those in the general population. Our study suggested that the frequency of seizures was not associated with genotypes of PWS (P = 0.35). In our study patients with PWS, 68% of the patients with seizures experienced initial episodes before they were 2 years old, and the seizures were relatively easier to manage. Copyright © 2013 Wiley Periodicals, Inc.

High levels of caregiver burden in Prader-Willi syndrome

PubMed Central

Farrar, Evan; Comtois, Katherine Anne; Strong, Theresa V.

2018-01-01

Objectives Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder that is characterized by hyperphagia, developmental delay, incomplete sexual development, mild-to-moderate intellectual disability, and a variety of challenging behavioral and psychiatric symptoms. The characteristics of PWS can be difficult for caregivers to cope with and are likely to cause significant and long- term caregiver burden. The current study examined burden in 142 caregivers of children and adults with PWS living in the US using the Zarit Burden Interview (ZBI). The study aimed to measure the level of burden in caregivers of individuals with PWS, to explore the impact of PWS on caregiver quality of life, and to assess ZBI as an indicator of that impact. Results Caregivers participating in this study were predominantly mothers, 30–59 years old, non-Hispanic Whites, married or in a relationship, with an annual household income slightly distributed towards higher income. Nearly 90% of the caregiver`s children with PWS lived at home. Caregivers experienced high caregiver burden with an average ZBI score of 44.4 ± 15.4. ZBI scores were highest for caregivers of teenage and young adult individuals with PWS (49.2 ± 14.6 and 49.2 ± 14.1, respectively), while those caring for older adults (>30) and the youngest age group had lower scores (38.6 ±10.5 and 34.8 ±12.5, respectively). Caregivers reported that caring for a person with PWS negatively impacted their romantic relationship, ability to work, sleep, and mood. Whereas we did not find strong correlations between family income or level of help the caregiver receives and ZBI scores, the results showed significant correlations and a linear relationship between ZBI scores and caregiver depressed mood, feelings of anxiety, negative romantic relationship impact, as well as sleep and work disruption. Conclusions Our study reveals that PWS incurs high caregiver burden and impacts many aspects of the lives of caregiver. We

High levels of caregiver burden in Prader-Willi syndrome.

PubMed

Kayadjanian, Nathalie; Schwartz, Lauren; Farrar, Evan; Comtois, Katherine Anne; Strong, Theresa V

2018-01-01

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder that is characterized by hyperphagia, developmental delay, incomplete sexual development, mild-to-moderate intellectual disability, and a variety of challenging behavioral and psychiatric symptoms. The characteristics of PWS can be difficult for caregivers to cope with and are likely to cause significant and long- term caregiver burden. The current study examined burden in 142 caregivers of children and adults with PWS living in the US using the Zarit Burden Interview (ZBI). The study aimed to measure the level of burden in caregivers of individuals with PWS, to explore the impact of PWS on caregiver quality of life, and to assess ZBI as an indicator of that impact. Caregivers participating in this study were predominantly mothers, 30-59 years old, non-Hispanic Whites, married or in a relationship, with an annual household income slightly distributed towards higher income. Nearly 90% of the caregiver`s children with PWS lived at home. Caregivers experienced high caregiver burden with an average ZBI score of 44.4 ± 15.4. ZBI scores were highest for caregivers of teenage and young adult individuals with PWS (49.2 ± 14.6 and 49.2 ± 14.1, respectively), while those caring for older adults (>30) and the youngest age group had lower scores (38.6 ±10.5 and 34.8 ±12.5, respectively). Caregivers reported that caring for a person with PWS negatively impacted their romantic relationship, ability to work, sleep, and mood. Whereas we did not find strong correlations between family income or level of help the caregiver receives and ZBI scores, the results showed significant correlations and a linear relationship between ZBI scores and caregiver depressed mood, feelings of anxiety, negative romantic relationship impact, as well as sleep and work disruption. Our study reveals that PWS incurs high caregiver burden and impacts many aspects of the lives of caregiver. We identified the ZBI as a good

An 18-year-old patient with Prader-Willi syndrome: a case report on dental management under sedation and general anesthesia.

PubMed

Song, Ki Un; Nam, Ok Hyung; Kim, Mi Sun; Choi, Sung Chul; Lee, Hyo-Seol

2015-12-01

Prader-Willi syndrome (PWS) is a rare genetic disorder reported rarely in dentistry. Dental practitioners should know the features of PWS because affected patients have a variety of dental symptoms. The current report describes a case of PWS. An 18-year-old male patient presented with traumatic injuries. Initial emergency treatments were performed under sedation, and further treatments were conducted under general anesthesia. After adequate healing, periodic follow-up and dietary management according to the patient's age and nutritional phase were recommended. Dental management of PWS patients consists of active preventive measures in addition to dietary consultation according to age and nutritional phase.

Sleepiness and Sleep Disordered Breathing in Prader-Willi Syndrome: Relationship to Genotype, Growth Hormone Therapy, and Body Composition

PubMed Central

Williams, Korwyn; Scheimann, Ann; Sutton, Vernon; Hayslett, Elizabeth; Glaze, Daniel G.

2008-01-01

Study Objectives: Patients with Prader-Willi syndrome (PWS) suffer from excessive sleepiness and sleep disordered breathing (SDB). We reviewed the polysomnograms (PSGs) and multiple sleep latency tests (MSLTs) in a cohort of PWS patients to determine the relationship of BMIz scores, daytime sleepiness, growth hormone (GH) treatments, and SDB. Methods: Attended overnight PSGs were performed for PWS patients referred for concern for SDB between January 2000 and January 2005. Age at time of study, genotype, use and dose of GH, sleepiness scale, normalized body-mass index (BMIz), total sleep time, latency to stage I and REM sleep, sleep stage percentages, apnea-hypopnea index (AHI), central apnea (CA) frequency, oxygen saturation nadir, maximum carbon dioxide tension, periodic limb movement index, presence of snoring, normality of EEG, and, in several patients, mean sleep latency testing were determined. Results: All patients exhibited some form of SDB. There was a positive correlation between the BMIz and AHI. The BMIz was significantly different between GH–treated and –untreated groups, but there was not a significant difference between AHI, CA, oxygen nadir, or maximum carbon dioxide tension of the GH–treated and –untreated groups. There was no significant correlation between the MSLT and the sleepiness scale or AHI. There was also no significant difference between the AHIs of patients with different genetic defects. Conclusions: There should be a low threshold for obtaining PSG to evaluate SDB, but the type and severity of SDB were not predictable based on a sleepiness scale score, BMIz, or underlying genetic defect. Citation: Williams K; Scheimann A; Sutton V; Hayslett E; Glaze DG. Sleepiness and sleep disordered breathing in Prader-Willi syndrome: relationship to genotype, growth hormone therapy, and body composition. J Clin Sleep Med 2007;4(2):111–118. PMID:18468308

Evaluating the Feasibility of a Play-Based Telehealth Intervention Program for Children with Prader-Willi Syndrome.

PubMed

Dimitropoulos, Anastasia; Zyga, Olena; Russ, Sandra

2017-09-01

Here we report the feasibility and acceptability of telehealth for direct intervention in children with Prader-Willi syndrome (PWS). Children with PWS have social-cognitive challenges that are similar to children with ASD. However, developing behavioral interventions for individuals with PWS is faced with the significant challenge of enrolling enough participants for local studies where multiple visits per week are indicated for effective intervention. This study delivered a 6-week play-based intervention via telehealth directly to eight children with PWS (6-12 years). Participants completed the program with minimal behavioral or technological difficulty (#sessions M = 11.875/12). Behavioral Intervention Rating Scale results indicate good acceptability (M = 5.54/6.00). These findings support using telehealth in rare disorders and delivering intervention directly to children with developmental delays through this modality.

Nutritional intervention with hypocaloric diet for weight control in children and adolescents with Prader-Willi Syndrome.

PubMed

Lima, Vivian Penner de; Emerich, Deisy Ribas; Mesquita, Maria Luiza Guedes de; Paternez, Ana Carolina Almada Colucci; Carreiro, Luiz Renato Rodrigues; Pina Neto, João Monteiro de; Teixeira, Maria Cristina Triguero Veloz

2016-04-01

Prader-Willi Syndrome (PWS) is a genetic disorder caused by the lack of expression of paternal alleles in the proximal region of the long arm of chromosome 15. Low inhibitory control and hyperphagia are two of the most severe neurobehavioral symptoms of the syndrome. The aim of the present study was to assess the efficiency of nutritional training program with the use hypocaloric diet for weight control in a group of five children and adolescents with PWS. The intervention program consisted of 10 sessions for parents' orientation during 8months. Patients had their anthropometric measures assessed (weight, height and body mass index - BMI). The main results indicate weight maintenance, height increase, and BMI decrease after intervention. These results were considered indicators of the program's efficiency. Copyright © 2016 Elsevier Ltd. All rights reserved.

Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster.

PubMed

Sahoo, Trilochan; del Gaudio, Daniela; German, Jennifer R; Shinawi, Marwan; Peters, Sarika U; Person, Richard E; Garnica, Adolfo; Cheung, Sau Wai; Beaudet, Arthur L

2008-06-01

Prader-Willi syndrome (PWS) is caused by deficiency for one or more paternally expressed imprinted transcripts within chromosome 15q11-q13, including SNURF-SNRPN and multiple small nucleolar RNAs (snoRNAs). Balanced chromosomal translocations that preserve expression of SNURF-SNRPN and centromeric genes but separate the snoRNA HBII-85 cluster from its promoter cause PWS. A microdeletion of the HBII-85 snoRNAs in a child with PWS provides, in combination with previous data, effectively conclusive evidence that deficiency of HBII-85 snoRNAs causes the key characteristics of the PWS phenotype, although some atypical features suggest that other genes in the region may make more subtle phenotypic contributions.

Appetite hormones and the transition to hyperphagia in children with Prader-Willi syndrome.

PubMed

Goldstone, A P; Holland, A J; Butler, J V; Whittington, J E

2012-12-01

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder with several nutritional phases during childhood proceeding from poor feeding, through normal eating without and with obesity, to hyperphagia and life-threatening obesity, with variable ages of onset. We investigated whether differences in appetite hormones may explain the development of abnormal eating behaviour in young children with PWS. In this cross-sectional study, children with PWS (n=42) and controls (n=9) aged 7 months-5 years were recruited. Mothers were interviewed regarding eating behaviour, and body mass index (BMI) was calculated. Fasting plasma samples were assayed for insulin, leptin, glucose, peptide YY (PYY), ghrelin and pancreatic polypeptide (PP). There was no significant relationship between eating behaviour in PWS subjects and the levels of any hormones or insulin resistance, independent of age. Fasting plasma leptin levels were significantly higher (mean ± s.d.: 22.6 ± 12.5 vs 1.97 ± 0.79 ng ml(-1), P=0.005), and PP levels were significantly lower (22.6 ± 12.5 vs 69.8 ± 43.8 pmol l(-1), P<0.001) in the PWS group compared with the controls, and this was independent of age, BMI, insulin resistance or IGF-1 levels. However, there was no significant difference in plasma insulin, insulin resistance or ghrelin levels between groups, though PYY declined more rapidly with age but not BMI in PWS subjects. Even under the age of 5 years, PWS is associated with low levels of anorexigenic PP, as in older children and adults. Hyperghrelinaemia or hypoinsulinaemia was not seen in these young children with PWS. Change in these appetite hormones was not associated with the timing of the transition to the characteristic hyperphagic phase. However, abnormal and/or delayed development or sensitivity of the effector pathways of these appetitive hormones (for example, parasympathetic and central nervous system) may interact with low PP levels, and later hyperghrelinaemia or hypoinsulinaemia

Neural Mechanisms Underlying Hyperphagia in Prader-Willi Syndrome

PubMed Central

Holsen, Laura M.; Zarcone, Jennifer R.; Brooks, William M.; Butler, Merlin G.; Thompson, Travis I.; Ahluwalia, Jasjit S.; Nollen, Nicole L.; Savage, Cary R.

2006-01-01

Objective Prader-Willi syndrome (PWS) is a genetic disorder associated with developmental delay, obesity, and obsessive behavior related to food consumption. The most striking symptom of PWS is hyperphagia; as such, PWS may provide important insights into factors leading to overeating and obesity in the general population. We used functional magnetic resonance imaging to study the neural mechanisms underlying responses to visual food stimuli, before and after eating, in individuals with PWS and a healthy weight control (HWC) group. Research Methods and Procedures Participants were scanned once before (pre-meal) and once after (post-meal) eating a standardized meal. Pictures of food, animals, and blurred control images were presented in a block design format during acquisition of functional magnetic resonance imaging data. Results Statistical contrasts in the HWC group showed greater activation to food pictures in the pre-meal condition compared with the post-meal condition in the amygdala, orbitofrontal cortex, medial prefrontal cortex (medial PFC), and frontal operculum. In comparison, the PWS group exhibited greater activation to food pictures in the post-meal condition compared with the pre-meal condition in the orbitofrontal cortex, medial PFC, insula, hippocampus, and parahippocampal gyrus. Between-group contrasts in the pre- and post-meal conditions confirmed group differences, with the PWS group showing greater activation than the HWC group after the meal in food motivation networks. Discussion Results point to distinct neural mechanisms associated with hyperphagia in PWS. After eating a meal, the PWS group showed hyperfunction in limbic and para-limbic regions that drive eating behavior (e.g., the amygdala) and in regions that suppress food intake (e.g., the medial PFC). PMID:16861608

Prader-Willi Syndrome: Obesity due to Genomic Imprinting

PubMed Central

Butler, Merlin G

2011-01-01

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder due to errors in genomic imprinting with loss of imprinted genes that are paternally expressed from the chromosome 15q11-q13 region. Approximately 70% of individuals with PWS have a de novo deletion of the paternally derived 15q11-q13 region in which there are two subtypes (i.e., larger Type I or smaller Type II), maternal disomy 15 (both 15s from the mother) in about 25% of cases, and the remaining subjects have either defects in the imprinting center controlling the activity of imprinted genes or due to other chromosome 15 rearrangements. PWS is characterized by a particular facial appearance, infantile hypotonia, a poor suck and feeding difficulties, hypogonadism and hypogenitalism in both sexes, short stature and small hands and feet due to growth hormone deficiency, mild learning and behavioral problems (e.g., skin picking, temper tantrums) and hyperphagia leading to early childhood obesity. Obesity is a significant health problem, if uncontrolled. PWS is considered the most common known genetic cause of morbid obesity in children. The chromosome 15q11-q13 region contains approximately 100 genes and transcripts in which about 10 are imprinted and paternally expressed. This region can be divided into four groups: 1) a proximal non-imprinted region; 2) a PWS paternal-only expressed region containing protein-coding and non-coding genes; 3) an Angelman syndrome region containing maternally expressed genes and 4) a distal non-imprinted region. This review summarizes the current understanding of the genetic causes, the natural history and clinical presentation of individuals with PWS. PMID:22043168

Assessment of physical function in adults with Prader-Willi syndrome.

PubMed

Sode-Carlsen, Rasmus; Farholt, Stense; Rabben, Kai Fr; Bollerslev, Jens; Sandahl Christiansen, Jens; Höybye, Charlotte

2009-01-01

To evaluate implementation of at test battery for assessing physical function in adults with Prader-Willi syndrome (PWS). Forty-three adults with PWS, 20 men and 23 women, mean age 29 +/- 9 years. Body mass index (BMI) and body composition were measured. A test battery a.m. Guralnik for standing balance, 2.4 m and 10 m walk and repeated rising from a chair was scored and evaluated. Mean BMI was 29.4 +/- 9.1 kg/m(2), body fat mass (FM) 26.0 +/- 16.1 kg. The adults with PWS managed the test battery well, and high scores were achieved for standing balance and 2.4 m walk. In contrast, only 13 managed maximum score in the repeated rising from a chair and 31 to walk 10 m for 6 s or faster. Significant correlations were seen between 2.4 m walk and FM ( p = 0.041) and between 10 m walk and BMI ( p = 0.001) and FM ( p = 0.019). Repeated rising from a chair and 10 m walk are useful assessments in clinical practice to identify adults with PWS with reduced physical function. Reduced performance was related to higher BMI and FM emphasising the importance of efforts to keep normal body weight and body composition in adults with PWS. These measures might be useful in monitoring effects of intervention.

Benefits and limitations of prenatal screening for Prader-Willi syndrome.

PubMed

Butler, Merlin G

2017-01-01

This review summarizes the status of genetic laboratory testing in Prader-Willi syndrome (PWS) with different genetic subtypes, most often a paternally derived 15q11-q13 deletion and discusses benefits and limitations related to prenatal screening. Medical literature was searched for prenatal screening and genetic laboratory testing methods in use or under development and discussed in relationship to PWS. Genetic testing includes six established laboratory diagnostic approaches for PWS with direct application to prenatal screening. Ultrasonographic, obstetric and cytogenetic reports were summarized in relationship to the cause of PWS and identification of specific genetic subtypes including maternal disomy 15. Advances in genetic technology were described for diagnosing PWS specifically DNA methylation and high-resolution chromosomal SNP microarrays as current tools for genetic screening and incorporating next generation DNA sequencing for noninvasive prenatal testing (NIPT) using cell-free fetal DNA. Positive experiences are reported with NIPT for detection of numerical chromosomal problems (aneuploidies) but not for structural problems (microdeletions). These reports will be discussed along with future directions for genetic screening of PWS. In summary, this review describes and discusses the status of established and ongoing genetic testing options for PWS applicable in prenatal screening including NIPT and future directions for early diagnosis in PWS. © 2016 John Wiley & Sons, Ltd. © 2016 John Wiley & Sons, Ltd.

The neuroanatomy of genetic subtype differences in Prader-Willi syndrome.

PubMed

Honea, Robyn A; Holsen, Laura M; Lepping, Rebecca J; Perea, Rodrigo; Butler, Merlin G; Brooks, William M; Savage, Cary R

2012-03-01

Despite behavioral differences between genetic subtypes of Prader-Willi syndrome (PWS), no studies have been published characterizing brain structure in these subgroups. Our goal was to examine differences in the brain structure phenotype of common subtypes of PWS [chromosome 15q deletions and maternal uniparental disomy 15 (UPD)]. Fifteen individuals with PWS due to a typical deletion [(DEL) type I; n = 5, type II; n = 10], eight with PWS due to UPD, and 25 age-matched healthy-weight individuals (HWC) participated in structural magnetic resonance imaging (MRI) scans. A custom voxel-based morphometry processing stream was used to examine regional differences in gray and white matter volume (WMV) between groups, covarying for age, sex, and body mass index (BMI). Overall, compared to HWC, PWS individuals had lower gray matter volumes (GMV) that encompassed the prefrontal, orbitofrontal and temporal cortices, hippocampus and parahippocampal gyrus, and lower WMVs in the brain stem, cerebellum, medial temporal, and frontal cortex. Compared to UPD, the DEL subtypes had lower GMV primarily in the prefrontal and temporal cortices, and lower white matter in the parietal cortex. The UPD subtype had more extensive lower gray and WMVs in the orbitofrontal and limbic cortices compared to HWC. These preliminary findings are the first structural neuroimaging findings to support potentially separate neural mechanisms mediating the behavioral differences seen in these genetic subtypes. Copyright © 2012 Wiley Periodicals, Inc.

Neurocognitive findings in Prader-Willi syndrome and early-onset morbid obesity.

PubMed

Miller, Jennifer; Kranzler, John; Liu, Yijun; Schmalfuss, Ilona; Theriaque, Douglas W; Shuster, Jonathan J; Hatfield, Ann; Mueller, O Thomas; Goldstone, Anthony P; Sahoo, Trilochan; Beaudet, Arthur L; Driscoll, Daniel J

2006-08-01

To examine whether early-onset morbid obesity is associated with cognitive impairment, neuropathologic changes, and behavioral problems. This case-control study compared head MRI scans and cognitive, achievement, and behavioral evaluations of subjects with Prader-Willi syndrome (PWS), early-onset morbid obesity (EMO), and normal-weight sibling control subjects from both groups. Head MRI was done on 17 PWS, 18 EMO, and 21 siblings, and cognitive, achievement, and behavioral evaluations were done on 19 PWS, 17 EMO, and 24 siblings. The mean General Intellectual Ability score of the EMO group was 77.4 +/- 17.8; PWS, 63.3 +/- 14.2; and control subjects, 106.4 +/- 13.0. Achievement scores for the three groups were EMO, 78.7 +/- 18.8; PWS, 71.2 +/- 17.0; and control subjects, 104.8 +/- 17.0. Significant negative behaviors and poor adaptive skills were found in the EMO group. White matter lesions were noted on brain MRI in 6 subjects with PWS and 5 with EMO. None of the normal-weight control subjects had these findings. Individuals with EMO have significantly lower cognitive function and more behavioral problems than control subjects with no history of childhood obesity. Both EMO and PWS subjects have white matter lesions on brain MRI that have not previously been described.

Influence of the Prader-Willi syndrome imprinting center on the DNA methylation landscape in the mouse brain

PubMed Central

Brant, Jason O; Riva, Alberto; Resnick, James L; Yang, Thomas P

2014-01-01

Reduced representation bisulfite sequencing (RRBS) was used to analyze DNA methylation patterns across the mouse brain genome in mice carrying a deletion of the Prader-Willi syndrome imprinting center (PWS-IC) on either the maternally- or paternally-inherited chromosome. Within the ∼3.7 Mb imprinted Angelman/Prader-Willi syndrome (AS/PWS) domain, 254 CpG sites were interrogated for changes in methylation due to PWS-IC deletion. Paternally-inherited deletion of the PWS-IC increased methylation levels ∼2-fold at each CpG site (compared to wild-type controls) at differentially methylated regions (DMRs) associated with 5′ CpG island promoters of paternally-expressed genes; these methylation changes extended, to a variable degree, into the adjacent CpG island shores. Maternal PWS-IC deletion yielded little or no changes in methylation at these DMRs, and methylation of CpG sites outside of promoter DMRs also was unchanged upon maternal or paternal PWS-IC deletion. Using stringent ascertainment criteria, ∼750,000 additional CpG sites were also interrogated across the entire mouse genome. This analysis identified 26 loci outside of the imprinted AS/PWS domain showing altered DNA methylation levels of ≥25% upon PWS-IC deletion. Curiously, altered methylation at 9 of these loci was a consequence of maternal PWS-IC deletion (maternal PWS-IC deletion by itself is not known to be associated with a phenotype in either humans or mice), and 10 of these loci exhibited the same changes in methylation irrespective of the parental origin of the PWS-IC deletion. These results suggest that the PWS-IC may affect DNA methylation at these loci by directly interacting with them, or may affect methylation at these loci through indirect downstream effects due to PWS-IC deletion. They further suggest the PWS-IC may have a previously uncharacterized function outside of the imprinted AS/PWS domain. PMID:25482058

DNA sequencing and copy number variation analysis of MCHR2 in a cohort of Prader Willi like (PWL) patients.

PubMed

Geets, Ellen; Aerts, Evi; Verrijken, An; Van Hoorenbeeck, Kim; Verhulst, Stijn; Van Gaal, Luc; Van Hul, Wim

Prader Willi Syndrome (PWS) is a syndromic form of obesity caused by a chromosomal aberration on chromosome 15q11.2-q13. Patients with a comparable phenotype to PWS not carrying the 15q11.2-q13 defect are classified as Prader Willi like (PWL). In literature, PWL patients do frequently harbor deletions at 6q16, which led to the identification of the single-minded 1 (SIM1) gene as a possible cause for the presence of obesity in these patients. However, our previous work in a PWL cohort showed a rather limited involvement of SIM1 in the obesity phenotype. In this paper, we investigated the causal role of the melanin-concentrating hormone receptor 2 (MCHR2) gene in PWL patients, as most of the reported 6q16 deletions also encompass this gene and it is suggested to be active in the control of feeding behavior and energy metabolism. Copy number variation analysis of the MCHR2 genomic region followed by mutation analysis of MCHR2 was performed in a PWL cohort. Genome-wide microarray analysis of 109 patients with PWL did not show any gene harboring deletions on chromosome 6q16. Mutation analysis in 92 patients with PWL demonstrated three MCHR2 variants: p.T47A (c.139A>G), p.A76A (c.228T>C) and c.*16A>G. We identified a significantly higher prevalence of the c.228T>C C allele in our PWL cohort compared to previously published results and controls of the ExAC Database. Overall, our results are in line with some previously performed studies suggesting that MCHR2 is not a major contributor to human obesity and the PWL phenotype. Copyright © 2017 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Inactivation of the mouse Magel2 gene results in growth abnormalities similar to Prader-Willi syndrome.

PubMed

Bischof, Jocelyn M; Stewart, Colin L; Wevrick, Rachel

2007-11-15

Prader-Willi syndrome (PWS) is an imprinted genetic obesity disorder characterized by abnormalities of growth and metabolism. Multiple mouse models with deficiency of one or more PWS candidate genes have partially correlated individual genes with aspects of the PWS phenotype, although the genetic origin of defects in growth and metabolism has not been elucidated. Gene-targeted mutation of the PWS candidate gene Magel2 in mice causes altered circadian rhythm output and reduced motor activity. We now report that Magel2-null mice exhibit neonatal growth retardation, excessive weight gain after weaning, and increased adiposity with altered metabolism in adulthood, recapitulating fundamental aspects of the PWS phenotype. Magel2-null mice provide an important opportunity to examine the physiological basis for PWS neonatal failure to thrive and post-weaning weight gain and for the relationships among circadian rhythm, feeding behavior, and metabolism.

Elevated ratio of acylated to unacylated ghrelin in children and young adults with Prader-Willi syndrome.

PubMed

Kuppens, R J; Diène, G; Bakker, N E; Molinas, C; Faye, S; Nicolino, M; Bernoux, D; Delhanty, P J D; van der Lely, A J; Allas, S; Julien, M; Delale, T; Tauber, M; Hokken-Koelega, A C S

2015-12-01

Prader-Willi syndrome (PWS) is characterized by a switch from failure to thrive to excessive weight gain and hyperphagia in early childhood. Hyperghrelinemia may be involved in the underlying mechanisms of the switch. The purpose of this study is to evaluate acylated ghrelin (AG) and unacylated ghrelin (UAG) levels in PWS and investigate their associations with hyperphagia. This is a cross-sectional clinical study conducted in three PWS expert centers in the Netherlands and France. Levels of AG and UAG and the AG/UAG ratio were determined in 138 patients with PWS (0.2-29.4 years) and compared with 50 age-matched obese subjects (4.3-16.9 years) and 39 healthy controls (0.8-28.6 years). AEBSF was used to inhibit deacylation of AG. As a group, PWS patients had higher AG but similar UAG levels as healthy controls (AG 129.1 vs 82.4 pg/ml, p = 0.016; UAG 135.3 vs 157.3 pg/ml, resp.), resulting in a significantly higher AG/UAG ratio (1.00 vs 0.61, p = 0.001, resp.). Obese subjects had significantly lower AG and UAG levels than PWS and controls (40.3 and 35.3 pg/ml, resp.), but also a high AG/UAG ratio (1.16). The reason for the higher AG/UAG ratio in PWS and obese was, however, completely different, as PWS had a high AG and obese a very low UAG. PWS patients without weight gain or hyperphagia had a similar AG/UAG ratio as age-matched controls, in contrast to those with weight gain and/or hyperphagia who had an elevated AG/UAG ratio. The switch to excessive weight gain in PWS seems to coincide with an increase in the AG/UAG ratio, even prior to the start of hyperphagia.

Outcomes of adenotonsillectomy in patients with Prader-Willi syndrome.

PubMed

Meyer, Stacy L; Splaingard, Mark; Repaske, David R; Zipf, William; Atkins, Joan; Jatana, Kris

2012-11-01

To assess the efficacy of upper airway surgical intervention in patients with Prader-Willi syndrome (PWS). Due to reports of sudden death in children undergoing treatment with growth hormone for PWS, detection of sleep-disordered breathing by polysomnography (PSG) has been recommended. Retrospective study. Multidisciplinary PWS Center at a tertiary care children's hospital. Thirteen pediatric patients with PWS who underwent adenotonsillectomy (T&A) with pre-PSG and post-PSG. Comparison of PSG results before and after T&A. Six of our patients were girls (46%); 8 had genetic characteristics consistent with deletion (61%), and the remaining 5 had genetic characteristics consistent with uniparental disomy (39%). The median age at T&A was 3 years (age range, 6 months to 11 years), and the median age at start of growth hormone treatment was 8.5 months (range, 2 months to 6 years). Nine of the 13 patients had mild to moderate obstructive sleep apnea (OSA) or obstructive hypoventilation (69%); in 8 of these 9, breathing normalized after T&A. Four children had severe OSA prior to surgery (31%). Breathing normalized in 2 of these after surgery, but 2 had PSG findings of residual combined obstructive and central apneas postoperatively. Adenotonsillectomy, while effective in most children with PWS who demonstrate mild to moderate OSA, may not be curative in children with severe OSA. An increase in central apneas can occur in some children with PWS postoperatively, and it is important to repeat PSG after surgery. Further studies are necessary to determine optimal treatment for some children with PWS and sleep-disordered breathing.

Scoliosis in patients with Prader Willi Syndrome - comparisons of conservative and surgical treatment.

PubMed

Weiss, Hans-Rudolf; Goodall, Deborah

2009-05-06

In children with Prader Willi syndrome (PWS), besides growth hormone (GH) therapy, control of the food environment and regular exercise, surgical treatment of scoliosis deformities seems the treatment of choice, even though the risks of spinal surgery in this specific population is very high. Therefore the question arises as to whether the risks of spinal surgery outweigh the benefits in a condition, which bears significant risks per se. The purpose of this systematic review of the Pub Med literature was to find mid or long-term results of spinal fusion surgery in patients with PWS, and to present the conservative treatment in a case study of nine patients with this condition. Types of studies included; all kinds of studies; retrospective and prospective ones, which reported upon the outcome of scoliosis surgery in patients with PWS.Types of participants included: patients with scoliosis and PWS.Type of intervention: surgery.Search strategy for identification of the studies; Pub Med; limited to English language and bibliographies of all reviewed articles.Nine patients with PWS from our data-base treated conservatively have been found, being 19 years or over at the time this study has been performed. The results of conservative management are described and related to the natural history and treatment results found in the Pub Med review. From 2210 titles displayed in the Pub Med database with the key word being "Prader Willi syndrome", 5 different papers were displayed at the date of the search containing some information on the outcome of surgery and none appeared to contain a mid or long-term follow-up. The PWS patients treated conservatively from our series all stayed below 70 degrees and some of which improved. If the curve of scoliosis patients with PWS can be kept within certain limits (usually below 70 degrees) conservatively, this treatment seems to have fewer complications than surgical treatments. The results of our retrospective study of nine patients

Characterisation of balance capacity in Prader-Willi patients.

PubMed

Capodaglio, Paolo; Menegoni, Francesco; Vismara, Luca; Cimolin, Veronica; Grugni, Graziano; Galli, Manuela

2011-01-01

Being severely overweight is a distinctive clinical feature of Prader-Willi Syndrome (PWS). This explorative study aims to characterise balance capacity in PWS as compared to non-genetically obese patients (O) and to a group of normal-weight individuals (CG). We enrolled 14 PWS patients: 8 females and 6 males (BMI = 41.3 ± 7.3 kg/m(2), age = 32.86+4.42 years), 44 obese individuals, 22 males and 22 females (BMI = 40.6 ± 4.6 kg/m(2), age = 34.2 ± 10.7 years) and 20 controls (CG: 10 females and 10 males; BMI: 21.6 ± 1.6 kg/m(2); age: 30.5 ± 5.3 years). Postural acquisitions were conducted by means of a force platform from which the COP pattern vs time was analysed. The participants were required to stand barefoot on the platform with eyes open and heels at standardized distance and position for 60s. All of the analysed parameters were statistically different from O and CG groups. PWS individuals showed greater displacements in both the A/P and M/L direction (RMS, RANGE and MV indices). Analysis of the overall planar movement of the CoP showed that the PWS patients were characterised by higher RMS distance from the centre (RMS(CoP) index) and area of confidence ellipse (AREA(CoP) index) when compared both to obese and healthy individuals. PWS patients showed a poorer balance capacity than their non-genetically obese counterparts and healthy individuals, with greater differences in both the A/P and M/L direction than O. Rehabilitation programs for PWS should take this finding into account. In addition to weight loss, strengthening of ankle flexors/extensors, and balance training, tailored interventions aimed at improving A/P control should be given particular consideration. Copyright © 2010 Elsevier Ltd. All rights reserved.

Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15.

PubMed

Olander, E; Stamberg, J; Steinberg, L; Wulfsberg, E A

2000-07-31

We report on a boy with mosaicism for trisomy 15 and Prader-Willi syndrome (PWS) due to maternal isodisomy for chromosome 15. His phenotype is consistent with PWS and trisomy 15 mosaicism. Although our patient is unusual in having maternal isodisomy rather than the more common maternal heterodisomy, we think that his more severe PWS phenotype is due to his trisomy 15 mosaicism rather than to homozygosity for deleterious chromosome 15 genes. We propose that individuals with PWS have one of three similar but distinctive phenotypes depending on the cause of their condition. Patients with paternal deletions have the typical PWS phenotype, patients with maternal UPD have a slightly milder phenotype with better cognitive function, and those with maternal UPD and mosaic trisomy 15 have the most severe phenotype with a high incidence of congenital heart disease. These phenotype-genotype differences are useful to guide the work-up of patients with suspected PWS and to provide prognostic counseling for families.

Neural correlates of self-injurious behavior in Prader-Willi syndrome.

PubMed

Klabunde, Megan; Saggar, Manish; Hustyi, Kristin M; Hammond, Jennifer L; Reiss, Allan L; Hall, Scott S

2015-10-01

Individuals with Prader-Willi syndrome (PWS), a genetic disorder caused by mutations to the q11-13 region on chromosome 15, commonly show severe skin-picking behaviors that can cause open wounds and sores on the body. To our knowledge, however, no studies have examined the potential neural mechanisms underlying these behaviors. Seventeen individuals with PWS, aged 6-25 years, who showed severe skin-picking behaviors, were recruited and scanned on a 3T scanner. We used functional magnetic resonance imaging (fMRI) while episodes of skin picking were recorded on an MRI-safe video camera. Three participants displayed skin picking continuously throughout the scan, three participants did not display skin picking, and the data for one participant evidenced significant B0 inhomogeneity that could not be corrected. The data for the remaining 10 participants (six male, four female) who displayed a sufficient number of picking and nonpicking episodes were subjected to fMRI analysis. Results showed that regions involved in interoceptive, motor, attention, and somatosensory processing were activated during episodes of skin-picking behavior compared with nonpicking episodes. Scores obtained on the Self-Injury Trauma scale were significantly negatively correlated with mean activation within the right insula and left precentral gyrus. These data indicate that itch and pain processes appear to underlie skin-picking behaviors in PWS, suggesting that interoceptive disturbance may contribute to the severity and maintenance of abnormal skin-picking behaviors in PWS. Implications for treatments are discussed. © 2015 Wiley Periodicals, Inc.

The use of medical care and the prevalence of serious illness in an adult Prader-Willi syndrome cohort.

PubMed

Sinnema, Margje; Maaskant, Marian A; van Schrojenstein Lantman-de Valk, Henny M J; Boer, Harm; Curfs, Leopold M G; Schrander-Stumpel, Constance T R M

2013-08-01

Adults with Prader-Willi syndrome (PWS) have an increased occurrence of several medical conditions. We report on the consequences of high morbidity rates such as prevalence rate of hospital admissions, medication use and surgery in a Dutch cohort of adults with PWS. Special attention is paid to causes and symptoms of serious illness. Participants were contacted via the Dutch Prader-Willi Parent Association and through physicians specializing in persons with ID. The persons with PWS and their main caregivers were visited at home. Information was collected through semi-structured interviews on 102 adults with PWS. The need for medical care in the neonatal period is associated with hypotonia and feeding problems. Hospital admissions for respiratory tract infections are frequent. During childhood most hospital admissions were due to PWS syndrome specific surgery. During adolescence hospital admissions occurred for scoliosis surgery and endocrine evaluations. At adult age, hospitalization was associated with inguinal hernia surgery, diabetes mellitus, psychosis, erysipelas, water and drug intoxications. In the older group, respiratory infections were again the main reason for hospital admissions. Frequently used medications at adult age included psychotropics, laxatives, anti-diabetics and dermatologic preparations. Abnormal drinking patterns, problems with anesthesia, decreased ability to vomit, abnormal pain awareness and unpredictable fever responses were frequent and often lead to delayed diagnoses of serious conditions. People with PWS are frequent users of medical-care. Reasons for hospitalization and medication use are age specific. Knowledge on the different presentation of symptoms in people with PWS is needed. In case of unexplained illness, disturbances of consciousness and behavioral changes in people with PWS, an infection should be ruled out in the first place. Information from this study may help in preventing conditions and recognizing conditions in an

Incidental memory for faces in children with different genetic subtypes of Prader-Willi syndrome.

PubMed

Key, Alexandra P; Dykens, Elisabeth M

2017-06-01

The present study examined the effects of genetic subtype on social memory in children (7-16 years) with Prader-Willi syndrome (PWS). Visual event-related potentials (ERPs) during a passive viewing task were used to compare incidental memory traces for repeated vs single presentations of previously unfamiliar social (faces) and nonsocial (houses) images in 15 children with the deletion subtype and 13 children with maternal uniparental disomy (mUPD). While all participants perceived faces as different from houses (N170 responses), repeated faces elicited more positive ERP amplitudes ('old/new' effect, 250-500ms) only in children with the deletion subtype. Conversely, the mUPD group demonstrated reduced amplitudes suggestive of habituation to the repeated faces. ERP responses to repeated vs single house images did not differ in either group. The results suggest that faces hold different motivational value for individuals with the deletion vs mUPD subtype of PWS and could contribute to the explanation of subtype differences in the psychiatric symptoms, including autism symptomatology. © The Author (2017). Published by Oxford University Press.

Zinc finger protein 274 regulates imprinted expression of transcripts in Prader-Willi syndrome neurons.

PubMed

Langouët, Maéva; Glatt-Deeley, Heather R; Chung, Michael S; Dupont-Thibert, Clémence M; Mathieux, Elodie; Banda, Erin C; Stoddard, Christopher E; Crandall, Leann; Lalande, Marc

2018-02-01

Prader-Willi syndrome (PWS) is characterized by neonatal hypotonia, developmental delay and hyperphagia/obesity and is caused by the absence of paternal contribution to chromosome 15q11-q13. Using induced pluripotent stem cell (iPSC) models of PWS, we previously discovered an epigenetic complex that is comprised of the zinc-finger protein ZNF274 and the SET domain bifurcated 1 (SETDB1) histone H3 lysine 9 (H3K9) methyltransferase and that silences the maternal alleles at the PWS locus. Here, we have knocked out ZNF274 and rescued the expression of silent maternal alleles in neurons derived from PWS iPSC lines, without affecting DNA methylation at the PWS-Imprinting Center (PWS-IC). This suggests that the ZNF274 complex is a separate imprinting mark that represses maternal PWS gene expression in neurons and is a potential target for future therapeutic applications to rescue the PWS phenotype. © The Author(s) 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

1p36 deletion syndrome associated with Prader-Willi-like phenotype.

PubMed

Tsuyusaki, Yu; Yoshihashi, Hiroshi; Furuya, Noritaka; Adachi, Masanori; Osaka, Hitoshi; Yamamoto, Kayono; Kurosawa, Kenji

2010-08-01

1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes, characterized by moderate to severe mental retardation, characteristic facial appearance, hypotonia, obesity, and seizures. The clinical features often overlap with those of Prader-Willi syndrome (PWS). To elucidate the phenotype-genotype correlation in 1p36 deletion syndrome, two cases involving a PWS-like phenotype were analyzed on molecular cytogenetics. Two patients presenting with the PWS-like phenotype but having negative results for PWS underwent fluorescence in situ hybridization (FISH). The size of the chromosome 1p36 deletions was characterized using probes of BAC clones based on the University of California, Santa Cruz (UCSC) Genome Browser. PWS was excluded on FISH and methylation-specific polymerase chain reaction. Subsequent FISH using the probe D1Z2 showed deletion of the 1p36.3 region, confirming the diagnosis of 1p36 deletion syndrome. Further analysis characterized the 1p36 deletions as being located between 4.17 and 4.36 Mb in patient 1 and between 4.89 and 6.09 Mb in patient 2. Patients with 1p36 deletion syndrome exhibit a PWS-like phenotype and are therefore probably underdiagnosed. The possible involvement of the terminal 4 Mb region of chromosome 1p36 in the PWS-like phenotype is hypothesized. © 2010 Japan Pediatric Society.

Feeding, eating and behavioral disturbances in Prader-Willi syndrome and non-syndromal obesity.

PubMed

Sonnengrün, Lilli; Schober, Celestina; Vogel, Mandy; Hiemisch, Andreas; Döhnert, Mirko; Hilbert, Anja; Kiess, Wieland

2016-08-01

Although most individuals with Prader-Willi syndrome (PWS) are obese, little is known about the impact of obesity-related psychosocial factors in PWS. In the present study we compared feeding, eating, and behavioral disturbances in children and adolescents with PWS, peers with non-syndromal obesity, and normal weight controls. Twelve persons with PWS, aged 7-22 years, age- and gender-matched obese and normal weight individuals were analyzed regarding parental feeding practices, eating disturbances, and behavioral problems via standardized questionnaires. Parents of individuals with PWS reported significantly more restrictive feeding and monitoring than did parents of obese or normal weight children without PWS (p<0.05). Social problems were more common in the obese and the PWS group than in the normal-weight group (p<0.05). Behavioral problems were significantly correlated with parental restrictive feeding practices. Our data show that children and adolescents with PWS are affected by psychosocial problems, and that restrictive feeding practices might be associated with more severe behavioral problems. Further studies in larger samples will be necessary to replicate these results and possibly provide new therapeutic approaches for the management of PWS.

Systematic review of the clinical and genetic aspects of Prader-Willi syndrome

PubMed Central

2011-01-01

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder that is caused by the lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13. This syndrome has a characteristic phenotype including severe neonatal hypotonia, early-onset hyperphagia, development of morbid obesity, short stature, hypogonadism, learning disabilities, behavioral problems, and psychiatric problems. PWS is an example of a genetic condition caused by genomic imprinting. It can occur via 3 main mechanisms that lead to the absence of expression of paternally inherited genes in the 15q11.2-q13 region: paternal microdeletion, maternal uniparental disomy, and an imprinting defect. Over 99% of PWS cases can be diagnosed using DNA methylation analysis. Early diagnosis of PWS is important for effective long-term management. Growth hormone (GH) treatment improves the growth, physical phenotype, and body composition of patients with PWS. In recent years, GH treatment in infants has been shown to have beneficial effects on the growth and neurological development of patients diagnosed during infancy. There is a clear need for an integrated multidisciplinary approach to facilitate early diagnosis and optimize management to improve quality of life, prevent complications, and prolong life expectancy in patients with PWS. PMID:21503198

Systematic review of the clinical and genetic aspects of Prader-Willi syndrome.

PubMed

Jin, Dong Kyu

2011-02-01

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder that is caused by the lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13. This syndrome has a characteristic phenotype including severe neonatal hypotonia, early-onset hyperphagia, development of morbid obesity, short stature, hypogonadism, learning disabilities, behavioral problems, and psychiatric problems. PWS is an example of a genetic condition caused by genomic imprinting. It can occur via 3 main mechanisms that lead to the absence of expression of paternally inherited genes in the 15q11.2-q13 region: paternal microdeletion, maternal uniparental disomy, and an imprinting defect. Over 99% of PWS cases can be diagnosed using DNA methylation analysis. Early diagnosis of PWS is important for effective long-term management. Growth hormone (GH) treatment improves the growth, physical phenotype, and body composition of patients with PWS. In recent years, GH treatment in infants has been shown to have beneficial effects on the growth and neurological development of patients diagnosed during infancy. There is a clear need for an integrated multidisciplinary approach to facilitate early diagnosis and optimize management to improve quality of life, prevent complications, and prolong life expectancy in patients with PWS.

[Phenotype-genotype correlation analysis of 12 cases with Angelman/Prader-Willi syndrome].

PubMed

Chen, Chen; Peng, Ying; Xia, Yan; Li, Haoxian; Zhu, Huimin; Pan, Qian; Yin, Fei; Wu, Lingqian

2014-12-01

To investigate the genotype-phenotype correlation in patients with Angelman syndrome/Prader-Willi syndrome (AS/PWS) and assess the application value of high-resolution single nucleotide polymorphism microarrays (SNP array) for such diseases. Twelve AS/PWS patients were diagnosed through SNP array, fluorescence in situ hybridization (FISH) and karyotype analysis. Clinical characteristics were analyzed. Deletions ranging from 4.8 Mb to 7.0 Mb on chromosome 15q11.2-13 were detected in 11 patients. Uniparental disomy (UPD) was detected in only 1 patient. Patients with deletions could be divided into 2 groups, including 7 cases with class I and 4 with class II. The two groups however had no significant phenotypic difference. The UPD patient had relatively better development and language ability. Deletions of 6 patients were confirmed by FISH to be of de novo in origin. The risk to their sibs was determined to be less than 1%. The phenotypic differences between AS/PWS patients with class I and class II deletion need to be further studied. SNP array is useful in detecting and distinguishing of patients with deletion or UPD. This method may be applied for studying the genotype-phenotype association and the mechanism underlying AS/PWS.

Effects of exenatide on weight and appetite in overweight adolescents and young adults with Prader-Willi syndrome.

PubMed

Salehi, P; Hsu, I; Azen, C G; Mittelman, S D; Geffner, M E; Jeandron, D

2017-06-01

Prader-Willi syndrome (PWS) is associated with hyperphagia and hyperghrelinemia with major morbidity because of obesity without effective medical treatment targeting hyperphagia. Exenatide (Byetta [synthetic Exendin-4]; AstraZeneca, Wilmington DE) is a GLP-1 receptor agonist which reduces appetite and weight and may be an effective treatment in PWS. The objective of this study is to determine the effect of a 6-month trial of exenatide on appetite, weight and gut hormones in youth with PWS. Ten overweight and obese subjects with PWS (13-25 years) were recruited for a 6-month open-label, non-randomized, longitudinal study conducted at Children's Hospital Los Angeles. Exenatide was given using standard diabetes dosing without dietary modifications. Weight, body mass index (BMI), truncal fat, appetite and plasma acylated ghrelin were measured over 6 months. Mixed meal tolerance tests were performed at 0 and 6 months. Appetite scores significantly decreased from baseline (32.2 ± 8.7) after 1, 3 and 6 moths of treatment (27.5 ± 8.8, 25.4 ± 9.3, and 25.4 ± 7.2 respectively; p = 0.004). Hemoglobin A1c decreased significantly after treatment, but weight, BMI z-score and adiposity did not. There was no significant change in ghrelin. This is the first longitudinal investigation of the effects of exenatide in subjects with PWS. It was effective in decreasing appetite, without change in weight or BMI in the short term. Larger, controlled, longer-term trials in patients with PWS are needed to confirm the efficacy and safety of exenatide and to evaluate whether its use might induce weight loss when given in conjunction with behavioural modification. © 2016 World Obesity Federation.

Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits.

PubMed

Myers, Susan E; Whitman, Barbara Y; Carrel, Aaron L; Moerchen, Victoria; Bekx, M Tracy; Allen, David B

2007-03-01

Infants with Prader-Willi syndrome (PWS) typically display failure to thrive and decreased muscle mass with excess body fat for age. Growth hormone (GH) therapy in children with PWS improves, but does not normalize, body composition and muscle strength and agility. The objective of this study was to determine the effects of earlier GH therapy on anthropometric measurements, body composition, and psychomotor development in affected PWS infants and toddlers. Twenty-five subjects, ages 4-37 months, were randomized to 2 years of GH therapy (1 mg/m(2)/day) or 1 year of observation without GH treatment and then placed on GH (1.5 mg/m(2).day) for 1 year only. Anthropometric measurements were obtained by standard methods: percent body fat, lean body mass, and total body bone mineral density by dual x-ray absorptiometry; motor constructs of mobility and stability by the Toddler Infant Motor Evaluation; and cognitive and language function by the Capute Scales of Infant Language and Cognitive Development. GH-treated PWS subjects demonstrated normalization of length/height standard deviation scores (SDS), faster head growth, increased lean body mass accrual, and decreased percent body fat (P < 0.005 for all parameters), as well as improved language (P = 0.05) and cognitive (P = 0.02) quotient Z-scores compared with similarly aged untreated PWS subjects after 1 year into the study. PWS subjects treated before their first birthday spoke their first words at a mean age of 14.4 +/- 2.8 months and walked independently at 23.3 +/- 4.8 months. GH therapy was well-tolerated; however, one PWS subject experienced scoliosis progression. As greater benefits were seen in our study with early treatment, prompt referral to a pediatric endocrinologist for consideration of GH therapy is recommended for PWS at an early age. (c) 2006 Wiley-Liss, Inc.

Scoliosis in patients with Prader Willi Syndrome – comparisons of conservative and surgical treatment

PubMed Central

Weiss, Hans-Rudolf; Goodall, Deborah

2009-01-01

In children with Prader Willi syndrome (PWS), besides growth hormone (GH) therapy, control of the food environment and regular exercise, surgical treatment of scoliosis deformities seems the treatment of choice, even though the risks of spinal surgery in this specific population is very high. Therefore the question arises as to whether the risks of spinal surgery outweigh the benefits in a condition, which bears significant risks per se. The purpose of this systematic review of the Pub Med literature was to find mid or long-term results of spinal fusion surgery in patients with PWS, and to present the conservative treatment in a case study of nine patients with this condition. Types of studies included; all kinds of studies; retrospective and prospective ones, which reported upon the outcome of scoliosis surgery in patients with PWS. Types of participants included: patients with scoliosis and PWS. Type of intervention: surgery. Search strategy for identification of the studies; Pub Med; limited to English language and bibliographies of all reviewed articles. Nine patients with PWS from our data-base treated conservatively have been found, being 19 years or over at the time this study has been performed. The results of conservative management are described and related to the natural history and treatment results found in the Pub Med review. From 2210 titles displayed in the Pub Med database with the key word being "Prader Willi syndrome", 5 different papers were displayed at the date of the search containing some information on the outcome of surgery and none appeared to contain a mid or long-term follow-up. The PWS patients treated conservatively from our series all stayed below 70° and some of which improved. If the curve of scoliosis patients with PWS can be kept within certain limits (usually below 70 degrees) conservatively, this treatment seems to have fewer complications than surgical treatments. The results of our retrospective study of nine patients

Prader-Willi syndrome mental health research strategy workshop proceedings: the state of the science and future directions.

PubMed

Schwartz, Lauren; Holland, Anthony; Dykens, Elisabeth; Strong, Theresa; Roof, Elizabeth; Bohonowych, Jessica

2016-09-29

This paper reports on the 'Prader-Willi Syndrome (PWS) Mental Health Research Strategy Workshop' that took place in March 2015. PWS is characterized by a complex phenotype affecting multiple systems with a high prevalence of maladaptive behaviours, and neuropsychiatric illness. Prader Willi syndrome results from the absence of paternally derived alleles located at the imprinted chromosomal locus, 15q11-13. The goal of the workshop was to highlight the state of the science of the mental health of people with this rare neurodevelopmental disorder. Mental ill health and maladaptive behaviors significantly impact quality of life for persons with PWS and their caregivers. Effective treatments and further research into this area are critically needed. A multidisciplinary group of scientists and health care professionals were brought together to discuss the mental health and behavioral needs of people with PWS. The workshop strategy was to integrate established work on PWS with other relevant areas of study. The meeting also focused on two neurobiological systems that research had suggested were relevant to understanding the broader mental health aspects of PWS: the autonomic nervous system and oxytocin/vasopressin pathways. Other relevant topics were considered and recommendations made. The workshop presentations and working group discussions revealed that no one approach was sufficient to fully conceptualize the mental health challenges in PWS. Workshop discussions pointed to the need for theoretically informed studies focused on clinical characterization, measurement, and the probing of specific neurobiological systems through pharmaceutical or other interventions. Future studies in this area should explore the use of advanced neuroimaging protocols, as well as molecular studies using iPS cells in order to create more informed theories. Within this framework, workshop participants identified and prioritized key research questions, and highlighted current opportunities

Non-Alcoholic Fatty Liver Disease (NAFLD) in children and adolescents with Prader-Willi Syndrome (PWS).

PubMed

Fintini, D; Inzaghi, E; Colajacomo, M; Bocchini, S; Grugni, G; Brufani, C; Cappa, M; Nobili, V; Cianfarani, S; Crinò, A

2016-06-01

We tested the hypothesis that patients with Prader-Willi syndrome (PWS) may be at lower risk of developing non-alcoholic fatty liver disease (NAFLD) because of a higher insulin sensitivity. Twenty-one PWS patients and 42 control subjects closely similar for age, gender, pubertal stage and body mass index (CNT), were studied. Metabolic profile and body composition were assessed. NAFLD was established by a validated method of US grading (range from G0 to G3). PWS patients showed a significantly better metabolic profile (lower waist circumference, fasting glucose levels, HOMA-IR, cholesterol, transaminase levels and trunk fat mass/fat mass ratio). Furthermore, NAFLD G1stage was significantly more frequent in PWS subjects (P < 0.05), whereas G2 stage was significantly more frequent in control patients (P < 0.05). NAFLD grading seems to correlate with body composition in PWS, also after adjustment for sex and GH treatment. To our knowledge, this is the first report suggesting a reduced risk of NAFLD in PWS children. © 2015 World Obesity.

Imprinting center analysis in Prader-Willi and Angelman syndrome patients with typical and atypical phenotypes.

PubMed

Camprubí, Cristina; Coll, Maria Dolors; Villatoro, Sergi; Gabau, Elisabeth; Kamli, Amine; Martínez, Maria Jesus; Poyatos, David; Guitart, Miriam

2007-01-01

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic disorders caused by a deficiency of imprinted gene expression from the paternal or maternal chromosome 15, respectively. This deficiency is due to the deletion of the 15q11-q13 region, parental uniparental disomy of the chromosome 15, or imprinting defect (ID). Mutation of the UBE3A gene causes approximately 10% of AS cases. In this present study, we describe the molecular analysis and phenotypes of two PWS patients and four AS patients with ID. One of the PWS patients has a non-familial imprinting center (IC) deletion and displayed a severe phenotype with an atypical PWS appearance, hyperactivity and psychiatric vulnerability. The other PWS and AS patients did not present genetic abnormalities in the IC, suggesting an epimutation as the genetic cause. The methylation pattern of two AS patients showed a faint maternal band corresponding to a mosaic ID. One of these mosaic patients displayed a mild AS phenotype while the other displayed a PWS-like phenotype.

Molecular genetic classification in Prader-Willi syndrome: a multisite cohort study.

PubMed

Butler, Merlin G; Hartin, Samantha N; Hossain, Waheeda A; Manzardo, Ann M; Kimonis, Virginia; Dykens, Elisabeth; Gold, June Anne; Kim, Soo-Jeong; Weisensel, Nicolette; Tamura, Roy; Miller, Jennifer L; Driscoll, Daniel J

2018-05-05

Prader-Willi syndrome (PWS) is due to errors in genomic imprinting. PWS is recognised as the most common known genetic cause of life-threatening obesity. This report summarises the frequency and further characterises the PWS molecular classes and maternal age effects. High-resolution microarrays, comprehensive chromosome 15 genotyping and methylation-specific multiplex ligation probe amplification were used to describe and further characterise molecular classes of maternal disomy 15 (UPD15) considering maternal age. We summarised genetic data from 510 individuals with PWS and 303 (60%) had the 15q11-q13 deletion; 185 (36%) with UPD15 and 22 (4%) with imprinting defects. We further characterised UPD15 findings into subclasses based on the presence (size, location) or absence of loss of heterozygosity (LOH). Additionally, significantly older mothers (mean age=32.5 years vs 27.7 years) were found in the UPD15 group (n=145) compared with the deletion subtype (n=200). We report on molecular classes in PWS using advanced genomic technology in the largest cohort to date. LOH patterns in UPD15 may impact the risk of having a second genetic condition if the mother carries a recessive mutant allele in the isodisomic region on chromosome 15. The risk of UPD15 may also increase with maternal age. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Metabolic syndrome in adult patients with Prader-Willi syndrome.

PubMed

Grugni, G; Crinò, A; Bedogni, G; Cappa, M; Sartorio, A; Corrias, A; Di Candia, S; Gargantini, L; Iughetti, L; Pagano, C; Ragusa, L; Salvatoni, A; Spera, S; Vettor, R; Chiumello, G; Brambilla, P

2013-11-01

Prader-Willi syndrome (PWS), the most common genetic cause of obesity, is characterized by elevated morbility and mortality in all ages. In this context, non-obese PWS children showed low frequency of metabolic syndrome (MetS), while a comparable prevalence was observed in obese PWS and obese controls. Aim of this study was to estimate the occurrence of MetS and its components in a large group of PWS adults, according to obesity status. A cross-sectional study was performed in 108 PWS aged 18.0-43.2 years (87 obese and 21 non-obese) and in 85 controls with nonsyndromic obesity matched for age, gender, and BMI with obese PWS. Non-obese PWS showed lower waist circumference, insulin, HOMA-index, triglycerides, diastolic blood pressure, and higher HDL-C than both obese PWS and obese controls (p < 0.017). Obese PWS showed higher glucose and systolic blood pressure than both non-obese PWS and obese controls (p < 0.017). MetS was found in 1/21 (4.8%) non-obese PWS, 36/87 (41.4%) obese PWS and 39/85 (45.9%) obese controls. Non-obese PWS showed lower frequency for each MetS component as compared with obese PWS and obese controls. PWS patients with deletion of the chromosome 15q11-13 showed a lower risk for low HDL-C (p < 0.01) and a trend towards a lower MetS risk (p < 0.06) compared to subjects without deletion. Our findings suggest the main role that obesity status plays on the individual metabolic risk clustering in PWS adults. Early identification of MetS could be helpful to improve morbidity and prevent mortality in such patients. Copyright © 2012 Elsevier B.V. All rights reserved.

The High Direct Medical Costs of Prader-Willi Syndrome.

PubMed

Shoffstall, Andrew J; Gaebler, Julia A; Kreher, Nerissa C; Niecko, Timothy; Douglas, Diah; Strong, Theresa V; Miller, Jennifer L; Stafford, Diane E; Butler, Merlin G

2016-08-01

To assess medical resource utilization associated with Prader-Willi syndrome (PWS) in the US, hypothesized to be greater relative to a matched control group without PWS. We used a retrospective case-matched control design and longitudinal US administrative claims data (MarketScan) during a 5-year enrollment period (2009-2014). Patients with PWS were identified by Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 759.81. Controls were matched on age, sex, and payer type. Outcomes included total, outpatient, inpatient and prescription costs. After matching and application of inclusion/exclusion criteria, we identified 2030 patients with PWS (1161 commercial, 38 Medicare supplemental, and 831 Medicaid). Commercially insured patients with PWS (median age 10 years) had 8.8-times greater total annual direct medical costs than their counterparts without PWS (median age 10 years: median costs $14 907 vs $819; P < .0001; mean costs: $28 712 vs $3246). Outpatient care comprised the largest portion of medical resource utilization for enrollees with and without PWS (median $5605 vs $675; P < .0001; mean $11 032 vs $1804), followed by mean annual inpatient and medication costs, which were $10 879 vs $1015 (P < .001) and $6801 vs $428 (P < .001), respectively. Total annual direct medical costs were ∼42% greater for Medicaid-insured patients with PWS than their commercially insured counterparts, an increase partly explained by claims for Medicaid Waiver day and residential habilitation. Direct medical resource utilization was considerably greater among patients with PWS than members without the condition. This study provides a first step toward quantifying the financial burden of PWS posed to individuals, families, and society. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Microstructural white matter tract alteration in Prader-Willi syndrome: A diffusion tensor imaging study.

PubMed

Rice, Lauren J; Lagopoulos, Jim; Brammer, Michael; Einfeld, Stewart L

2017-09-01

Prader-Willi Syndrome (PWS) is a genetic disorder characterized by infantile hypotonia, hyperphagia, hypogonadism, growth hormone deficiency, intellectual disability, and severe emotional and behavioral problems. The brain mechanisms that underpin these disturbances are unknown. Diffusion tensor imaging (DTI) enables in vivo investigation of the microstructural integrity of white matter pathways. To date, only one study has used DTI to examine white matter alterations in PWS. However, that study used selected regions of interest, rather than a whole brain analysis. In the present study, we used diffusion tensor and magnetic resonance (T 1-weighted) imaging to examine microstructural white matter changes in 15 individuals with PWS (17-30 years) and 15 age-and-gender-matched controls. Whole-brain voxel-wise statistical analysis of FA was carried out using tract-based spatial statistics (TBSS). Significantly decreased fractional anisotropy was found localized to the left hemisphere in individuals with PWS within the splenium of the corpus callosum, the internal capsule including the posterior thalamic radiation and the inferior frontal occipital fasciculus (IFOF). Reduced integrity of these white matter pathways in individuals with PWS may relate to orientating attention, emotion recognition, semantic processing, and sensorimotor dysfunction. © 2017 Wiley Periodicals, Inc.

The oro-dental phenotype in Prader-Willi syndrome: a survey of 15 patients.

PubMed

Bailleul-Forestier, Isabelle; Verhaeghe, Veroniek; Fryns, Jean-Pierre; Vinckier, Frans; Declerck, Dominique; Vogels, Annick

2008-01-01

Prader-Willi syndrome (PWS) is a rare disorder caused by genetic defects in certain regions of chromosome 15q11-13. It is characterized by severe neonatal hypotonia and feeding problems, childhood-onset hyperphagia and obesity, short stature, facial dysmorphy, hypogonadism, learning and behavioural difficulties, and dental abnormalities. To describe the oro-dental phenotypic spectrum of patients with PWS. Fifteen PWS patients (3-35 years of age) being followed at the Centre for Human Genetics of the University Hospital of Leuven were examined at the dental clinic of the same institution. Medical information collected included age at diagnosis, body mass index (BMI) and level of cognitive functioning. Oral, clinical and radiological evaluations were performed. Caries experience (cavitation level), dental erosion and salivary flow rates were assessed. The 15 patients had dmft/DMFT scores ranging from 0 to 28, while nine were cavity-free. Those with severe caries experience also presented advanced dental erosion. BMI ranged from 16 to 42.6. There was no association between BMI and caries experience or erosive tooth wear. The PWS patients in our survey presented with a more favourable oral health status than those in previous studies. This might be due to early diet management or better oral hygiene during childhood or both.

Prader-Willi syndrome: From genetics to behaviour, with special focus on appetite treatments.

PubMed

Griggs, Joanne L; Sinnayah, Puspha; Mathai, Michael L

2015-12-01

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder resulting from a deletion in the expression of the paternally derived alleles in the region of 15q11-q13. PWS has a prevalence rate of 1:10,000-1:30,000 and is characterized by marked endocrine abnormalities including growth hormone deficiency and raised ghrelin levels. The hyperphagic phenotype in PWS is established over a number of phases and is exacerbated by impaired satiety, low energy expenditure and intellectual difficulties including obsessive-compulsive disorder and/or autistic behaviours. Clinical management in PWS typically includes familial/carer restriction and close supervision of food intake. If the supervision of food is left unmanaged, morbid obesity eventuates, central to the risk of cardiorespiratory disorder. None of the current appetite management/intervention strategies for PWS include pharmacological treatment, though recent research shows some promise. We review the established aberrant genetics and the endocrine and neuronal attributes which may determine disturbed regulatory processes in PWS. Focusing on clinical trials for appetite behaviours in PWS, we define the effectiveness of pharmacological treatments with a view to initiating and focusing research towards possible targets for modulating appetite in PWS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Three siblings with Prader-Willi syndrome caused by imprinting center microdeletions and review.

PubMed

Hartin, Samantha N; Hossain, Waheeda A; Weisensel, Nicolette; Butler, Merlin G

2018-04-01

Prader-Willi syndrome (PWS) is a complex genetic imprinting disorder characterized by childhood obesity, short stature, hypogonadism/hypogenitalism, hypotonia, cognitive impairment, and behavioral problems. Usually PWS occurs sporadically due to the loss of paternally expressed genes on chromosome 15 with the majority of individuals having the 15q11-q13 region deleted. Examples of familial PWS have been reported but rarely. To date 13 families have been reported with more than one child with PWS and without a 15q11-q13 deletion secondary to a chromosome 15 translocation, inversion, or uniparental maternal disomy 15. Ten of those 13 families were shown to carry microdeletions in the PWS imprinting center. The microdeletions were found to be of paternal origin in nine of the ten cases in which family studies were carried out. Using a variety of techniques, the microdeletions were identified in regions within the complex SNRPN gene locus encompassing the PWS imprinting center. Here, we report the clinical and genetic findings in three adult siblings with PWS caused by a microdeletion in the chromosome 15 imprinting center inherited from an unaffected father that controls the activity of genes in the 15q11-q13 region and summarize the 13 reported cases in the literature. © 2018 Wiley Periodicals, Inc.

Body composition, adipokines, bone mineral density and bone remodeling markers in relation to IGF-1 levels in adults with Prader-Willi syndrome.

PubMed

van Nieuwpoort, I Caroline; Twisk, Jos W R; Curfs, Leopold M G; Lips, Paul; Drent, Madeleine L

2018-01-01

In patients with Prader-Willi syndrome (PWS) body composition is abnormal and alterations in appetite regulating factors, bone mineral density and insulin-like growth factor-1 (IGF-1) levels have been described. Studies in PWS adults are limited. In this study, we investigated body composition, appetite regulating peptides, bone mineral density and markers of bone remodeling in an adult PWS population. Furthermore, we investigated the association between these different parameters and IGF-1 levels because of the described similarities with growth hormone deficient patients. In this cross-sectional observational cohort study in a university hospital setting we studied fifteen adult PWS patients. Anthropometric and metabolic parameters, IGF-1 levels, bone mineral density and bone metabolism were evaluated. The homeostasis model assessment of insulin resistance (HOMA2-IR) was calculated. Fourteen healthy siblings served as a control group for part of the measurements. In the adult PWS patients, height, fat free mass, IGF-1 and bone mineral content were significantly lower when compared to controls; body mass index (BMI), waist, waist-to-hip ratio and fat mass were higher. There was a high prevalence of osteopenia and osteoporosis in the PWS patients. Also, appetite regulating peptides and bone remodelling markers were aberrant when compared to reference values. Measurements of body composition were significantly correlated to appetite regulating peptides and high-sensitive C-reactive protein (hs-CRP), furthermore HOMA was correlated to BMI and adipokines. In adults with Prader-Willi syndrome alterations in body composition, adipokines, hs-CRP and bone mineral density were demonstrated but these were not associated with IGF-1 levels. Further investigations are warranted to gain more insight into the exact pathophysiology and the role of these alterations in the metabolic and cardiovascular complications seen in PWS, so these complications can be prevented or treated as

Effect of cessation of GH treatment on cognition during transition phase in Prader-Willi syndrome: results of a 2-year crossover GH trial.

PubMed

Kuppens, R J; Mahabier, E F; Bakker, N E; Siemensma, E P C; Donze, S H; Hokken-Koelega, A C S

2016-11-16

Patients with Prader-Willi syndrome (PWS) have a cognitive impairment. Growth hormone (GH) treatment during childhood improves cognitive functioning, while cognition deteriorates in GH-untreated children with PWS. Cessation of GH treatment at attainment of adult height (AH) might deteriorate their GH-induced improved cognition, while continuation might benefit them. We, therefore, investigated the effects of placebo versus GH administration on cognition in young adults with PWS who were GH-treated for many years during childhood and had attained AH. Two-year, randomized, double-blind, placebo-controlled cross-over study in 25 young adults with PWS. Cross-over intervention with placebo and GH (0.67 mg/m 2 /day), both during 1 year. Total (TIQ), verbal (VIQ) and performance IQ (PIQ) did not deteriorate during 1 year of placebo, compared to GH treatment (p > 0.322). Young adults with a lower TIQ had significantly more loss of TIQ points during placebo versus GH, in particular VIQ decreased more in those with a lower VIQ. The effect of placebo versus GH on TIQ, VIQ and PIQ was not different for gender or genotype. Compared to GH treatment, 1 year of placebo did not deteriorate cognitive functioning of GH-treated young adults with PWS who have attained AH. However, patients with a lower cognitive functioning had more loss in IQ points during placebo versus GH treatment. The reassuring finding that 1 year of placebo does not deteriorate cognitive functioning does, however, not exclude a gradual deterioration of cognitive functioning on the long term. ISRCTN24648386 , NTR1038 , Dutch Trial Register, www.trialregister.nl . Registered 16 August 2007.

Differential gene expression reveals mitochondrial dysfunction in an imprinting center deletion mouse model of Prader-Willi syndrome.

PubMed

Yazdi, Puya G; Su, Hailing; Ghimbovschi, Svetlana; Fan, Weiwei; Coskun, Pinar E; Nalbandian, Angèle; Knoblach, Susan; Resnick, James L; Hoffman, Eric; Wallace, Douglas C; Kimonis, Virginia E

2013-10-01

Prader-Willi syndrome (PWS) is a genetic disorder caused by deficiency of imprinted gene expression from the paternal chromosome 15q11-15q13 and clinically characterized by neonatal hypotonia, short stature, cognitive impairment, hypogonadism, hyperphagia, morbid obesity, and diabetes. Previous clinical studies suggest that a defect in energy metabolism may be involved in the pathogenesis of PWS. We focused our attention on the genes associated with energy metabolism and found that there were 95 and 66 mitochondrial genes differentially expressed in PWS muscle and brain, respectively. Assessment of enzyme activities of mitochondrial oxidative phosphorylation complexes in the brain, heart, liver, and muscle were assessed. We found the enzyme activities of the cardiac mitochondrial complexes II+‫III were up-regulated in the PWS imprinting center deletion mice compared to the wild-type littermates. These studies suggest that differential gene expression, especially of the mitochondrial genes may contribute to the pathophysiology of PWS. © 2013 Wiley Periodicals, Inc.

Anthropometric adjustments are helpful in the interpretation of BMD and BMC Z-scores of pediatric patients with Prader-Willi syndrome.

PubMed

Hangartner, T N; Short, D F; Eldar-Geva, T; Hirsch, H J; Tiomkin, M; Zimran, A; Gross-Tsur, V

2016-12-01

Anthropometric adjustments of bone measurements are necessary in Prader-Willi syndrome patients to correctly assess the bone status of these patients. This enables physicians to get a more accurate diagnosis of normal versus abnormal bone, allow for early and effective intervention, and achieve better therapeutic results. Bone mineral density (BMD) is decreased in patients with Prader-Willi syndrome (PWS). Because of largely abnormal body height and weight, traditional BMD Z-scores may not provide accurate information in this patient group. The goal of the study was to assess a cohort of individuals with PWS and characterize the development of low bone density based on two adjustment models applied to a dataset of BMD and bone mineral content (BMC) from dual-energy X-ray absorptiometry (DXA) measurements. Fifty-four individuals, aged 5-20 years with genetically confirmed PWS, underwent DXA scans of spine and hip. Thirty-one of them also underwent total body scans. Standard Z-scores were calculated for BMD and BMC of spine and total hip based on race, sex, and age for all patients, as well as of whole body and whole-body less head for those patients with total-body scans. Additional Z-scores were generated based on anthropometric adjustments using weight, height, and percentage body fat and a second model using only weight and height in addition to race, sex, and age. As many PWS patients have abnormal anthropometrics, addition of explanatory variables weight, height, and fat resulted in different bone classifications for many patients. Thus, 25-70 % of overweight patients, previously diagnosed as normal, were subsequently diagnosed as below normal, and 40-60 % of patients with below-normal body height changed from below normal to normal depending on bone parameter. This is the first study to include anthropometric adjustments into the interpretation of BMD and BMC in children and adolescents with PWS. This enables physicians to get a more accurate diagnosis of

Intranasal carbetocin reduces hyperphagia in individuals with Prader-Willi syndrome.

PubMed

Dykens, Elisabeth M; Miller, Jennifer; Angulo, Moris; Roof, Elizabeth; Reidy, Michael; Hatoum, Hind T; Willey, Richard; Bolton, Guy; Korner, Paul

2018-06-21

Prader-Willi syndrome (PWS) is a genetic neurodevelopmental disorder of life-threatening hyperphagia, obesity, intellectual deficits, compulsivity, and other behavioral problems. The efficacy and safety of i.n. carbetocin, an oxytocin analog, was evaluated in a prospective, randomized, double-blinded trial in adolescents with PWS. Eligible patients aged 10-18 years with genetically confirmed PWS were randomized (1:1) to i.n. carbetocin or placebo 3 times daily for 14 days. The primary efficacy endpoint was change in parent/caregiver-rated Hyperphagia in PWS Questionnaire-Responsiveness (HPWSQ-R) total score. Secondary efficacy endpoints included HPWSQ-R behavior, drive, and severity domains; clinician-rated HPWSQ; Children's Yale-Brown Obsessive-Compulsive Severity Scale; food domain of the Reiss Profile; and Clinical Global Impression-Improvement scale. Endpoints were assessed using analysis of covariance. Relationship between primary and secondary endpoints was assessed using Pearson correlation coefficients. Safety was assessed throughout the study. Demographics and clinical characteristics were similar between treatment groups (carbetocin, n = 17; placebo, n = 20). Patients receiving carbetocin had statistically significant reductions in HPWSQ-R total score at study end (-15.6) versus patients receiving placebo (-8.9; P = 0.029); several secondary efficacy endpoints also demonstrated significant differences (P < 0.05). Treatment effects for the primary and secondary endpoints were highly correlated (P ≤ 0.0001). Incidence of adverse events (AEs) was similar between treatment groups. I.n. carbetocin was well tolerated and improved hyperphagia and behavioral symptoms of PWS. ClinicalTrials.gov: NCT01968187FUNDING. The study was funded by Ferring Pharmaceuticals. Recruitment was aided by ongoing work in PWS performed through Eunice Kennedy Shriver National Institute of Child Health and Human Development grant U54 HD083211.

Growth charts for non-growth hormone treated Prader-Willi syndrome.

PubMed

Butler, Merlin G; Lee, Jaehoon; Manzardo, Ann M; Gold, June-Anne; Miller, Jennifer L; Kimonis, Virginia; Driscoll, Daniel J

2015-01-01

The goal of this study was to generate and report standardized growth curves for weight, height, head circumference, and BMI for non-growth hormone-treated white male and female US subjects with Prader-Willi syndrome (PWS) between 3 and 18 years of age and develop standardized growth charts. Anthropometric measures (N = 133) were obtained according to standard methods from 120 non-growth hormone-treated white subjects (63 males and 57 females) with PWS between 3 and 18 years of age. Standardized growth curves were developed for the third, 10th, 25th, 50th, 75th, 90th, and 97th percentiles by using the LMS method for weight, height, head circumference, and BMI for PWS subjects along with the normative third, 50th, and 97th percentiles from national and international growth data. The LMS smoothing procedure summarized the distribution of the anthropometric variables at each age using three parameters: power of the Box-Cox transformation λ (L), median μ (M) and coefficient of variation δ (S). Weight, height, head circumference, and BMI standardized growth charts representing 7 percentile ranges were developed from 120 non-growth hormone-treated white male and female US subjects with PWS (age range: 3-18 years) and normative third, 50th, and 97th percentiles from national and international data. We encourage the use of syndrome-specific growth standards to examine and evaluate subjects with PWS when monitoring growth patterns and determining nutritional and obesity status. These variables can be influenced by culture, individual medical care, diet intervention, and physical activity plans. Copyright © 2015 by the American Academy of Pediatrics.

Autism spectrum disorder in Prader-Willi syndrome: A systematic review.

PubMed

Bennett, Jeffrey A; Germani, Tamara; Haqq, Andrea M; Zwaigenbaum, Lonnie

2015-12-01

Prader-Willi syndrome (PWS) is a rare genetic disorder that results from lack of expression of paternally-derived genes on chromosome 15q11-13; caused by a deletion (DEL), uniparental disomy (UPD), or a rare imprinting center defect. PWS is associated with a distinct behavioral phenotype that in some respects overlaps with autism spectrum disorder (ASD), a neurodevelopmental disorder characterized by restricted or repetitive behaviors (RRBs) and social-communication impairment. The goal of this review was to (i) review published literature investigating core ASD symptoms in PWS and (ii) provide a prevalence estimate of ASD in PWS. Two independent reviewers searched Medline, CINAHL, PsychINFO, Embase, and Web of Science to find studies that answered the research questions. Individuals with PWS demonstrate significant levels of RRBs and social-communication impairment, in some reports reaching similar levels to those of non-PWS ASD comparison groups. Individuals with UPD had more social-communication impairment than those with DEL. Of 786 PWS participants, 210 (26.7%) were reported as meeting criteria for ASD, either based on clinical diagnosis or by exceeding clinical cut-points on relevant ASD symptom measures. In studies that distinguished genetic subtypes, rates of ASD were higher in individuals with PWS with UPD (67 of 190; 35.3%) than those with DEL (47 of 254; 18.5%). Published data on the association of PWS and ASD to date are limited to sample means of 8 years of age and older. Further research is needed to identify early markers of ASD in PWS children, to support earlier diagnosis and intervention for this important comorbidity. © 2015 Wiley Periodicals, Inc.

Increased plasma chemokine levels in children with Prader-Willi syndrome.

PubMed

Butler, Merlin G; Hossain, Waheeda; Sulsona, Carlos; Driscoll, Daniel J; Manzardo, Ann M

2015-03-01

Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes from the 15q11-q13 region and reportedly rearranged as a cause of autism. Additionally, increased inflammatory markers and features of autism are reported in PWS. Cytokines encoded by genes involved with inflammation, cell proliferation, migration, and adhesion play a role in neurodevelopment and could be disturbed in PWS as abnormal plasma cytokine levels are reported in autism. We analyzed 41 plasma cytokines in a cohort of well-characterized children with PWS between 5 and 11 years of age and unaffected unrelated siblings using multiplex sandwich immunoassays with the Luminex magnetic-bead based platform. Data were analyzed using ANOVA testing for effects of diagnosis, gender, body mass index (BMI) and age on the 24 cytokines meeting laboratory criteria for inclusion. No significant effects were observed for age, gender or BMI. The log-transformed levels of the 24 analyzable cytokines were examined simultaneously using MANOVA adjusting for age and gender and a main effect of diagnosis was found (P-value <0.03). Four of 24 plasma cytokine levels (MCP1, MDC, Eotaxin, RANTES) were significantly higher in children with PWS compared with controls and classified as bioinflammatory chemokines supporting a disturbed immune response unrelated to obesity status. BMI was not statistically different in the two subject groups (PWS or unaffected unrelated siblings) and chemokine levels were not correlated with percentage of total body fat. Additional studies are required to identify whether possible early immunological disturbances and chemokine inflammatory processes found in PWS may contribute to neurodevelopment and behavioral features. © 2015 Wiley Periodicals, Inc.

The neurobiological drive for overeating implicated in Prader-Willi syndrome.

PubMed

Zhang, Yi; Wang, Jing; Zhang, Guansheng; Zhu, Qiang; Cai, Weiwei; Tian, Jie; Zhang, Yi Edi; Miller, Jennifer L; Wen, Xiaotong; Ding, Mingzhou; Gold, Mark S; Liu, Yijun

2015-09-16

Prader-Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous fMRI studies examined the activation of eating-related neural circuits in PWS patients with or without exposures to food cues and found an excessive eating motivation and a reduced inhibitory control of cognitive processing of food. However, the effective connectivity between various brain areas or neural circuitry critically implicated in both the biological and behavioral control of overeating in PWS is largely unexplored. The current study combined resting-state fMRI and Granger causality analysis (GCA) techniques to investigate interactive causal influences among key neural pathways underlying overeating in PWS. We first defined the regions of interest (ROIs) that demonstrated significant alterations of the baseline brain activity levels in children with PWS (n = 21) as compared to that of their normal siblings controls (n = 18), and then carried out GCA to characterize the region-to-region interactions among these ROIs. Our data revealed significantly enhanced causal influences from the amygdala to the hypothalamus and from both the medial prefrontal cortex and anterior cingulate cortex to the amygdala in patients with PWS (P < 0.001). These alterations offer new explanations for hypothalamic regulation of homeostatic energy intake and impairment in inhibitory control circuit. The deficits in these dual aspects may jointly contribute to the extreme hyperphagia in PWS. This study provides both a new methodological and a neurobiological perspective to aid in a better understanding of neural mechanisms underlying obesity in the general public. This article is part of a Special Issue entitled 1618. Copyright © 2015 Elsevier B.V. All rights reserved.

Psychiatric Adverse Effects of Rimonobant in Adults with Prader-Willi syndrome

PubMed Central

Motaghedi, Roja; Lipman, Elizabeth G; Hogg, Jeannette E.; Christos, Paul J.; Vogiatzi, Maria G.; Angulo, Moris A.

2010-01-01

Background Prader Willi syndrome (PWS) without strict environmental modifications can lead to obesity associated with significant morbidity and mortality. In addition to increased appetite, these individuals have decreased energy expenditure with lower insulin like growth factor 1 (IGF-1), which contributes to adiposity. No effective treatment is available for this condition. Endocannabinoid receptor CB1 antagonist, rimonobant, has been effective for treatment of obesity in adult subjects. Rimonabant promotes weight loss by multiple proposed mechanisms, including decreased appetite and lipogenesis, and increased energy expenditure. Therefore, we conducted this pilot study to evaluate the effect of rimonabant on body weight and composition of adults with PWS. Method This was a double blind placebo controlled study. Body weight, total fat mass, fasting ghrelin, leptin, IGF1 and insulin like growth factor binding protein (IGFBP3) were collected at baseline, and after 90 and 180 days of treatment with placebo or 20 mg of rimonabant. Results Due to psychiatric adverse effects, 50% of subjects in the rimonabant group withdrew, and the study was terminated early (N=10) for safety concerns. There was a trend for weight loss, lower fat mass and higher IGF1 level at the end of study in this group. Leptin followed the fat mass and decreased with rimonabant treatment. Conclusion Rimonabant administration may be efficacious for weight loss in adults with PWS; unfortunately it is associated with an unacceptably high risk of psychiatric side effects. Future CB1 antagonists will need a better psychiatric profile before considered in the treatment of obesity in this genetic condition. PMID:20965292

Behavior in Prader-Willi syndrome: relationship to genetic subtypes and age.

PubMed

Dykens, Elisabeth M; Roof, Elizabeth

2008-09-01

Some behavioral features of Prader-Willi syndrome (PWS) are associated with the major genetic subtypes of this disorder. While most agree that those with maternal uniparental disomy (UPD) have a distinctive cognitive and psychiatric profile, findings are more controversial regarding possible differences among persons who vary in paternal deletion size. Caregivers of 88 persons with PWS aged 5 to 51 years (M = 22 years) were administered measures of problem behavior, compulsivity, hyperphagia, and adaptive skills. The sample was well characterized as having relatively large, Type I (n = 26) or smaller, Type II (n = 29) deletions, or UPD (n = 33). No significant behavioral differences were found between the Type I versus Type II deletion groups. Within each genetic subtype, however, differences emerged in how advancing age related to behavior. Although age did not emerge as a significant correlate of behavior in the Type II or UPD groups, in the Type I group age was consistently associated with lower problem behaviors, adaptive skills, and externalizing symptoms. Although differences between deletion subtypes were not found, significant within-subtype differences emerged in relationships between age and behavior. Negative associations between age and behavior in the Type I group only may relate to non-imprinted genes that are deleted in Type I but not Type II cases, including CYFIP1. Altered expression of CYFIP1 is seen in other developmental disabilities, including 15q disorders, and haploinsufficiency of CYFIP1 in Type I PWS cases may be associated with age-related phenotypic effects. Findings underscore the importance of a life-span perspective in phenotypic research.

Molecular and clinical overlap of Angelman and Prader-Willi syndrome phenotypes.

PubMed

Kirkilionis, A J; Chudley, A E; Gregory, C A; Hamerton, J L

1991-09-15

The Prader-Willi (PWS) and Angelman syndromes (AS) share the same apparent cytogenetic and molecular lesions of 15q11-13 and yet exhibit distinct clinical phenotypes. The etiology of PWS or AS appears to depend on the parental origin of the aberrant chromosome 15. Substantial clinical overlap has not been reported between deletion-positive PWS and AS patients. In the present study, we report the clinical, cytogenetic, and molecular findings in three AS patients. The first patient is a mentally retarded woman with a visible deletion of 15q11-13 with typical craniofacial, behavioral, and neurologic changes of AS. This patient is hyperphagic, and she is moderately obese for her height. Her hands and feet are small. These manifestations are more characteristic of PWS and not of AS. The molecular studies showed deletions of maternal origin for five distal PWCR loci. The most proximal locus, D15S18, was not deleted. These findings are identical to those found in our third AS patient who does not have any PWS features. To the best of our knowledge, this is the first report of concurrence of hyperphagia with consequent obesity and the AS phenotype in a patient with a del 15(q11-13) of maternal origin. These clinical findings suggest that overlap in the symptoms of PWS and AS can occur. Our second AS patient presents with atypical molecular findings in that he cannot be classed into any of the three proposed sub-groups of AS patients and may be representative of a fourth sub-group of AS patients.

Psychiatric disorders in a cohort of individuals with Prader-Willi syndrome.

PubMed

Shriki-Tal, L; Avrahamy, H; Pollak, Y; Gross-Tsur, V; Genstil, L; Hirsch, H J; Benarroch, F

2017-07-01

Psychiatric manifestations in Prader-Willi Syndrome (PWS) are common and often are the most debilitating problem in these individuals. We present an epidemiological nation-wide survey of psychiatric diagnoses in the PWS population, based on full-range psychiatric interviews. We studied the distribution of psychiatric diagnoses (as opposed to a symptom-based approach) in the Israel national cohort of adolescents and adults with PWS. There was a total of 53 (32 males) ages 12 years and older. All individuals and their caretakers were interviewed using standardized psychiatric questionnaires. Demographic and clinical variables, Clinical Global Impression (CGI) score, IQ, severity of hyperphagia and quality of life (QOL) were also assessed and correlations with NPD (number of psychiatric diagnoses) calculated. An overwhelming majority (89%) of the study participants had at least one psychiatric diagnosis. The most common were disruptive behavior disorders (DBD) (68%), obsessive compulsive disorder (OCD) (45%) and skin picking (35%). Individuals with DBD were at increased risk for OCD and skin picking. Psychotic disorders were found in 11%. NPD had a significant negative influence on QOL. There was no correlation between NPD and BMI, IQ, hyperphagia severity, hormonal profile or genetic subtypes. Psychiatric diagnoses are very frequent in PWS and strongly influence QOL. Furthermore, characterizing the profile of psychiatric comorbidity in PWS is crucial for planning effective interventions. Precise behavioral phenotyping in PWS in combination with a well-defined genetic etiology may aid biological research linking biological correlates to behavior. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Assessment of pretend play in Prader-Willi syndrome: a direct comparison to autism spectrum disorder.

PubMed

Zyga, Olena; Russ, Sandra; Ievers-Landis, Carolyn E; Dimitropoulos, Anastasia

2015-04-01

Children with Prader-Willi syndrome (PWS) are at risk for autism spectrum disorder (ASD), including pervasive social deficits. While play impairments in ASD are well documented, play abilities in PWS have not been evaluated. Fourteen children with PWS and ten children with ASD were administered the Autism Diagnostic Observation Schedule (ADOS) (Lord et al. in Autism Diagnostic Observation Schedule manual. Western Psychological Services, Los Angeles, 2006) as part of a larger project. A modified Affect in Play Scale (APS; Russ in Play in child development and psychotherapy: toward empirically supported practice. Lawrence Erlbaum Associates Publishers, Mahwah, 2004; Pretend play in childhood: foundation of adult creativity. APA Books, Washington, 2014) was used to score ADOS play activities. Results indicate both groups scored below normative data on measures of imagination, organization, and affective expression during individual play. In addition, the inclusion of a play partner in both groups increased all scaled scores on the APS. These findings suggest children with PWS show impaired pretend play abilities similar to ASD. Further research is warranted and should focus on constructing and validating programs aimed at improving symbolic and functional play abilities within these populations.

Congenital hypothyroidism due to ectopic sublingual thyroid gland in Prader-Willi Syndrome: a case report.

PubMed

Bocchini, Sarah; Fintini, Danilo; Grugni, Graziano; Boiani, Arianna; Convertino, Alessio; Crinò, Antonino

2017-09-22

Thyroid gland disorders are variably associated with Prader-Willi syndrome (PWS). Many of the clinical features in newborns with PWS are similar to those found in congenital hypothyroidism (CH). We report a case of a girl with CH and PWS. At the age of 9 months CH caused by an ectopic sublingual thyroid was diagnosed, and hormone replacement therapy was started. In spite of this treatment a decrease in growth velocity, weight excess and delayed development were observed. At the age of 9 years PWS was suspected on the basis of phenotype and genetic tests confirmed a maternal uniparental disomy of chromosome 15. This is the second reported case of hypothyroidism due to an ectopic sublingual thyroid gland in PWS suggesting that, although rare, an association between CH and PWS may exist. In our case diagnosis of PWS was delayed because mental retardation, hypotonia, obesity and short stature were initially attributed to hypothyroidism. In this context PWS should be considered in obese children with CH who do not improve adequately with l-thyroxine therapy. Also, thyroid function in all PWS children should be assessed regularly in order to avoid delayed diagnosis of hypothyroidism.

The relationship between specific cognitive impairment and behaviour in Prader-Willi syndrome.

PubMed

Woodcock, K A; Oliver, C; Humphreys, G W

2011-02-01

Individuals with Prader-Willi syndrome (PWS) have been shown to demonstrate a particular cognitive deficit in attention switching and high levels of preference for routine and temper outbursts. This study assesses whether a specific pathway between a cognitive deficit and behaviour via environmental interaction can exist in individuals with PWS. Four individuals with PWS participated in a series of three single-case experiments including laboratory-based and natural environment designs. Cognitive (computer-based) challenges placed varying demands on attention switching or controlled for the cognitive demands of the tasks while placing no demands on switching. Unexpected changes to routines or expectations were presented in controlled games, or imposed on participants' natural environments and compared with control conditions during which no unexpected changes occurred. Behaviour was observed and heart rate was measured. Participants showed significantly increased temper outburst related behaviours during cognitive challenges that placed demands on attention switching, relative to the control cognitive challenges. Participants showed significantly increased temper outburst related behaviours when unexpected changes occurred in an experimental or the natural environment compared with when no changes occurred. Difficult behaviours that could be triggered reliably in an individual by a specific cognitive demand could also be triggered via manipulation of the environment. Results suggest that a directional relationship between a specific cognitive deficit and behaviour, via environmental interaction, can exist in individuals with PWS. © 2011 The Authors. Journal of Intellectual Disability Research © 2011 Blackwell Publishing Ltd.

A mindfulness-based intervention for self-management of verbal and physical aggression by adolescents with Prader-Willi syndrome.

PubMed

Singh, Nirbhay N; Lancioni, Giulio E; Myers, Rachel E; Karazsia, Bryan T; Courtney, Theresa M; Nugent, Kristen

2017-07-01

There is a dearth of clinical and research literature on the treatment of maladaptive behaviors in adolescents with Prader-Willi syndrome (PWS). The purpose of this study was to evaluate the effectiveness of a mindfulness-based intervention, Meditation on the Soles of the Feet (SoF), to facilitate self-management of verbal and physical aggression. We utilized a multiple-baseline design across participants to test the intervention with three adolescents diagnosed with PWS. Relative to baseline, verbal aggression decreased to minimal levels following mindfulness-based practice and physical aggression was nearly eliminated. Intervention effects were maintained at 12-month follow-up. Quantitative analytics confirmed statistically significant outcomes. The SoF mindfulness intervention was effective in reducing verbal and physical aggression in three adolescents with PWS. Future research should test the SoF intervention with this clinical population in a larger clinical trial, and the SoF intervention may be applicable to other pediatric populations.

Obstructive sleep apnea syndrome in Prader-Willi Syndrome: an unrecognized and untreated cause of cognitive and behavioral deficits?

PubMed

Camfferman, Danny; Lushington, Kurt; O'Donoghue, Fergal; Doug McEvoy, R

2006-09-01

Prader-Willi Syndrome (PWS) is a rare genetic disorder characterized by a range of physical, psychological, and physiological abnormalities. It is also distinguished by the high prevalence of obstructive sleep apnea syndrome (OSAS), i.e., repetitive upper airway collapse during sleep resulting in hypoxia and sleep fragmentation. In non-PWS populations, OSAS is associated with a range of neurocognitive and psychosocial deficits. Importantly, these deficits are at least partly reversible following treatment. Given the findings in non-PWS populations, it is possible that OSAS may contribute to neurocognitive and psychosocial deficits in PWS. The present review examines this possibility. While acknowledging a primary contribution from the primary genetic abnormality to central neural dysfunction in PWS, we conclude that OSAS may be an important secondary contributing factor to reduced neurocognitive and psychosocial performance. Treatment of OSAS may have potential benefits in improving neurocognitive performance and behavior in PWS, but this awaits confirmatory investigation.

Genetic factors in human sleep disorders with special reference to Norrie disease, Prader-Willi syndrome and Moebius syndrome.

PubMed

Parkes, J D

1999-06-01

Sleep-wake problems are common in specific inborn errors of metabolism and structure of the central nervous system. Psychological factors, behavioural difficulties, metabolic disturbances, and widespread rather than focal damage to the nervous system are present in many of these diseases and all influence the sleep-wake cycle. However, a number of conditions cause relatively focal damage to the neuroanatomical substrate of sleeping and waking. These include fatal familial insomnia, with involvement of the prion protein gene on chromosome 20, Norrie disease, the Prader-Willi syndrome and the Moebius syndrome. The last three important conditions, although rare, are considered in detail in this review. They result in sensory deprivation, hypothalamic and mid-brain damage, and involve the X-chromosome, chromosome 15, and chromosome 13, respectively. These conditions cause a wide variety of sleep disturbance, including parasomnias, daytime sleepiness, and a condition like cataplexy. The place of the relevant gene products in normal sleep regulation needs further exploration.

The transition between the phenotypes of Prader-Willi syndrome during infancy and early childhood.

PubMed

Butler, Jill V; Whittington, Joyce E; Holland, Anthony J; McAllister, Catherine J; Goldstone, Anthony P

2010-06-01

Prader-Willi syndrome (PWS) is a genetic disorder historically characterized by two phenotypic stages. The early phenotype in infants is associated with hypotonia, poor suck, and failure to thrive. In later childhood, PWS is associated with intellectual disability, hyperphagia, as well as growth and sex hormone deficiency. Little is known about the transition between phenotypes. This study investigates the nature of the change in infancy and childhood PWS. Forty-six children (22 females, 24 males; mean age 2 y 9 mo, SD 18.9 mo; range 7 mo-5 y) with genetically confirmed PWS participated. Information was obtained on childhood height and weight, and eating behaviour from case notes and by parental interview. Weight standard deviation scores (SDS) started to exceed height by the end of the first year. Height SDS appeared to fall from near normal at birth until stabilizing below normal around 2 years. Half of the children whose body mass index (BMI) was higher than normal at interview had food interests greater than that of their peers, and the age at which increased age-appropriate eating was first noted was later than the increase of BMI SDS. Obesity may develop before the increased interest in food, suggesting underlying physiological factors independent of appetite control may be important.

Enhanced appetitive learning and reversal learning in a mouse model for Prader-Willi syndrome.

PubMed

Relkovic, Dinko; Humby, Trevor; Hagan, Jim J; Wilkinson, Lawrence S; Isles, Anthony R

2012-06-01

Prader-Willi syndrome (PWS) is caused by lack of paternally derived gene expression from the imprinted gene cluster on human chromosome 15q11-q13. PWS is characterized by severe hypotonia, a failure to thrive in infancy and, on emerging from infancy, evidence of learning disabilities and overeating behavior due to an abnormal satiety response and increased motivation by food. We have previously shown that an imprinting center deletion mouse model (PWS-IC) is quicker to acquire a preference for, and consume more of a palatable food. Here we examined how the use of this palatable food as a reinforcer influences learning in PWS-IC mice performing a simple appetitive learning task. On a nonspatial maze-based task, PWS-IC mice acquired criteria much quicker, making fewer errors during initial acquisition and also reversal learning. A manipulation where the reinforcer was devalued impaired wild-type performance but had no effect on PWS-IC mice. This suggests that increased motivation for the reinforcer in PWS-IC mice may underlie their enhanced learning. This supports previous findings in PWS patients and is the first behavioral study of an animal model of PWS in which the motivation of behavior by food rewards has been examined. © 2012 American Psychological Association

Weight control and behavior rehabilitation in a patient suffering from Prader Willi syndrome.

PubMed

Di Lorenzo, Rosaria; Sberveglieri, Sara; Marrama, Donatella; Landi, Giulia; Ferri, Paola

2016-04-01

This study reports a case of Prader Willi syndrome (PWS), a genomic imprinting disease related to chromosome regions 15q11.2-q13 15, which includes hypothalamic dysfunction leading to hyperphagia, obesity, shortness, sleep abnormalities. Our case is extremely severe, in comparison to other PWS cases described in literature, due to the association with severe emotional and psychiatric symptoms: oppositional behaviour, rigidity of thought, skin picking and pathological hoarding. We described the case of a Caucasian male patient suffering from PWS, treated in outpatient care by local Mental Health Centre and supported by Social Service, who was admitted to a residential rehabilitative facility. After a 2-year follow-up, the patient showed a global improvement in symptoms and functioning, as registered by the rating scales administered. At the end of observation period, we also reported an important improvement in weight control, reducing the risk of obesity and related diseases, therefore improving the prognosis of life. This case highlights the need for long-term, individualized and multi-professional treatment in patients suffering from a complex genetic syndrome with both organic and psychological alterations, for which medical care setting and pharmacological treatments are not sufficient. Clinical observation of this case leads us to compare PWS to drug addiction and indirectly endorse the neurophysiological hypothesis that food and drugs stimulate the same brain circuits in the limbic system.

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

PubMed

Wilson, Kathleen S; Wiersma, Lenny D; Rubin, Daniela A

2016-10-01

The purpose of this study was to evaluate the use of the Peds QL4.0 instrument to assess quality of life (QL) in children with Prader Willi Syndrome (PWS). This study also sought to compare differences in parent and child report as well as between children with PWS and without PWS. Parents and children with PWS (N=44) completed the PedsQL 4.0 instrument. A sub-sample of children completed the Peds QL 4.0 a second time to assess test-retest reliability. A comparison sample of children who were obese but without PWS (N=66) also completed the PedsQL 4.0. PedsQL 4.0 showed acceptable internal consistency for the child report (αs >0.72) and was acceptable for 4 out of the 6 scales for the parent report (αs >0.66). Test-retest reliability coefficients showed support for the reliability of the instrument (ICCs>0.64). Parents perceived lower QL than children with PWS. Children with PWS also showed lower QL than children without PWS. This study provides support for the use of the PedsQL 4.0 instrument in children with PWS. As observed in other populations, parents perceive a lower QL for their children with PWS than the children themselves. Copyright © 2016 Elsevier Ltd. All rights reserved.

Development of the eating behaviour in Prader-Willi Syndrome: advances in our understanding.

PubMed

McAllister, C J; Whittington, J E; Holland, A J

2011-02-01

Prader-Willi Syndrome (PWS) is a genetically determined neurodevelopmental disorder associated with mild to moderate intellectual disability, growth and sex-hormone deficiencies and a propensity to overeat that leads to severe obesity. The PWS phenotype changes from an early disinterest in food to an increasing pre-occupation with eating and a failure of the normal satiety response to food intake. The prevention of severe obesity is primarily through strict control of access to food and it is this aspect that most limits the independence of those with PWS. This review considers the eating disorder in PWS, specifically how the as yet uncertain genetics of the syndrome and the transition from the early to the later phenotype might account for the later hyperphagia. On the basis of behavioural and imaging studies, a failure of satiety and excessive activation of neural reward pathways have both been suggested. We speculate that the overeating behaviour, consequent upon one or other of the above, could either be due to a direct effect of the PWS genotype on the feeding pathways of the hypothalamus or a consequence of prenatal changes in the regulation of genes responsible for energy balance that sets a high satiation threshold. Understanding the overeating in PWS will lead to more focused and successful management and ultimately, treatment of this life-threatening behaviour.

Postural adaptations to long-term training in Prader-Willi patients.

PubMed

Capodaglio, Paolo; Cimolin, Veronica; Vismara, Luca; Grugni, Graziano; Parisio, Cinzia; Sibilia, Olivia; Galli, Manuela

2011-05-15

Improving balance and reducing risk of falls is a relevant issue in Prader-Willi Syndrome (PWS). The present study aims to quantify the effect of a mixed training program on balance in patients with PWS. Eleven adult PWS patients (mean age: 33.8 ± 4.3 years; mean BMI: 43.3 ± 5.9 Kg/m2) attended a 2-week training program including balance exercises during their hospital stay. At discharge, Group 1 (6 patients) continued the same exercises at home for 6 months, while Group 2 (5 patients) quitted the program. In both groups, a low-calorie, well-balanced diet of 1.200 kcal/day was advised. They were assessed at admission (PRE), after 2 weeks (POST1) and at 6-month (POST2). The assessment consisted of a clinical examination, video recording and 60-second postural evaluation on a force platform. Range of center of pressure (CoP) displacement in the antero-posterior direction (RANGEAP index) and the medio-lateral direction (RANGEML index) and its total trajectory length were computed. At POST1, no significant changes in all of the postural parameters were observed. At completion of the home program (POST2), the postural assessment did not reveal significant modifications. No changes in BMI were observed in PWS at POST2. Our results showed that a long-term mixed, but predominantly home-based training on PWS individuals was not effective in improving balance capacity. Possible causes of the lack of effectiveness of our intervention include lack of training specificity, an inadequate dose of exercise, an underestimation of the neural and sensory component in planning rehabilitation exercise and failed body weight reduction during the training. Also, the physiology of balance instability in these patients may possibly compose a complex puzzle not affected by our exercise training, mainly targeting muscle weakness.

Growth hormone therapy for Prader-willi syndrome: challenges and solutions.

PubMed

Grugni, Graziano; Sartorio, Alessandro; Crinò, Antonino

2016-01-01

Prader-Willi syndrome (PWS) is characterized by a dysregulation of growth hormone (GH)/insulin-like growth factor I axis, as the consequence of a complex hypothalamic involvement. PWS' clinical picture seems to resemble the classic non-PWS GH deficiency (GHD), including short stature, excessive body fat, decreased muscle mass, and impaired quality of life. GH therapy is able to ameliorate the phenotypic appearance of the syndrome, as well as to improve body composition, physical strength, and cognitive level. In this regard, however, some pathophysiologic and clinical questions still remain, representing a challenge to give the most appropriate care to PWS patients. Data about the prevalence of GHD in PWS children are not unequivocal, ranging from 40% to 100%. In this context, to establish whether the presence (or not) of GHD may have a different effect on clinical course during GH therapy may be helpful. In addition, the comparison of GH effects in PWS children diagnosed as small for gestational age with those obtained in subjects born appropriate for gestational age is of potential interest for future trials. Emerging information seems to demonstrate the maintenance of beneficial effects of GH therapy in PWS subjects after adolescent years. Thus, GH retesting after achievement of final height should be taken into consideration for all PWS patients. However, it is noteworthy that GH administration exerts positive effects both in PWS adults with and without GHD. Another critical issue is to clarify whether the genotype-phenotype correlations may be relevant to specific outcome measures related to GH therapy. Moreover, progress of our understanding of the role of GH replacement and concomitant therapies on bone characteristics of PWS is required. Finally, a long-term surveillance of benefits and risks of GH therapy is strongly recommended for PWS population, since most of the current studies are uncontrolled and of short duration.

Postural adaptations to long-term training in Prader-Willi patients

PubMed Central

2011-01-01

Background Improving balance and reducing risk of falls is a relevant issue in Prader-Willi Syndrome (PWS). The present study aims to quantify the effect of a mixed training program on balance in patients with PWS. Methods Eleven adult PWS patients (mean age: 33.8 ± 4.3 years; mean BMI: 43.3 ± 5.9 Kg/m2) attended a 2-week training program including balance exercises during their hospital stay. At discharge, Group 1 (6 patients) continued the same exercises at home for 6 months, while Group 2 (5 patients) quitted the program. In both groups, a low-calorie, well-balanced diet of 1.200 kcal/day was advised. They were assessed at admission (PRE), after 2 weeks (POST1) and at 6-month (POST2). The assessment consisted of a clinical examination, video recording and 60-second postural evaluation on a force platform. Range of center of pressure (CoP) displacement in the antero-posterior direction (RANGEAP index) and the medio-lateral direction (RANGEML index) and its total trajectory length were computed. Results At POST1, no significant changes in all of the postural parameters were observed. At completion of the home program (POST2), the postural assessment did not reveal significant modifications. No changes in BMI were observed in PWS at POST2. Conclusions Our results showed that a long-term mixed, but predominantly home-based training on PWS individuals was not effective in improving balance capacity. Possible causes of the lack of effectiveness of our intervention include lack of training specificity, an inadequate dose of exercise, an underestimation of the neural and sensory component in planning rehabilitation exercise and failed body weight reduction during the training. Also, the physiology of balance instability in these patients may possibly compose a complex puzzle not affected by our exercise training, mainly targeting muscle weakness. PMID:21575153

Academic underachievement by people with Prader-Willi syndrome.

PubMed

Whittington, J; Holland, A; Webb, T; Butler, J; Clarke, D; Boer, H

2004-02-01

Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder that is associated with the under-expression of maternally imprinted genes at the 15q11-q13 chromosomal locus. In addition to a characteristic physical and behavioural phenotype, those with the syndrome have impaired social cognition, literal mindedness and inflexibility. The present authors investigated the relationship between the PWS cognitive and behavioural phenotype, educational experience, and levels of attainment in reading, writing and arithmetic. All subjects from a population-based sample of people with PWS, augmented by those with PWS living in other regions together with a contrast group of people with learning disability (LD) of other aetiologies, are included in the present study. Those children over 3 years of age whose families consented or adults who themselves consented were assessed for ability and attainment (over 7 years of age), and information on functional ability was also obtained from an informant. Underachievement was defined as the difference between the score predicted from full-scale IQ and the actual achievement score. Commonly, levels of achievement were lower than would have been predicted on the basis of IQ among those in the groups with PWS and LD. In the group with PWS, underachievement across academic domains was positively correlated with the percentage of time in education in a special school and negatively correlated with Vineland Socialization domain standard score. There were no across-domain significant correlations in the group with LD. When using multiple regression analysis, the percentage of time in special school was the only predictor of underachievement and only in the group with PWS. However, some children with PWS in special schools did achieve as expected in at least one academic domain. Children with PWS may be placed in special schools largely because of their behavioural problems or physical disabilities, or expectations based

Gait patterns in Prader-Willi and Down syndrome patients

PubMed Central

2010-01-01

Background Prader-Willi (PWS) and Down Syndrome (DS) are two genetic disorders characterised by some common clinical and functional features. A quantitative description and comparison of their patterns would contribute to a deeper understanding of the determinants of motor disability in these two syndromes. The aim of this study was to measure gait pattern in PWS and DS in order to provide data for developing evidence-based deficit-specific or common rehabilitation strategies. Methods 19 PWS patients (17.7-40 yr) and 21 DS patients (18-39 yr) were evaluated with an optoelectronic system and force platforms for measuring kinematic and kinetic parameters during walking. The results were compared with those obtained in a group of normal-weight controls (Control Group: CG; 33.4 + 9.6 yr). Results and Discussion The results show that PWS and DS are characterised by different gait strategies. Spatio-temporal parameters indicated a cautious, abnormal gait in both groups, but DS walked with a less stable strategy than PWS. As for kinematics, DS showed a significantly reduced hip and knee flexion, especially at initial contact and ankle range of motion than PWS. DS were characterised by lower ranges of motion (p < 0.05) in all joints than CG and PWS. As for ankle kinetics, both PWS and DS showed a significantly lower push-off during terminal stance than CG, with DS yielding the lowest values. Stiffness at hip and ankle level was increased in DS. PWS showed hip stiffness values close to normal. At ankle level, stiffness was significantly decreased in both groups. Conclusions Our data show that DS walk with a less physiological gait pattern than PWS. Based on our results, PWS and DS patients need targeted rehabilitation and exercise prescription. Common to both groups is the aim to improve hypotonia, muscle strength and motor control during gait. In DS, improving pelvis and hip range of motion should represent a major specific goal to optimize gait pattern. PMID:20565926

Gait patterns in Prader-Willi and Down syndrome patients.

PubMed

Cimolin, Veronica; Galli, Manuela; Grugni, Graziano; Vismara, Luca; Albertini, Giorgio; Rigoldi, Chiara; Capodaglio, Paolo

2010-06-21

Prader-Willi (PWS) and Down Syndrome (DS) are two genetic disorders characterised by some common clinical and functional features. A quantitative description and comparison of their patterns would contribute to a deeper understanding of the determinants of motor disability in these two syndromes. The aim of this study was to measure gait pattern in PWS and DS in order to provide data for developing evidence-based deficit-specific or common rehabilitation strategies. 19 PWS patients (17.7-40 yr) and 21 DS patients (18-39 yr) were evaluated with an optoelectronic system and force platforms for measuring kinematic and kinetic parameters during walking. The results were compared with those obtained in a group of normal-weight controls (Control Group: CG; 33.4 + 9.6 yr). The results show that PWS and DS are characterised by different gait strategies. Spatio-temporal parameters indicated a cautious, abnormal gait in both groups, but DS walked with a less stable strategy than PWS. As for kinematics, DS showed a significantly reduced hip and knee flexion, especially at initial contact and ankle range of motion than PWS. DS were characterised by lower ranges of motion (p < 0.05) in all joints than CG and PWS. As for ankle kinetics, both PWS and DS showed a significantly lower push-off during terminal stance than CG, with DS yielding the lowest values. Stiffness at hip and ankle level was increased in DS. PWS showed hip stiffness values close to normal. At ankle level, stiffness was significantly decreased in both groups. Our data show that DS walk with a less physiological gait pattern than PWS. Based on our results, PWS and DS patients need targeted rehabilitation and exercise prescription. Common to both groups is the aim to improve hypotonia, muscle strength and motor control during gait. In DS, improving pelvis and hip range of motion should represent a major specific goal to optimize gait pattern.

[Prader-Willi and Angelman syndromes: 21 years of experience].

PubMed

Royo Pérez, D; Monge Galindo, L; López Pisón, J; Pérez Delgado, R; Lafuente Hidalgo, M; Peña Segura, J L; Miramar Gallart, M D; Rodriguez Valle, A; Calvo Martín, M T

2012-09-01

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) were the first syndromes in humans that were known to originate from the phenomenon of the genomic imprinting. We review our experience of 21 years with PWS and AS that were confirmed with the genetically. Of the 13,875 patients recorded during the study period, 11 were diagnosed with PWS (18%), 7 males (63.6%) and 4 females (36.4%), with a mean age of 9.06 years (+/- 6.92, range: 0.68-21.6). The time of the follow up of this group was 3.83 years (+/- 4.03, range: 0.49-15.3), and the age at diagnosis was 4.4 years (+/- 6.84, range: 0.03-19.38). Almost three quarters (72.7% of the PWS patients had a uniparental dysomy and 27.3% a paternal deletion. Six patients (8%) were diagnosed with AS, 4 females (66.6%) and 2 males (33.4%), with a mean age of 14.65 years (+/- 11.89, range: 1.3-30.7). The time of follow up was 6.76 years (+/- 5.89,range: 0.16-15), and the age at diagnosis was 8.84 years (+/- 9.11, range: 1.10-23). A maternal deletion was present in 83.3% of the AS patients and 16.7% had a maternal dysomy. As genetic advances are made these pathologies are confirmed before. Unlike the data in the literature, in our series most patients diagnosed with PWS (72'3%) had uniparental disomy. Recent studies correlation genotype with phenotype, in PWS is more serious if it occurs a deletion and in SA is milder in the case of uniparental disomy. Genetic studies must be performed in view of the established clinical symptoms: neonatal hypotonia of unknown cause in PWS and psychomotor deficits with autism features, particularly associated with epilepsy, must be evaluated in AS to prevent diagnostic uncertainties, unnecessary complementary examinations and to provide early genetic counselling. Copyright © 2011 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

What Are the Treatments for Prader-Willi Syndrome?

MedlinePlus

... GH therapy can help improve speech, improve abstract reasoning, and often allow information to be processed more ... Willi syndrome: A 4-year study. Journal of Clinical Endocrinology & Metabolism, 87 , 1581-1585. Buiting, K., Dittrich, ...

Growth hormone improves body composition and motor development in infants with Prader-Willi syndrome after six months.

PubMed

Whitman, Barbara; Carrel, Aaron; Bekx, Tracy; Weber, Colleen; Allen, David; Myers, Susan

2004-04-01

Infants with Prader-Willi syndrome (PWS) show abnormalities of body composition. Children with PWS treated with growth hormone (GH) demonstrate improved body composition and motor skills. To assess body composition and motor changes in infants with PWS following 6 months GH therapy. Twenty-five infants with PWS (mean age 15.5 mo) underwent dual energy X-ray absorptiometry (DEXA) assessment of body composition, and motor assessment with the Toddler Infant Motor Evaluation (TIME). Patients were then randomized to treatment (Genotropin, 1 mg/m2/day) or control, with reassessment at 6 months. GH treatment significantly increased lean body mass (6.4 +/- 2.4 kg to 8.9 +/- 2.7 kg) and decreased body fat (27.6 +/- 9.9% to 22.4 +/- 10.3%). Age equivalent motor scores improved 4 months in the treated group vs 2 months in controls (p < 0.01). Infants with PWS show significant body composition and motor development improvement following 6 months GH therapy. We are investigating whether this improvement leads to long-term reductions in obesity.

Unique and atypical deletions in Prader-Willi syndrome reveal distinct phenotypes.

PubMed

Kim, Soo-Jeong; Miller, Jennifer L; Kuipers, Paul J; German, Jennifer Ruth; Beaudet, Arthur L; Sahoo, Trilochan; Driscoll, Daniel J

2012-03-01

Prader-Willi syndrome (PWS) is a multisystem, contiguous gene disorder caused by an absence of paternally expressed genes within the 15q11.2-q13 region via one of the three main genetic mechanisms: deletion of the paternally inherited 15q11.2-q13 region, maternal uniparental disomy and imprinting defect. The deletion class is typically subdivided into Type 1 and Type 2 based on their proximal breakpoints (BP1-BP3 and BP2-BP3, respectively). Despite PWS being a well-characterized genetic disorder the role of the specific genes contributing to various aspects of the phenotype are not well understood. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is a recently developed technique that detects copy number changes and aberrant DNA methylation. In this study, we initially applied MS-MLPA to elucidate the deletion subtypes of 88 subjects. In our cohort, 32 had a Type 1 and 49 had a Type 2 deletion. The remaining seven subjects had unique or atypical deletions that were either smaller (n=5) or larger (n=2) than typically described and were further characterized by array-based comparative genome hybridization. In two subjects both the PWS region (15q11.2) and the newly described 15q13.3 microdeletion syndrome region were deleted. The subjects with a unique or an atypical deletion revealed distinct phenotypic features. In conclusion, unique or atypical deletions were found in ∼8% of the deletion subjects with PWS in our cohort. These novel deletions provide further insight into the potential role of several of the genes within the 15q11.2 and the 15q13.3 regions.

Anthropometric study with emphasis on hand and foot measurements in the Prader-Willi syndrome: sex, age and chromosome effects.

PubMed

Butler, M G; Haynes, J L; Meaney, F J

1991-01-01

Age, sex and chromosome effects on weight, height, sitting height, three head dimensions, and five hand and three foot measurements were analyzed from 57 patients (35 males and 22 females) with the Prader-Willi syndrome (PWS). No significant differences were observed in anthropometric data between PWS patients with the 15q chromosome deletion and those with normal chromosomes. Preschool children were found to have dolichocephaly, while hand and foot measurements, stature and sitting height were within normal range, although foot size was smaller than hand size in females when compared with PWS males. However, anthropometric measurements, excluding weight, head length and ankle breadth, were less than -2 SD in adult patients. Abnormal growth patterns apparently exist with significant negative correlations with age, particularly in PWS males, for height, sitting height, head circumference, and hand and foot measurements, but a significant positive correlation for weight was found in patients below 10 years of age.

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

PubMed

Bedogni, Giorgio; Grugni, Graziano; Tringali, Gabriella; Agosti, Fiorenza; Sartorio, Alessandro

2015-01-01

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. To test whether the estimation of FFM from bioelectrical impedance analysis (BIA) in PWS subjects requires population-specific equations. 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. 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). Population-specific equations are needed to estimate FFM from BIA in obese PWS women.

A novel deletion of SNURF/SNRPN exon 1 in a patient with Prader-Willi-like phenotype.

PubMed

Cao, Yang; AlHumaidi, Susan S; Faqeih, Eissa A; Pitel, Beth A; Lundquist, Patrick; Aypar, Umut

2017-08-01

Here we report the smallest deletion involving SNURF/SNRPN that causes major symptoms of Prader-Willi syndrome (PWS), including hypotonia, dysmorphic features, intellectual disability, and obesity. A female patient with the aforementioned and additional features was referred to the Mayo Clinic Cytogenetics laboratory for genetic testing. Chromosomal microarray analysis and subsequent Sanger sequencing identified a de novo 6.4 kb deletion at 15q11.2, containing exon 1 of the SNURF gene and exon 1 of the shortest isoform of the SNRPN gene. SNURF/SNRPN exon 1, which is methylated on the silent maternal allele, is associated with acetylated histones on the expressed paternal allele. This region also overlaps with the PWS-imprinting center (IC). Subsequent molecular methylation analysis was performed using methylation-specific MLPA (MS-MLPA), which characterized that the deletion of SNURF/SNRPN exon 1 was paternal in origin, consistent with the PWS-like phenotype. Since SNURF/SNRPN gene and the PWS-IC are known to regulate snoRNAs, it is likely that the PWS-like phenotype observed in patients with paternal SNURF/SNRPN deletion is due to the disrupted expression of SNORD116 snoRNAs. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Decreased Bone Mineral Density in Prader-Willi Syndrome: Comparison With Obese Subjects

PubMed Central

Butler, Merlin G.; Haber, Lawrence; Mernaugh, Ray; Carlson, Michael G.; Price, Ron; Feurer, Irene D.

2016-01-01

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. PMID:11745993

Regional cerebral blood flow and abnormal eating behavior in Prader-Willi syndrome.

PubMed

Ogura, Kaeko; Fujii, Toshikatsu; Abe, Nobuhito; Hosokai, Yoshiyuki; Shinohara, Mayumi; Fukuda, Hiroshi; Mori, Etsuro

2013-05-01

Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder and is generally regarded as a genetic model of obesity. Individuals with PWS exhibit behavioral symptoms including temper tantrums, rigid thinking, and compulsive behavior. The most striking feature of PWS is abnormal eating behavior, including hyperphagia, intense preoccupation with food, and incessant food seeking. To explore brain regions associated with the behavioral symptoms of PWS, we investigated differences in resting-state regional cerebral blood flow (rCBF) between individuals with PWS and healthy controls. Correlation analyses were also performed to examine the relationship between rCBF and altered eating behavior in PWS individuals. Twelve adults with PWS and 13 age- and gender-matched controls underwent resting-state single photon emission computerized tomography (SPECT) with N-isopropyl-p-[(123)I] iodoamphetamine (IMP). The rCBF data were analyzed on a voxel-by-voxel basis using SPM5 software. The results demonstrated that compared with controls, individuals with PWS had significantly lower rCBF in the right thalamus, left insular cortex, bilateral lingual gyrus, and bilateral cerebellum. They had significantly higher rCBF in the right inferior frontal gyrus, left middle/inferior frontal gyrus (anterior and posterior clusters), and bilateral angular gyrus. Additionally, rCBF in the left insula, which was significantly lower in PWS individuals, was negatively correlated with the eating behavior severity score. These results suggest that specific brain regions, particularly the left insula, may be partly responsible for the behavioral symptoms in PWS. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

A model to characterize psychopathological features in adults with Prader-Willi syndrome.

PubMed

Thuilleaux, Denise; Laurier, Virginie; Copet, Pierre; Tricot, Julie; Demeer, Geneviève; Mourre, Fabien; Tauber, Maithé; Jauregi, Joseba

2018-01-01

High prevalence of behavioral and psychiatric disorders in adults with Prader-Willi Syndrome (PWS) has been reported in last few years. However, data are confusing and often contradictory. In this article, we propose a model to achieve a better understanding of the psychopathological features in adults with PWS. The study is based on clinical observations of 150 adult inpatients, males and females. Non-parametric statistics were performed to analyse the association of psychopathological profiles with genotype, gender and age. We propose a model of psychiatric disorders in adults with PWS based on cognitive, emotional and behavioural issues. This model defines four psychopathological profiles: Basic, Impulsive, Compulsive, and Psychotic. The Basic profile is defined by traits and symptoms that are present in varying degrees in all persons with PWS. In our cohort, this Basic profile corresponds to 55% of the patients. The rest show, in addition to these characteristics, salient features of impulsivity (Impulsive profile, 19%), compulsivity (Compulsive profile, 7%), or psychosis (Psychotic profile, 19%). The analysis of factors associated with different profiles reveals an effect of genotype on Basic and Psychotic profiles (Deletion: 70% Basic, 9% Psychotic; Non-deletion: 23% Basic, 43% Psychotic) and a positive correlation between male sex and impulsivity, unmediated by sex hormone treatment. This is a clinical study, based on observation proposing an original model to understand the psychiatric and behavioural disorders in adults with PWS. Further studies are needed in order to test the validity of this model. © 2017 Wiley Periodicals, Inc.

Risk for ingestion of toxic substances in children with Prader-Willi syndrome.

PubMed

McCandless, Shawn E; Powell, Karen Potter; Sandberg, Ulrika

2012-11-01

Individuals with Prader-Willi syndrome (PWS) have several common findings that may predispose to ingestion of potentially dangerous items. This study examined whether individuals with PWS have an increased prevalence of toxic ingestions. A survey regarding history of ingestions in PWS individuals and sibling controls was designed, piloted, and distributed on-line. The subjects were individuals with PWS (N = 129). The subjects' non-PWS siblings served as controls (N = 134). Participants who completed the anonymous online survey were either the parents or the primary caretaker of individuals with PWS. Responses were submitted by 141 participants, providing information about 130 PWS subjects (M/F: 66:64) and 134 sibling controls. Subjects and controls ranged in age from 2 to 18 years at the time of the survey. Eleven participants did not answer the questions regarding ingestions. History of toxic ingestion was more prevalent in PWS subjects (20% vs. 2% of controls). Several features of PWS, including history of searching for food and eating unusual objects, along with decreased cognitive ability, appeared to associate with increased prevalence of toxic ingestion in PWS individuals. PWS children appear to have an ∼12-fold increased risk of ingesting toxins compared to the general population. Geneticists should include this information in counseling and in recommendations to primary care providers. Also, poison control centers need to be aware of this association and of the physiological and behavioral aspects of PWS that may complicate the diagnosis and management of a toxic ingestion. Copyright © 2012 Wiley Periodicals, Inc.

Experimental functional analysis of severe skin-picking behavior in Prader-Willi syndrome.

PubMed

Hall, Scott S; Hustyi, Kristin M; Chui, Clara; Hammond, Jennifer L

2014-10-01

Skin picking is an extremely distressing and treatment resistant behavior commonly shown by individuals with Prader-Willi syndrome (PWS). However, with the exception of a limited number of published single-case and survey studies, little is known about the environmental determinants of skin picking in this population. In this study, functional analyses were conducted with thirteen individuals with PWS, aged 6-23 years, who engaged in severe skin-picking behavior. In addition to the conditions typically employed in a functional analysis (i.e., alone, attention, play, demand), we included an ignore condition to examine potential effects of stimulus control by the presence of an adult. Twelve participants engaged in skin picking during the functional analysis, with the highest levels occurring in the alone and ignore conditions for eight participants, suggesting that skin picking in these participants was maintained by automatic reinforcement. For the remaining four participants, an undifferentiated pattern of low-rate skin picking was observed across conditions. These data confirm previous studies indicating that skin picking in PWS may be maintained most often by automatically produced sensory consequences. There were no associations between demographic characteristics of the participants (e.g., sex, age, IQ or BMI) and levels of skin picking observed in the functional analysis. Additional investigations are needed to identify the nature of the sensory consequences produced during episodes of skin picking in PWS. Behavioral interventions designed to extinguish or compete with the potential sensory consequences arising from skin picking in PWS are also warranted. Copyright © 2014 Elsevier Ltd. All rights reserved.

Special Care Dentistry in a Patient with Prader-Willi Syndrome through the Use of Atraumatic Restorative Treatment under General Anesthesia.

PubMed

Roman-Torres, Caio Vinícius Gonçalves; Kussaba, Sérgio Takashi; Bantim, Yasmin Comoti Vita; de Oliveira, Roberta de Barros Antunes Almeida

2017-01-01

Prader-Willi syndrome described in 1956 has a genetic origin, affecting both genders, varying in presence and intensity from individual to individual. A precocious diagnosis, before the manifestation of symptoms, has brought some improvement in the quality of life of the carriers in the last years. The objective of this case report was to describe the treatment realized in a 3-year-old boy who presented grade II obesity, difficulty of locomotion, hypotonia, and history of cardiopathy. A dental treatment under general anesthesia was defined, allowing an oral adequation in a single section, in which it was planned the extraction of the element 74 and atraumatic restorative treatment (ART) technique in the other teeth. The precocious intervention in this 3-year-old patient by the therapy realized with ART under general anesthesia was done with success, avoiding unnecessary extractions, preserving dental elements, and maintaining the oral cavity in adequate function.

MR of the pituitary in patients with Prader-Willi syndrome: size determination and imaging findings.

PubMed

Miller, L; Angulo, M; Price, D; Taneja, S

1996-01-01

Prader-Willi syndrome (PWS) is an unusual genetic disorder characterized by short stature, obesity, hypogonadism, hypotonia, cognitive impairment, and dysmorphic facies. There is an interstitial deletion of the proximal long arm of chromosome 15 in about 70 % of patients. Some of these clinical features suggest a central hypothalamic/pituitary dysfunction, and recent investigations have demonstrated a marked impairment in spontaneous growth hormone (GH) secretion. We studied 15 GH-deficient PWS patients by magnetic resonance imaging (MRI) to determine whether there was a diminution in the gross morphological size of the anterior pituitary gland, the site of GH synthesis. We also set out to catalog the pertinent imaging findings in this patient population. Our results indicate that this is the first report documenting pituitary size by MRI in PWS patients. No statistically significant difference was found in the height of the anterior pituitary gland in PWS patients compared with either normal children or children with isolated GH deficiency. An interesting imaging finding is that three of 15 patients (20 %) demonstrated complete absence of the posterior pituitary bright spot (PPBS), and a fourth patient demonstrated a small PPBS. These observations reflect an objective physiologic disturbance in the hypothalamus. The clinical and radiologic implications of these findings are discussed.

Clinical comparison of 59 Prader-Willi patients with and without the 15(q12) deletion.

PubMed

Wenger, S L; Hanchett, J M; Steele, M W; Maier, B V; Golden, W L

1987-12-01

Fifty-nine patients with Prader-Willi syndrome (PWS) (including three blacks) were enrolled in a behavior modification program including dietary restriction, nutritional education for self-management of food intake, and exercise. Caloric intake for most patients was 700-800 calories per day. The average stay per patient was 5 weeks with a mean weight loss of 6.6 kg. Thirty-one patients (53%) had apparently normal chromosomes compared to 25 patients (42%) with apparent 15(q12) deletion. Three patients had other chromosome abnormalities including two with mosaicism for idic(15)(q11) and one with a de novo apparently balanced translocation t(8q;18q). There were no differences in manifestations or the effects of the behavior modification program between chromosomally normal and abnormal patients. However, the mean weight loss in the 59 PWS patients was less than would have been expected based on their calculated daily caloric requirements suggesting that PWS patients have reduced caloric needs per unit of body weight compared to normal individuals. Supporting this also was that weight maintenance could be accomplished with only 1000 calories per day on the average. In general, behavioral response to the modification program was successful in that tantrum responses, while not eliminated, were reduced in frequency and severity.

Phenotype of a child with Angelman syndrome born to a woman with Prader-Willi syndrome.

PubMed

Ostergaard, John R

2015-09-01

This report describes the phenotype, from early childhood to adolescence, of a girl with Angelman syndrome (AS) born following a maternal transmission of a germline paternal 15q11.2-q13 deletion. During early childhood, she showed a typical AS phenotype, such as jerky movements, poor sleep, high voltage electroencephalography pattern, epilepsy, and a severe developmental disability. As she grew older, indications of phenotypical traits similar to Prader-Willi syndrome (PWS) appeared, in particular hyperphagic behavior and a body fat distribution similar to that reported in PWS. She generally showed cheerful AS behavior and had the characteristic outbursts of laughter, but her attitude to other people did not reflect the usual shared enjoyment of interaction seen in children with AS. In unfamiliar surroundings, she withdrew socially, similar to children with PWS, and her insistence on the same, rigid routines was similar to behavior patterns in PWS. The dysmorphic facial features that characterize AS were blurred in adolescence. The specified features that this AS patient had in common with PWS were hardly incidental and, if verified by upcoming case reports of children born to women with a paternal 15q11.2-q13 deletion, they may show new aspects of genetic imprinting. © 2015 Wiley Periodicals, Inc.

Long-term effects of recombinant human growth hormone therapy in children with Prader-Willi syndrome.

PubMed

Wolfgram, Peter M; Carrel, Aaron L; Allen, David B

2013-08-01

Recombinant human growth hormone (hGH) therapy in children with Prader-Willi syndrome (PWS) improves linear growth, body composition, physical strength and agility, and other metabolic parameters. These benefits must be weighed against potential adverse effects, including rare occurrences of sudden death. This review summarizes recent evidence important to a benefit-risk analysis of hGH use in children with PWS. Studies consistently show that hGH improves stature, body composition, fat percentage and distribution, and other metabolic markers in children with PWS. Preliminary reports of improved cognitive development during hGH have also emerged. Scoliosis progression is influenced by growth rate, but frequency of occurrence and severity are not increased by hGH exposure. PWS genotype does not appear to affect response to hGH. Concerns about hGH-associated sudden death persist, but recent studies show either absence of change in sleep-disordered breathing or improved sleep cardiovascular function during hGH therapy. Recent studies confirm and expand reported benefits of hGH therapy in children with PWS, including a possible salutary role in cognitive development. These findings support previous assertions that hGH can reduce morbidity and improve function in children with PWS, and suggest that potential risks of such treatment are favorably balanced by its benefits.

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome.

PubMed

Burnett, Lisa C; LeDuc, Charles A; Sulsona, Carlos R; Paull, Daniel; Rausch, Richard; Eddiry, Sanaa; Carli, Jayne F Martin; Morabito, Michael V; Skowronski, Alicja A; Hubner, Gabriela; Zimmer, Matthew; Wang, Liheng; Day, Robert; Levy, Brynn; Fennoy, Ilene; Dubern, Beatrice; Poitou, Christine; Clement, Karine; Butler, Merlin G; Rosenbaum, Michael; Salles, Jean Pierre; Tauber, Maithe; Driscoll, Daniel J; Egli, Dieter; Leibel, Rudolph L

2017-01-03

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell-derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p-/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p-/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p-/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH-releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency.

Deficiency in prohormone convertase PC1 impairs prohormone processing in Prader-Willi syndrome

PubMed Central

Burnett, Lisa C.; LeDuc, Charles A.; Sulsona, Carlos R.; Paull, Daniel; Rausch, Richard; Eddiry, Sanaa; Carli, Jayne F. Martin; Morabito, Michael V.; Skowronski, Alicja A.; Hubner, Gabriela; Zimmer, Matthew; Wang, Liheng; Day, Robert; Levy, Brynn; Dubern, Beatrice; Poitou, Christine; Clement, Karine; Rosenbaum, Michael; Salles, Jean Pierre; Tauber, Maithe; Egli, Dieter

2016-01-01

Prader-Willi syndrome (PWS) is caused by a loss of paternally expressed genes in an imprinted region of chromosome 15q. Among the canonical PWS phenotypes are hyperphagic obesity, central hypogonadism, and low growth hormone (GH). Rare microdeletions in PWS patients define a 91-kb minimum critical deletion region encompassing 3 genes, including the noncoding RNA gene SNORD116. Here, we found that protein and transcript levels of nescient helix loop helix 2 (NHLH2) and the prohormone convertase PC1 (encoded by PCSK1) were reduced in PWS patient induced pluripotent stem cell–derived (iPSC-derived) neurons. Moreover, Nhlh2 and Pcsk1 expression were reduced in hypothalami of fasted Snord116 paternal knockout (Snord116p–/m+) mice. Hypothalamic Agrp and Npy remained elevated following refeeding in association with relative hyperphagia in Snord116p–/m+ mice. Nhlh2-deficient mice display growth deficiencies as adolescents and hypogonadism, hyperphagia, and obesity as adults. Nhlh2 has also been shown to promote Pcsk1 expression. Humans and mice deficient in PC1 display hyperphagic obesity, hypogonadism, decreased GH, and hypoinsulinemic diabetes due to impaired prohormone processing. Here, we found that Snord116p–/m+ mice displayed in vivo functional defects in prohormone processing of proinsulin, pro-GH–releasing hormone, and proghrelin in association with reductions in islet, hypothalamic, and stomach PC1 content. Our findings suggest that the major neuroendocrine features of PWS are due to PC1 deficiency. PMID:27941249

Impairment of adipose tissue in Prader-Willi syndrome rescued by growth hormone treatment.

PubMed

Cadoudal, T; Buléon, M; Sengenès, C; Diene, G; Desneulin, F; Molinas, C; Eddiry, S; Conte-Auriol, F; Daviaud, D; Martin, P G P; Bouloumié, A; Salles, J-P; Tauber, M; Valet, P

2014-09-01

Prader-Willi syndrome (PWS) results from abnormalities in the genomic imprinting process leading to hypothalamic dysfunction with an alteration of growth hormone (GH) secretion. PWS is associated with early morbid obesity and short stature which can be efficiently improved with GH treatment. Our aims were to highlight adipose tissue structural and functional impairments in children with PWS and to study the modifications of those parameters on GH treatment. Plasma samples and adipose tissue biopsies were obtained from 23 research centers in France coordinated by the reference center for PWS in Toulouse, France. Lean controls (n=33), non-syndromic obese (n=53), untreated (n=26) and GH-treated PWS (n=43) children were enrolled in the study. Adipose tissue biopsies were obtained during scheduled surgeries from 15 lean control, 7 untreated and 8 GH-treated PWS children. Children with PWS displayed higher insulin sensitivity as shown by reduced glycemia, insulinemia and HOMA-IR compared with non-syndromic obese children. In contrast, plasma inflammatory cytokines such as TNF-α, MCP-1 and IL-8 were increased in PWS. Analysis of biopsies compared with control children revealed decreased progenitor cell content in the stromal vascular fraction of adipose tissue and an impairment of lipolytic response to β-adrenergic agonist in PWS adipocytes. Interestingly, both of these alterations in PWS seem to be ameliorated on GH treatment. Herein, we report adipose tissue dysfunctions in children with PWS which may be partially restored by GH treatment.

Aging in Prader-Willi syndrome: twelve persons over the age of 50 years.

PubMed

Sinnema, Margje; Schrander-Stumpel, Constance T R M; Maaskant, Marian A; Boer, Harm; Curfs, Leopold M G

2012-06-01

The life expectancy of persons with Prader-Willi syndrome (PWS) has increased in recent years. Because of the paucity of reports on older persons with PWS, the natural history, the onset, and type of age-related problems are poorly understood. Twelve persons with a genetically confirmed diagnosis of PWS aged over 50 years are described (4 deletion; 8 mUPD). Data on physical, behavioral, psychiatric, and aging characteristics were collected through semi-structured interviews with the individuals with PWS and their main carers. Cardiovascular diseases, diabetes, dermatological, and orthopedic problems were common physical complaints in older people with PWS. Functioning in activities of daily living, psychological functioning, physical functions, and care dependence were substantially worse in the older age group (50+) compared to the control group (18-49 years). Seven out of eight persons with mUPD had a history of psychiatric illness. Behavioral problems were observed in the older age group. Given the combination of age-related physical morbidity, physical appearance, behavioral and psychiatric problems, and functional decline in our cohort, we hypothesize that premature aging occurs in PWS. The care for older people with PWS requires a lifespan approach that recognizes the presence, progression, and consequences of specific morbidity. Special medical surveillance of people with PWS from 40 years onwards would ensure that intervention and support is offered with respect to specific areas of decline at the earliest possible time. Copyright © 2012 Wiley Periodicals, Inc.

Social responsiveness and competence in Prader-Willi syndrome: direct comparison to autism spectrum disorder.

PubMed

Dimitropoulos, Anastasia; Ho, Alan; Feldman, Benjamin

2013-01-01

Prader-Willi syndrome (PWS), a neurodevelopmental disorder primarily characterized by hyperphagia and food preoccupations, is caused by the absence of expression of the paternally active genes in the proximal arm of chromosome 15. Although maladaptive behavior and the cognitive profile in PWS have been well characterized, social functioning has only more recently been systematically examined. Findings to date indicate the social impairment exhibited may reflect specific difficulty interpreting and using social information effectively. In addition, evidence suggests that there is an increased risk of social deficits in people with the maternally-derived uniparental disomy (mUPD) subtype of PWS in comparison to those with 15q11-13 paternal deletion (DEL). Using the Social Responsiveness Scale (SRS) and the Social Competence Inventory, our goal was to compare social functioning in PWS to individuals with autism spectrum disorder (ASD). Participants with mUPD scored similarly to the ASD group across most SRS domains. All groups had difficulty with social competence, although the DEL group scored highest on prosocial behavior. Findings suggest further characterization of social behavior in PWS is necessary to aid in advancing the understanding of the contributions of genes in the 15q11-13 critical region to ASD susceptibility, particularly with respect to the overexpression of maternally expressed genes in this region, as well as aiding in awareness and development/implementation of interventions.

Comparison of phenotype in uniparental disomy and deletion Prader-Willi syndrome: Sex specific differences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mitchell, J.; Langlois, S.; Robinson, W.P.

1996-10-16

Prader-Willi syndrome (PWS) results primarily from either a paternal deletion of 15q11-q13 or maternal uniparental disomy (UPD) 15. Birth parameters and clinical presentation of 79 confirmed UPD cases and 43 deletion patients were compared in order to test whether any manifestations differ between the two groups. There were no major clinical differences between the two classes analyzed as a whole, other than the presence of hypopigmentation predominantly in the deletion group. However, there was a significant bias in sex-ratio (P<.001) limited to the UPD group with a predominance (68%) of males. An equal number of males and females was observedmore » in the deletion group. When analyzed by sex, several significant differences between the UPD and deletion groups were observed. Female UPD patients were found to be less severely affected than female deletion patients in terms of length of gavage feeding and a later onset of hyperphagia. Although these traits are likely to be influenced by external factors, they may reflect a milder presentation of female UPD patients which could explain the observed sex bias by causing under-ascertainment of female UPD. Alternatively, there may be an effect of sex on either early trisomy 15 survival or the probability of somatic loss of a chromosome from a trisomic conceptus. 26 refs., 1 tab.« less

Analysis of Circulating Mediators of Bone Remodeling in Prader-Willi Syndrome.

PubMed

Brunetti, G; Grugni, G; Piacente, L; Delvecchio, M; Ventura, A; Giordano, P; Grano, M; D'Amato, G; Laforgia, D; Crinò, A; Faienza, M F

2018-06-01

We tested the hypothesis that the levels of bone remodeling mediators may be altered in Prader-Willi syndrome (PWS). We assessed RANKL, OPG, sclerostin, DKK-1 serum levels, and bone metabolism markers in 12 PWS children (7.8 ± 4.3 years), 14 PWS adults (29.5 ± 7.2 years), and 31 healthy controls matched for sex and age. Instrumental parameters of bone mineral density (BMD) were also evaluated. Lumbar spine BMD Z-scores were reduced in PWS children (P < 0.01), reaching osteopenic levels in PWS adults. PWS patients showed lower 25(OH)-vitamin D serum levels than controls (P < 0.001). Osteocalcin was increased in PWS children but reduced in adults respect to controls (P < 0.005 and P < 0.01, respectively). RANKL levels were higher in both pediatric and PWS adults than controls (P < 0.004), while OPG levels were significantly reduced (P < 0.004 and P < 0.006, respectively). Sclerostin levels were increased in children (P < 0.04) but reduced in adults compared to controls (P < 0.01). DKK-1 levels did not show significant difference between patients and controls. In PWS patients, RANKL, OPG, and sclerostin significantly correlated with metabolic and bone instrumental parameters. Consistently, with adjustment for age, multiple linear regression analysis showed that BMD and osteocalcin were the most important predictors for RANKL, OPG, and sclerostin in children, and GH and sex steroid replacement treatment in PWS adults. We demonstrated the involvement of RANKL, OPG, and sclerostin in the altered bone turnover of PWS subjects suggesting these molecules as markers of bone disease and new potential pharmacological targets to improve bone health in PWS.

Ventilatory Responses During Submaximal Exercise in Children With Prader-Willi Syndrome.

PubMed

Hyde, Adam M; McMurray, Robert G; Chavoya, Frank A; Rubin, Daniela A

2018-02-27

Prader-Willi syndrome (PWS) is a genetic neurobehavioral disorder presenting hypothalamic dysfunction and adiposity. At rest, PWS exhibits hypoventilation with hypercapnia. We characterized ventilatory responses in children with PWS during exercise. Participants were children aged 7-12 years with PWS (n = 8) and without PWS with normal weight (NW; n = 9, body mass index ≤ 85th percentile) or obesity (n = 9, body mass index ≥ 95th percentile). Participants completed three 5-minute ambulatory bouts at 3.2, 4.0, and 4.8 km/h. Oxygen uptake, carbon dioxide output, ventilation, breathing frequency, and tidal volume were recorded. PWS had slightly higher oxygen uptake (L/min) at 3.2 km/h [0.65 (0.46-1.01) vs 0.49 (0.34-0.83)] and at 4.8 km/h [0.89 (0.62-1.20) vs 0.63 (0.45-0.97)] than NW. PWS had higher ventilation (L/min) at 3.2 km/h [16.2 (13.0-26.5) vs 11.5 (8.4-17.5)], at 4.0 km/h [16.4 (13.9-27.9) vs 12.7 (10.3-19.5)], and at 4.8 km/h [19.7 (17.4-31.8) vs 15.2 (9.5-21.6)] than NW. PWS had greater breathing frequency (breaths/min) at 3.2 km/h [38 (29-53) vs 29 (22-35)], at 4.0 km/h [39 (29-58) vs 29 (23-39)], and at 4.8 km/h [39 (33-58) vs 32 (23-42)], but similar tidal volume and ventilation/carbon dioxide output to NW. PWS did not show impaired ventilatory responses to exercise. Hyperventilation in PWS may relate to excessive neural stimulation and metabolic cost.

An Early Postnatal Oxytocin Treatment Prevents Social and Learning Deficits in Adult Mice Deficient for Magel2, a Gene Involved in Prader-Willi Syndrome and Autism.

PubMed

Meziane, Hamid; Schaller, Fabienne; Bauer, Sylvian; Villard, Claude; Matarazzo, Valery; Riet, Fabrice; Guillon, Gilles; Lafitte, Daniel; Desarmenien, Michel G; Tauber, Maithé; Muscatelli, Françoise

2015-07-15

Mutations of MAGEL2 have been reported in patients presenting with autism, and loss of MAGEL2 is also associated with Prader-Willi syndrome, a neurodevelopmental genetic disorder. This study aimed to determine the behavioral phenotype of Magel2-deficient adult mice, to characterize the central oxytocin (OT) system of these mutant mice, and to test the curative effect of a peripheral OT treatment just after birth. We assessed the social and cognitive behavior of Magel2-deficient mice, analyzed the OT system of mutant mice treated or not by a postnatal administration of OT, and determined the effect of this treatment on the brain. Magel2 inactivation induces a deficit in social recognition and social interaction and a reduced learning ability in adult male mice. In these mice, we reveal anatomical and functional modifications of the OT system and show that these defects change from birth to adulthood. Daily administration of OT in the first postnatal week was sufficient to prevent deficits in social behavior and learning abilities in adult mutant male mice. We show that this OT treatment partly restores a normal OT system. Thus, we report that an alteration of the OT system around birth has long-term consequences on behavior and on cognition. Importantly, an acute OT treatment of Magel2-deficient pups has a curative effect. Our study reveals that OT plays a crucial role in setting social behaviors during a period just after birth. An early OT treatment in this critical period could be a novel therapeutic approach for the treatment of neurodevelopmental disorders such as Prader-Willi syndrome and autism. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome.

PubMed

Duker, Angela L; Ballif, Blake C; Bawle, Erawati V; Person, Richard E; Mahadevan, Sangeetha; Alliman, Sarah; Thompson, Regina; Traylor, Ryan; Bejjani, Bassem A; Shaffer, Lisa G; Rosenfeld, Jill A; Lamb, Allen N; Sahoo, Trilochan

2010-11-01

Prader-Willi syndrome (PWS) is a neurobehavioral disorder manifested by infantile hypotonia and feeding difficulties in infancy, followed by morbid obesity secondary to hyperphagia. It is caused by deficiency of paternally expressed transcript(s) within the human chromosome region 15q11.2. PWS patients harboring balanced chromosomal translocations with breakpoints within small nuclear ribonucleoprotein polypeptide N (SNRPN) have provided indirect evidence for a role for the imprinted C/D box containing small nucleolar RNA (snoRNA) genes encoded downstream of SNRPN. In addition, recently published data provide strong evidence in support of a role for the snoRNA SNORD116 cluster (HBII-85) in PWS etiology. In this study, we performed detailed phenotypic, cytogenetic, and molecular analyses including chromosome analysis, array comparative genomic hybridization (array CGH), expression studies, and single-nucleotide polymorphism (SNP) genotyping for parent-of-origin determination of the 15q11.2 microdeletion on an 11-year-old child expressing the major components of the PWS phenotype. This child had an ∼236.29 kb microdeletion at 15q11.2 within the larger Prader-Willi/Angelman syndrome critical region that included the SNORD116 cluster of snoRNAs. Analysis of SNP genotypes in proband and mother provided evidence in support of the deletion being on the paternal chromosome 15. This child also met most of the major PWS diagnostic criteria including infantile hypotonia, early-onset morbid obesity, and hypogonadism. Identification and characterization of this case provide unequivocal evidence for a critical role for the SNORD116 snoRNA molecules in PWS pathogenesis. Array CGH testing for genomic copy-number changes in cases with complex phenotypes is proving to be invaluable in detecting novel alterations and enabling better genotype-phenotype correlations.

Are Angelman and Prader-Willi syndromes more similar than we thought? Food-related behavior problems in Angelman, Cornelia de Lange, fragile X, Prader-Willi and 1p36 deletion syndromes.

PubMed

Welham, Alice; Lau, Johnny; Moss, Joanna; Cullen, Jenny; Higgs, Suzanne; Warren, Gemma; Wilde, Lucy; Marr, Abby; Cook, Faye; Oliver, Chris

2015-03-01

Food-related behavior problems are well documented in Prader-Willi syndrome (PWS), with impaired satiety, preoccupation with food and negative food-related behaviors (such as taking and storing food) frequently reported as part of the behavioral phenotype of older children and adults. Food-related behavior problems in other genetic neurodevelopmental syndromes remain less well studied, including those seen in Angelman Syndrome (AS), the 'sister imprinted disorder' of PWS. Food-related behavior problems were assessed in 152 participants each with one of five genetic neurodevelopmental syndromes – PWS, AS, 1p36 deletion, Cornelia de Lange, and fragile X. Predictably, levels of food-related behavior problems reported in participants with PWS significantly exceeded those of at least one other groups in most areas (impaired satiety; preoccupation with food; taking and storing food; composite negative behavior). However, in some areas people with AS were reported to display food-related problems at least as severe as those with PWS, with the AS group reported to display significantly more food-related behavior problems than at least one comparison group on measures of taking and storing food, composite negative behaviors, impaired satiety and preoccupation with food. Over 50% of participants in the AS group scored above the median point of the distribution of PWS scores on a measure of taking and storing food. These findings indicate further investigation of eating problems in AS are warranted and have implications for current theoretical interpretations of the behavioral differences between AS and PWS. © 2015 Wiley Periodicals, Inc.

[Effect of psychotherapeutic interventions on weight reduction and personality development of a 13-year-old boy with Prader-Willi syndrome].

PubMed

Wurst, E; Möslinger, D; Widhalm, K

1992-01-01

A 12.10-year old boy (actual weight 88.8 kg, actual height 131.2 cm; 228% overweight) with Prader-Willi-syndrome achieved, after repeated ineffective therapy attempts over a period of 10 years, a weight reduction of 11.8 kg (185% overweight) during a 9-week in-patient treatment. In the following out-patient phase of therapy a further weight reduction of 20 kg (109% overweight) was achieved over a period of 16 months. Apart from the usual modes of action of therapy (reduced energy intake, physical exercise, behaviour modification), family therapeutic and special education interventions were used. These achieved an improvement of the patient's self-esteem, an increase in his competence to act and in his autonomy concerning his diet management, as well as a positive experience of his own abilities and social acceptance by other children and the stabilisation of the dysfunctional family system. It may be assumed that this therapeutic success is dependent on consequent compliance with the system model.

Leisure Activities in Prader-Wlli Syndrome: Implications for Health, Cognition and Adaptive Functioning

ERIC Educational Resources Information Center

Dykens, Elisabeth M.

2014-01-01

Although hyperphagia and compulsivity in Prader-Willi syndrome (PWS) are well described, recreation and adaptive skills are relatively unexplored. Parents of 123 participants with PWS (4--48 years) completed measures of their child's adaptive, recreation, and problem behaviors. Offspring received cognitive testing. Watching TV was the most…

Water intake and risk of hyponatraemia in Prader-Willi syndrome.

PubMed

Akefeldt, A

2009-06-01

Unusual water intake and drinking behaviour has occasionally been observed in individuals with Prader-Willi syndrome (PWS). The aim of this study is to explore whether this observation is a part of the PWS phenotype and what the consequences may be. The parents of 51 individuals with PWS (age range 2-40 years) were asked by questionnaire to answer on past and present water intake, drinking behaviour, fluid preferences and medical treatment in their PWS-affected and unaffected children. Questionnaires with information on 47 PWS individuals and 17 without PWS were returned for analysis. The questionnaire information was complemented with information from the individual's medical records. Siblings to PWS individuals made up the control group. The study was approved by the regional medical research ethics committee. During infancy, 36 (76%) individuals with PWS disliked water without any flavouring and had an extremely small daily intake of water. Seven individuals (15%) increased the daily water intake to unusually high amounts. In 45 the clinical PWS diagnosis was confirmed by molecular (genetic) testing: nine of them with a confirmed PWS diagnosis had a deletion of chromosome 15q11-13, in nine individuals no deletion was identified. The majority of individuals who increased their water consumption to extreme values belonged to the non-deletion group. Two in the non-deletion group developed hyponatraemia while receiving psychiatric medication. Infants with PWS seem to be predisposed to unusual drinking behaviour. They dislike and have an unusually small intake of pure water without flavouring, and most of them continue this even after infancy. Some individuals, especially those without deletion, increase their fluid intake and also accept pure water. They have an increased risk of developing water retention and severe hyponatraemia if exposed to medication known to cause side effects like the syndrome of inappropriate antidiuretic hormone secretion. Perhaps this

Clinical Application of an Innovative Multiplex-Fluorescent-Labeled STRs Assay for Prader-Willi Syndrome and Angelman Syndrome.

PubMed

Zhang, Kaihui; Liu, Shu; Feng, Bing; Yang, Yali; Zhang, Haiyan; Dong, Rui; Liu, Yi; Gai, Zhongtao

2016-01-01

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two clinically distinct neurodevelopmental disorders caused by absence of paternally or maternally expressed imprinted genes on chr15q11.2-q13.3. Three mechanisms are known to be involved in the pathogenesis: microdeletions, uniparental disomy (UPD) and imprinting defects. Both disorders are difficult to be definitely diagnosed at early age if no available molecular cytogenetic tests. In this study, we identified 5 AS patients with the maternal deletion and 26 PWS patients with paternal deletion on chr15q11-q13 by using an innovative multiplex-fluorescent-labeled short tandem repeats (STRs) assay based on linkage analysis, and validated by the methylation-specific PCR and array comparative genomic hybridization techniques. More interesting, one of these PWS patients was confirmed as maternal uniparental isodisomy by the STR linkage analysis. The phenotypic and genotypic characteristics of these individuals were also presented. Our results indicate that the new linkage analysis is much faster and easier for large-scale screening deletion and uniparental disomy, thus providing a valuable method for early diagnosis of PWS/AS patients, which is critical for genetic diagnosis, management and improvement of prognosis.

Clinical Application of an Innovative Multiplex-Fluorescent-Labeled STRs Assay for Prader-Willi Syndrome and Angelman Syndrome

PubMed Central

Feng, Bing; Yang, Yali; Zhang, Haiyan; Dong, Rui; Liu, Yi; Gai, Zhongtao

2016-01-01

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are two clinically distinct neurodevelopmental disorders caused by absence of paternally or maternally expressed imprinted genes on chr15q11.2-q13.3. Three mechanisms are known to be involved in the pathogenesis: microdeletions, uniparental disomy (UPD) and imprinting defects. Both disorders are difficult to be definitely diagnosed at early age if no available molecular cytogenetic tests. In this study, we identified 5 AS patients with the maternal deletion and 26 PWS patients with paternal deletion on chr15q11-q13 by using an innovative multiplex-fluorescent-labeled short tandem repeats (STRs) assay based on linkage analysis, and validated by the methylation-specific PCR and array comparative genomic hybridization techniques. More interesting, one of these PWS patients was confirmed as maternal uniparental isodisomy by the STR linkage analysis. The phenotypic and genotypic characteristics of these individuals were also presented. Our results indicate that the new linkage analysis is much faster and easier for large-scale screening deletion and uniparental disomy, thus providing a valuable method for early diagnosis of PWS/AS patients, which is critical for genetic diagnosis, management and improvement of prognosis. PMID:26841067

Change in prevalence of congenital defects in children with Prader-Willi syndrome.

PubMed

Torrado, M; Foncuberta, M E; Perez, M F de Castro; Gravina, L P; Araoz, H V; Baialardo, E; Chertkoff, L P

2013-02-01

The aim of this study was to assess the prevalence of congenital defects observed in patients with Prader-Willi syndrome (PWS) and to compare this prevalence with that described in the general population. In addition, these findings were correlated with the different etiologic subtypes. A total of 180 children with PWS followed for 13 years were included in this study. Diagnosis was confirmed by the methylation test, and genetic subtypes were established by using fluorescence in situ hybridization or multiplex ligation-dependent probe amplification and microsatellite analyses. The prevalence of congenital defects was compared with national and international registries of congenital defects in the general population (Estudio Colaborativo Latinoamericano de Malformaciones Congénitas, European Surveillance of Congenital Anomalies, and the New York Registry). Twenty-two percent of the patients presented congenital defects with a risk of 5.4 to 18.7 times higher than that of the general population. The most frequent congenital defects were heart defects, renoureteral malformations, vertebral anomalies, hip dysplasia, clubfoot, and agenesis/hypoplasia of the corpus callosum. Each of these congenital defects was significantly more frequent in the children with PWS than in the general population. The congenital heart defects were more frequent in girls than in boys with PWS. No significant differences were found when the defects were correlated with the different etiologic subtypes. An increased prevalence of congenital defects was found in our PWS patients. This finding suggests the need for further studies in PWS children that allow physicians to detect the congenital defects found in this series and, thus, to anticipate complications, with the ultimate aim of enhancing the management of PWS patients.

Induced Pluripotent Stem Cells Can Be Used to Model the Genomic Imprinting Disorder Prader-Willi Syndrome*

PubMed Central

Yang, Jiayin; Cai, Jie; Zhang, Ya; Wang, Xianming; Li, Wen; Xu, Jianyong; Li, Feng; Guo, Xiangpeng; Deng, Kang; Zhong, Mei; Chen, Yonglong; Lai, Liangxue; Pei, Duanqing; Esteban, Miguel A.

2010-01-01

The recent discovery of induced pluripotent stem cell (iPSC) technology provides an invaluable tool for creating in vitro representations of human genetic conditions. This is particularly relevant for those diseases that lack adequate animal models or where the species comparison is difficult, e.g. imprinting diseases such as the neurogenetic disorder Prader-Willi syndrome (PWS). However, recent reports have unveiled transcriptional and functional differences between iPSCs and embryonic stem cells that in cases are attributable to imprinting errors. This has suggested that human iPSCs may not be useful to model genetic imprinting diseases. Here, we describe the generation of iPSCs from a patient with PWS bearing a partial translocation of the paternally expressed chromosome 15q11-q13 region to chromosome 4. The resulting iPSCs match all standard criteria of bona fide reprogramming and could be readily differentiated into tissues derived from the three germ layers, including neurons. Moreover, these iPSCs retain a high level of DNA methylation in the imprinting center of the maternal allele and show concomitant reduced expression of the disease-associated small nucleolar RNA HBII-85/SNORD116. These results indicate that iPSCs may be a useful tool to study PWS and perhaps other genetic imprinting diseases as well. PMID:20956530

Small gray matter volume in orbitofrontal cortex in Prader-Willi syndrome: a voxel-based MRI study.

PubMed

Ogura, Kaeko; Fujii, Toshikatsu; Abe, Nobuhito; Hosokai, Yoshiyuki; Shinohara, Mayumi; Takahashi, Shoki; Mori, Etsuro

2011-07-01

Prader-Willi syndrome (PWS) is a genetically determined neurodevelopmental disorder presenting with behavioral symptoms including hyperphagia, disinhibition, and compulsive behavior. The behavioral problems in individuals with PWS are strikingly similar to those in patients with frontal pathologies, particularly those affecting the orbitofrontal cortex (OFC). However, neuroanatomical abnormalities in the frontal lobe have not been established in PWS. The aim of this study was to look, using volumetric analysis, for morphological changes in the frontal lobe, especially the OFC, of the brains of individuals with PWS. Twelve adults with PWS and 13 age- and gender-matched control subjects participated in structural magnetic resonance imaging (MRI) scans. The whole-brain images were segmented and normalized to a standard stereotactic space. Regional gray matter volumes were compared between the PWS group and the control group using voxel-based morphometry. The PWS subjects showed small gray-matter volume in several regions, including the OFC, caudate nucleus, inferior temporal gyrus, precentral gyrus, supplementary motor area, postcentral gyrus, and cerebellum. The small gray-matter volume in the OFC remained significant in a separate analysis that included total gray matter volume as a covariate. These preliminary findings suggest that the neurobehavioral symptoms in individuals with PWS are related to structural brain abnormalities in these areas. Copyright © 2010 Wiley-Liss, Inc.

Impact of molecular mechanisms, including deletion size, on Prader-Willi syndrome phenotype: study of 75 patients.

PubMed

Varela, M C; Kok, F; Setian, N; Kim, C A; Koiffmann, C P

2005-01-01

Prader-Willi syndrome (PWS) can result from a 15q11-q13 paternal deletion, maternal uniparental disomy (UPD), or imprinting mutations. We describe here the phenotypic variability detected in 51 patients with different types of deletions and 24 patients with UPD. Although no statistically significant differences could be demonstrated between the two main types of PWS deletion patients, it was observed that type I (BP1-BP3) patients acquired speech later than type II (BP2-BP3) patients. Comparing the clinical pictures of our patients with UPD with those with deletions, we found that UPD children presented with lower birth length and started walking earlier and deletion patients presented with a much higher incidence of seizures than UPD patients. In addition, the mean maternal age in the UPD group was higher than in the deletion group. No statistically significant differences could be demonstrated between the deletion and the UPD group with respect to any of the major features of PWS. In conclusion, our study did not detect significant phenotypic differences among type I and type II PWS deletion patients, but it did demonstrate that seizures were six times more common in patients with a deletion than in those with UPD.

Silent aspiration in infants with Prader-Willi syndrome identified by videofluoroscopic swallow study.

PubMed

Salehi, Parisa; Stafford, Holly J; Glass, Robin P; Leavitt, Anne; Beck, Anita E; McAfee, Amber; Ambartsumyan, Lusine; Chen, Maida

2017-12-01

Feeding intolerance in Prader-Willi syndrome (PWS) infants is well-recognized, but their swallow physiology is not well understood. Swallow dysfunction increases risks of respiratory compromise and choking, which have a high incidence in PWS. To investigate swallow pathology in PWS infants we undertook a retrospective review of videofluoroscopic swallow studies (VFSS) in infants with PWS seen at our institution. We hypothesize that VFSS will characterize swallow pathology suspected by clinical observation during a feeding evaluation and may help determine feeding safety in these infants.Retrospective review of 23 VFSS on 10 PWS infants (average age 9.7 ± 8.4 months; range 3 weeks-29 months). Logistic regression models evaluated associations between gender, genetic subtype, and growth hormone (GH) use on aspiration incidence. Polysomnographic (PSG) studies conducted on the same participant ±1 year from VFSS were examined to characterize respiratory abnormalities.There was a high rate of swallowing dysfunction (pharyngeal residue 71%, aspiration events 87%) and disordered sleep. All aspiration events were silent. There were no differences in rates of aspiration for gender, genetic subtype, or GH use.A high incidence of aspiration was identified indicating swallow dysfunction may frequently be present in infants with PWS. Comprehensive evaluation of feeding and swallowing is essential and requires a multidisciplinary approach. Providers should recognize risk factors for swallow dysfunction and consider a multidisciplinary approach to guide decision making and optimize feeding safety in PWS. Copyright © 2017 The Authors. Published by Wolters Kluwer Health, Inc. All rights reserved.

Cognitive deficits in the Snord116 deletion mouse model for Prader-Willi syndrome.

PubMed

Adhikari, Anna; Copping, Nycole A; Onaga, Beth; Pride, Michael C; Coulson, Rochelle L; Yang, Mu; Yasui, Dag H; LaSalle, Janine M; Silverman, Jill L

2018-05-23

Prader-Willi syndrome (PWS) is an imprinted neurodevelopmental disease caused by a loss of paternal genes on chromosome 15q11-q13. It is characterized by cognitive impairments, developmental delay, sleep abnormalities, and hyperphagia often leading to obesity. Clinical research has shown that a lack of expression of SNORD116, a paternally expressed imprinted gene cluster that encodes multiple copies of a small nucleolar RNA (snoRNA) in both humans and mice, is most likely responsible for many PWS symptoms seen in humans. The majority of previous research using PWS preclinical models focused on characterization of the hyperphagic and metabolic phenotypes. However, a crucial understudied clinical phenotype is cognitive impairments and thus we investigated the learning and memory abilities using a model of PWS, with a heterozygous deletion in Snord116. We utilized the novel object recognition task, which doesn't require external motivation, or exhaustive swim training. Automated findings were further confirmed with manual scoring by a highly trained blinded investigator. We discovered deficits in Snord116+/- mutant mice in the novel object recognition, location memory and tone cue fear conditioning assays when compared to age-, sex- matched, littermate control Snord116+/+ mice. Further, we confirmed that despite physical neo-natal developmental delays, Snord116+/- mice had normal exploratory and motor abilities. These results show that the Snord116+/- deletion murine model is a valuable preclinical model for investigating learning and memory impairments in individuals with PWS without common confounding phenotypes. Copyright © 2018 Elsevier Inc. All rights reserved.

Necdin, a Prader-Willi syndrome candidate gene, regulates gonadotropin-releasing hormone neurons during development.

PubMed

Miller, Nichol L G; Wevrick, Rachel; Mellon, Pamela L

2009-01-15

Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by hyperphagia, obesity and hypogonadotrophic hypogonadism, all highly suggestive of hypothalamic dysfunction. The NDN gene, encoding the MAGE family protein, necdin, maps to the PWS chromosome region and is highly expressed in mature hypothalamic neurons. Adult mice lacking necdin have reduced numbers of gonadotropin-releasing hormone (GnRH) neurons, but the mechanism for this reduction is unknown. Herein, we show that, although necdin is not expressed in an immature, migratory GnRH neuronal cell line (GN11), high levels are present in a mature GnRH neuronal cell line (GT1-7). Furthermore, overexpression of necdin activates GnRH transcription through cis elements bound by the homeodomain repressor Msx that are located in the enhancer and promoter of the GnRH gene, and knock-down of necdin expression reduces GnRH gene expression. In fact, overexpression of Necdin relieves Msx repression of GnRH transcription through these elements and necdin co-immunoprecipitates with Msx from GnRH neuronal cells, indicating that necdin may activate GnRH gene expression by preventing repression of GnRH gene expression by Msx. Finally, necdin is necessary for generation of the full complement of GnRH neurons during mouse development and extension of GnRH axons to the median eminence. Together, these results indicate that lack of necdin during development likely contributes to the hypogonadotrophic hypogonadal phenotype in individuals with PWS.

A modified MS-PCR approach to diagnose patients with Prader-Willi and Angelman syndrome.

PubMed

Dos Santos, Jéssica Fernandes; Mota, Laís R; Rocha, Pedro Henrique Silva Andrade; Ferreira de Lima, Renata Lúcia L

2016-11-01

Prader-Willi (PWS) and Angelman (AS) syndromes are clinically distinct neurodevelopmental genetic diseases with multiple phenotypic manifestations. They are one of the most common genetic syndromes caused by non-Mendelian inheritance in the form of genomic imprinting, and can be attributable to the loss of gene expression due to imprinting within the chromosomal region 15q11-q13. Clinical diagnosis of PWS and AS is challenging, and the use of molecular and cytomolecular studies is recommended to help in determining the diagnosis of these conditions. The methylation analysis is a sensible approach; however there are several techniques for this purpose, such as the methylation-sensitive polymerase chain reaction (MS-PCR). This study aims to optimize the MS-PCR assay for the diagnosis of potential PWS and AS patients using DNA modified by sodium bisulfite. We used the MS-PCR technique of PCR described by Kosaki et al. (1997) adapted with betaine. All different concentrations of betaine used to amplify the methylated and unmethylated chromosomal region 15q11-q13 on the gene SNRPN showed amplification results, which increased proportionally to the concentration of betaine. The methylation analysis is a technically robust and reproducible screening method for PWS and AS. The MS-PCR assures a faster, cheaper and more efficient method for the primary diagnosis of the SNRPN gene in cases with PWS and AS, and may detect all of the three associated genetic abnormalities: deletion, uniparental disomy or imprinting errors.

Developmental profiles and mentality in preschool children with Prader-Willi syndrome: a preliminary study.

PubMed

Chen, Chien-Min; Chen, Chia-Ling; Hou, Jia-Woei; Hsu, Hung-Chih; Chung, Chia-Ying; Chou, Shih-Wei; Lin, Chu-Hsu; Chen, Kai-Hua

2010-01-01

A majority of the children with Prader-Willi syndrome (PWS) have global developmental delay and mental delay. The aim of this study was to investigate the developmental profiles and mental assessments among preschool children with PWS. Ten children with PWS between the ages of 15 months to 6 years, and 11 children with typical development were enrolled. Developmental profiles in terms of their developmental quotient (DQ) for the eight domains of the Chinese Children Developmental Inventory (CCDI) and mental assessments in terms of intelligence quotient (IQ) and developmental index (DI) were carried out for all children. The DQs of all eight domains, including gross motor, fine motor, expressive language, concept comprehension, situation comprehension, self help, personal- social and general development, in the PWS group were lower than the DQs of the children from the typical development group (p < 0.01). Children with PWS had better DQs in the fine motor domain than in the gross motor domain and in the receptive language domain than in the expressive language domain. Furthermore, their verbal IQ were better than their performance IQ and their mental DI was better than their psychomotor DI. These findings suggest that the children with PWS show an uneven global developmental delay together with an uneven mental delay. The results of this study should allow clinicians to better understand the developmental functioning of children with PWS and this will help with the planning of treatment strategies.

Adiposity indices in German children and adolescents with genetically confirmed Prader-Willi syndrome (PWS).

PubMed

Hauffa, B P; Schlippe, G; Gillessen-Kaesbach, G

2001-05-01

Morbid obesity develops as a result of hyperphagia and compulsive eating behavior in patients with Prader-Willi syndrome (PWS), if caloric intake is not rigorously controlled. PWS-specific centile curves for adiposity indices constructed in the past were based on clinically diagnosed patients. With the advent of molecular genetic methods, allowing for an unequivocal diagnosis, new PWS curves based exclusively on molecularly diagnosed patients are becoming available, eliminating a potential diagnostic bias. To compare fat distribution in molecularly confirmed German PWS patients to that of clinically diagnosed American PWS patients and a healthy reference population. Cross-sectional anthropometric study. One hundred German patients (49 F) with molecularly confirmed PWS (age: <30 y). Triceps (subscapular) skinfold thickness, waist and hip circumference. Skinfold thickness was massively elevated in the majority of the molecularly confirmed German PWS patients compared to a healthy reference population. Whereas triceps skinfold thickness was in good agreement with American PWS patients, subscapular skinfold thickness in German girls rose earlier than in American PWS girls, indicating possible differences between caloric intake or the proportion of patients entering puberty spontaneously. Waist circumference and waist-hip ratio (n=89) were elevated in a relative small proportion of patients only and did not reflect lower abdominal fat. This may be due to the peculiar shape of many patients with a typical fat accumulation around the buttocks. In addition to body mass index, use of skinfold thickness is recommended for follow-up of dietary interventions in PWS.

A new deletion refines the boundaries of the murine Prader-Willi syndrome imprinting center.

PubMed

Dubose, Amanda J; Smith, Emily Y; Yang, Thomas P; Johnstone, Karen A; Resnick, James L

2011-09-01

The human chromosomal 15q11-15q13 region is subject to both maternal and paternal genomic imprinting. Absence of paternal gene expression from this region results in Prader-Willi syndrome (PWS), while absence of maternal gene expression leads to Angelman syndrome. Transcription of paternally expressed genes in the region depends upon an imprinting center termed the PWS-IC. Imprinting defects in PWS can be caused by microdeletions and the smallest commonly deleted region indicates that the PWS-IC lies within a region of 4.3 kb. The function and location of the PWS-IC is evolutionarily conserved, but delineation of the PWS-IC in mouse has proven difficult. The first targeted mutation of the PWS-IC, a deletion of 35 kb spanning Snrpn exon 1, exhibited a complete PWS-IC deletion phenotype. Pups inheriting this mutation paternally showed a complete loss of paternal gene expression and died neonatally. A reported deletion of 4.8 kb showed only a reduction in paternal gene expression and incomplete penetrance of neonatal lethality, suggesting that some PWS-IC function had been retained. Here, we report that a 6 kb deletion spanning Snrpn exon 1 exhibits a complete PWS-IC deletion phenotype. Pups inheriting this mutation paternally lack detectable expression of all PWS genes and paternal silencing of Ube3a, exhibit maternal DNA methylation imprints at Ndn and Mkrn3 and suffer failure to thrive leading to a fully penetrant neonatal lethality.

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

PubMed

Descheemaeker, Mie-Jef; Govers, Veerle; Vermeulen, Peter; Fryns, Jean-Pierre

2006-06-01

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. Copyright 2006 Wiley-Liss, Inc.

The effect of growth hormone treatment or physical training on motor performance in Prader-Willi syndrome: a systematic review.

PubMed

Reus, Linda; van Vlimmeren, Leo A; Staal, J Bart; Otten, Barto J; Nijhuis-van der Sanden, Maria W G

2012-09-01

Although motor problems in Prader-Willi syndrome (PWS) are prominent in infants, and continue into childhood and adulthood, there is little insight into the factors important for clinical management. The literature was reviewed to: (1) provide an overview of the characteristics and prevalence of motor problems and (2) evaluate the effects of growth hormone (GH) treatment and physical training on motor performance. A systematic search revealed 34 papers: 13 on motor performance; 12 on GH treatment; and nine on physical training. In infants, motor development is 30-57% of the normal reference values, and children and adults also have significant problems in skill acquisition, muscle force, cardiovascular fitness, and activity level. GH treatment positively influenced motor performance in infants, children, and adults, although not all studies demonstrated an effect. All studies on physical training demonstrated beneficial effects in PWS patients. We suggest a combination of GH treatment and physical training to be started as soon as possible, especially in infants, to improve motor development as this will positively influence general development. Copyright © 2012 Elsevier Ltd. All rights reserved.

Growth hormone combined with child-specific motor training improves motor development in infants with Prader-Willi syndrome: a randomized controlled trial.

PubMed

Reus, Linda; Pelzer, Ben J; Otten, Barto J; Siemensma, Elbrich P C; van Alfen-van der Velden, Janielle A A E M; Festen, Dederieke A M; Hokken-Koelega, Anita C S; Nijhuis-van der Sanden, Maria W G

2013-10-01

Although severe motor problems in infants with Prader-Willi syndrome (PWS) are striking, motor development has never been studied longitudinally and the results of growth hormone (GH) treatment on motor development are contradictory. The authors studied whether GH treatment can enhance the effect of physical training on motor development in infants with PWS. Twenty-two infants were followed for two years during a randomized controlled trial. The treatment and control groups began GH after baseline or following a control period, respectively. Both groups followed a child-specific physical training program. Motor performance was measured every three months. Multi-level regression analysis revealed that motor development differed significantly between infants (p<.001), and this could be partially explained by baseline motor developmental level (p<.01). GH treatment enhanced the effects of child-specific physical training on both motor developmental rate and motor developmental potential. Moreover, this effect was more pronounced when GH treatment was initiated at a younger age. Copyright © 2013 Elsevier Ltd. All rights reserved.

Growth hormone treatment in adults with Prader-Willi syndrome: the Scandinavian study.

PubMed

Sode-Carlsen, Rasmus; Farholt, Stense; Rabben, Kai Fr; Bollerslev, Jens; Schreiner, Thomas; Jurik, Anne Grethe; Christiansen, Jens Sandahl; Höybye, Charlotte

2012-04-01

Prader-Willi syndrome (PWS) is characterized by short stature, muscular hypotonia, cognitive dysfunction, and hyperphagia usually leading to severe obesity. Patients with PWS share similarities with growth hormone deficiency (GHD). Few studies have dealt with growth hormone (GH) treatment in PWS adults. The purpose of the Scandinavian study was to evaluate the effects of GH on body composition, lipid and glucose metabolism, physical performance and safety parameters in adults with PWS. Twenty-five women and 21 men with PWS were randomized to treatment with GH or placebo during 1 year followed by 2 years of open labeled GH treatment. At baseline 1/3 had normal BMI, six patients severe GHD, ten impaired glucose tolerance and seven diabetes. At 1 year insulin-like growth factor I (IGF-I) SDS had increased by 1.51 (P < 0.001) and body composition improved in the GH treated group. Visceral fat decreased by 22.9 ml (P = 0.004), abdominal subcutaneous fat by 70.9 ml (P = 0.003) and thigh fat by 21.3 ml (P = 0.013), whereas thigh muscle increased 6.0 ml (P = 0.005). Lean body mass increased 2.25 kg (P = 0.005), and total fat mass decreased 4.20 kg (P < 0.001). The positive effects on body composition were maintained after 2 years of GH treatment. Peak expiratory flow increased by 12% (P < 0.001) at 2 years of GH treatment. Lipid and glucose metabolism were unchanged, however, three patients developed diabetes at 2 years of GH treatment. In conclusion GH treatment had beneficial effects on the abnormal body composition without serious adverse events making it a logic treatment option in adults with PWS.

Deficits in voice and multisensory processing in patients with Prader-Willi syndrome.

PubMed

Salles, Juliette; Strelnikov, Kuzma; Carine, Mantoulan; Denise, Thuilleaux; Laurier, Virginie; Molinas, Catherine; Tauber, Maïthé; Barone, Pascal

2016-05-01

Prader-Willi syndrome (PWS) is a rare neurodevelopmental and genetic disorder that is characterized by various expression of endocrine, cognitive and behavioral problems, among which a true obsession for food and a deficit of satiety that leads to hyperphagia and severe obesity. Neuropsychological studies have reported that PWS display altered social interactions with a specific weakness in interpreting social information and in responding to them, a symptom closed to that observed in autism spectrum disorders (ASD). Based on the hypothesis that atypical multisensory integration such as face and voice interactions would contribute in PWS to social impairment we investigate the abilities of PWS to process communication signals including the human voice. Patients with PWS recruited from the national reference center for PWS performed a simple detection task of stimuli presented in an uni-o or bimodal condition, as well as a voice discrimination task. Compared to control typically developing (TD) individuals, PWS present a specific deficit in discriminating human voices from environmental sounds. Further, PWS present a much lower multisensory benefits with an absence of violation of the race model indicating that multisensory information do not converge and interact prior to the initiation of the behavioral response. All the deficits observed in PWS were stronger for the subgroup of patients suffering from Uniparental Disomy, a population known to be more sensitive to ASD. Altogether, our study suggests that the deficits in social behavior observed in PWS derive at least partly from an impairment in deciphering the social information carried by voice signals, face signals, and the combination of both. In addition, our work is in agreement with the brain imaging studies revealing an alteration in PWS of the "social brain network" including the STS region involved in processing human voices. Copyright © 2016 Elsevier Ltd. All rights reserved.

Investigating Autism-Related Symptoms in Children with Prader-Willi Syndrome: A Case Study

PubMed Central

Bennett, Jeffrey A.; Hodgetts, Sandra; Mackenzie, Michelle L.; Haqq, Andrea M.; Zwaigenbaum, Lonnie

2017-01-01

Prader-Willi syndrome (PWS), a rare genetic disorder caused by the lack of expression of paternal genes from chromosome 15q11-13, has been investigated for autism spectrum disorder (ASD) symptomatology in various studies. However, previous findings have been variable, and no studies investigating ASD symptomatology in PWS have exclusively studied children. We aimed to characterize social communication functioning and other ASD-related symptoms in children with PWS, and assessed agreement across measures and rates of ASD diagnosis. Measures included the Autism Diagnostic Observation Schedule-2 (ADOS-2), the Social Communication Questionnaire (SCQ), Social Responsiveness Scale-2 (SRS-2), Social Skills Improvement System-Rating Scales (SSIS-RS), and the Vineland Adaptive Behavioral Scales-II (VABS-II). General adaptive and intellectual skills were also assessed. Clinical best estimate (CBE) diagnosis was determined by an experienced developmental pediatrician, based on history and review of all available study measures, and taking into account overall developmental level. Participants included 10 children with PWS, aged 3 to 12 years. Three of the 10 children were male and genetic subtypes were two deletion (DEL) and eight uniparental disomy (UPD) (with a total of 6 female UPD cases). Although 8 of the 10 children exceeded cut-offs on at least one of the ASD assessments, agreement between parent questionnaires (SCQ, SRS-2, SSIS-RS) and observational assessment (ADOS-2) was very poor. None of the children were assigned a CBE diagnosis of ASD, with the caveat that the risk may have been lower because of the predominance of girls in the sample. The lack of agreement between the assessments emphasizes the complexity of interpreting ASD symptom measures in children with PWS. PMID:28264487

Investigating Autism-Related Symptoms in Children with Prader-Willi Syndrome: A Case Study.

PubMed

Bennett, Jeffrey A; Hodgetts, Sandra; Mackenzie, Michelle L; Haqq, Andrea M; Zwaigenbaum, Lonnie

2017-02-28

Prader-Willi syndrome (PWS), a rare genetic disorder caused by the lack of expression of paternal genes from chromosome 15q11-13, has been investigated for autism spectrum disorder (ASD) symptomatology in various studies. However, previous findings have been variable, and no studies investigating ASD symptomatology in PWS have exclusively studied children. We aimed to characterize social communication functioning and other ASD-related symptoms in children with PWS, and assessed agreement across measures and rates of ASD diagnosis. Measures included the Autism Diagnostic Observation Schedule-2 (ADOS-2), the Social Communication Questionnaire (SCQ), Social Responsiveness Scale-2 (SRS-2), Social Skills Improvement System-Rating Scales (SSIS-RS), and the Vineland Adaptive Behavioral Scales-II (VABS-II). General adaptive and intellectual skills were also assessed. Clinical best estimate (CBE) diagnosis was determined by an experienced developmental pediatrician, based on history and review of all available study measures, and taking into account overall developmental level. Participants included 10 children with PWS, aged 3 to 12 years. Three of the 10 children were male and genetic subtypes were two deletion (DEL) and eight uniparental disomy (UPD) (with a total of 6 female UPD cases). Although 8 of the 10 children exceeded cut-offs on at least one of the ASD assessments, agreement between parent questionnaires (SCQ, SRS-2, SSIS-RS) and observational assessment (ADOS-2) was very poor. None of the children were assigned a CBE diagnosis of ASD, with the caveat that the risk may have been lower because of the predominance of girls in the sample. The lack of agreement between the assessments emphasizes the complexity of interpreting ASD symptom measures in children with PWS.

25OH vitamin D levels in pediatric patients affected by Prader-Willi syndrome.

PubMed

Fintini, D; Pedicelli, S; Bocchini, S; Bizzarri, C; Grugni, G; Cappa, M; Crinò, A

2018-06-01

Obesity, insulin resistance, and puberty seem to influence and been inversely associated with 25-hydroxy vitamin D (25OHD) levels. To our knowledge, a study on 25OHD in children and adolescents with Prader-Willi syndrome (PWS), a genetic form of obesity, is not yet available. To analyze the 25OHD values in pediatric PWS subjects in comparison with a control group (CNT), highlighting the possible correlations with IR, BMD, body composition, pubertal stage, and GH therapy (GHT). Auxological and laboratory parameters, HOMA-IR, Vitamin D status, and bone density and body composition by DEXA scan were analyzed in 52 PWS and 110 controls (CNT), gender-, age-, and BMI-SD matched. None of them was on calcium or vitamin D. 20 PWS were on growth hormone (GH) therapy and 32 were previously treated. Altogether, PWS had similar values of 25OHD compared to CNT.16 PWS (30.7%) and 27 CNT (24.5%) had low 25OHD levels (< 20 ng/ml) (p = NS). 25OHD of PWS on GHT were comparable to those previously treated. In both groups, univariate analysis showed a negative correlation between 25OHD and fat mass% (FM%). GH therapy and pubertal stage were positively correlated with bone parameters analyzed by DXA. Multivariate regression confirmed only FM% as negative predictor of 25HOD in PWS patients, as previously described. GHT does not seem to influence 25OHD in PWS. Our data showed that PWS had similar values of 25OHD compared to CNT. As already described, FM seems to be the only parameter influencing 25OHD levels. Finally, GHT does not seem to influence 25OHD metabolism in PWS.

Prader Willi syndrome and obstructive sleep apnea: co-occurrence in the pediatric population.

PubMed

Sedky, Karim; Bennett, David S; Pumariega, Andres

2014-04-15

A high prevalence of obstructive sleep apnea (OSA) occurs in children with Prader-Willi syndrome (PWS). Yet, due in part to the relatively small samples previously used, the prevalence of OSA has varied greatly across studies. It is also unclear if factors such as age, gender, body mass index (BMI), or type of genetic imprinting are associated with increased risk for OSA among children with PWS. To evaluate the (a) prevalence of OSA, as well as narcolepsy, in pediatric populations diagnosed with PWS; (b) effects of age, gender, body mass index, and genetic imprinting on OSA severity; and (c) efficacy of adenotonsillectomy (AT) for decreasing OSA severity in this population. All studies assessing OSA among children with PWS through August 2013 were identified using the PubMed/Medline, Psych Info, Cochrane library, and Google Scholar data bases. Fourteen studies of children diagnosed with PWS and who were assessed for OSA using polysomnography (PSG) met inclusion criteria (n = 224 children). The prevalence of OSA across studies was 79.91% (n = 179/224). Among youths with OSA, 53.07% had mild OSA, 22.35% moderate OSA, and 24.58% severe OSA. Narcolepsy was found to occur in 35.71% of children with PWS. Adenotonsillectomy was associated with improvement in OSA for most children with PWS. However, residual OSA was present in the majority of cases post-surgery. This study confirms the high prevalence of OSA and narcolepsy among children with PWS. Screening for OSA and narcolepsy among children with PWS is recommended. In addition, while adenotonsillectomy was effective in reducing OSA for some children, alternative treatments may need to be considered, given the only moderate response rate.

Clinical-etiologic correlation in children with Prader-Willi syndrome (PWS): an interdisciplinary study.

PubMed

Torrado, Maria; Araoz, Veronica; Baialardo, Edgardo; Abraldes, Karina; Mazza, Carmen; Krochik, Gabriela; Ozuna, Blanca; Leske, Vivian; Caino, Silvia; Fano, Virginia; Chertkoff, Lilien

2007-03-01

Prader-Willi syndrome (PWS) is a multisystemic disorder caused by the loss of expression of paternally transcribed genes within chromosome 15q11-q13. Most cases are due to paternal deletion of this region; the remaining cases result from maternal uniparental disomy (UPD) and imprinting defects. To better understand the phenotypic variability of PWS, a genotype-phenotype correlation study was performed in 91 children with PWS. Patients were diagnosed by Southern Blot Methylation assay and genetic subtypes were established using FISH and microsatellite analyses. Fifty-nine subjects with deletion (31/28 males/females; mean age 3.86 years), 30 with UPD (14/16 males/females; mean age 3.89 years) and 2 girls with a presumed imprinting defect (mean age 0.43 yrs) were identified. For correlation purposes patients were grouped as "deleted" and "non-deleted." An increased maternal age was found in the UPD group. Four of Holm's criteria were more frequently present in the deleted group: need for special feeding techniques, sleep disturbance, hypopigmentation, and speech articulation defects. Concerning cognitive assessments, only 9.52% of subjects with deletion had Full-Scale IQ (FSIQ) > or =70, while 61.53% of subjects without deletion had FSIQ > or =70. Similar results were found in behavioral measures. Sleep disorders and carbohydrate metabolism were systematically assessed. Polysomnoghaphic studies revealed a higher frequency of central events with desaturations > or =10% in the deleted group (P = 0.020). In summary, the phenotype was significantly different between both groups in certain parameters related to the CNS. These results might be related to the differences in brain gene expression of the genetic subtypes. (c) 2006 Wiley-Liss, Inc.

An interstitial 15q11-q14 deletion: expanded Prader-Willi syndrome phenotype.

PubMed

Butler, Merlin G; Bittel, Douglas C; Kibiryeva, Nataliya; Cooley, Linda D; Yu, Shihui

2010-02-01

We present an infant girl with a de novo interstitial deletion of the chromosome 15q11-q14 region, larger than the typical deletion seen in Prader-Willi syndrome (PWS). She presented with features seen in PWS including hypotonia, a poor suck, feeding problems, and mild micrognathia. She also presented with features not typically seen in PWS such as preauricular ear tags, a high-arched palate, edematous feet, coarctation of the aorta, a PDA, and a bicuspid aortic valve. G-banded chromosome analysis showed a large de novo deletion of the proximal long arm of chromosome 15 confirmed using FISH probes (D15511 and GABRB3). Methylation testing was abnormal and consistent with the diagnosis of PWS. Because of the large appearing deletion by karyotype analysis, an array comparative genomic hybridization (aCGH) was performed. A 12.3 Mb deletion was found which involved the 15q11-q14 region containing approximately 60 protein coding genes. This rare deletion was approximately twice the size of the typical deletion seen in PWS and involved the proximal breakpoint BP1 and the distal breakpoint was located in the 15q14 band between previously recognized breakpoints BP5 and BP6. The deletion extended slightly distal to the AVEN gene including the neighboring CHRM5 gene. There is no evidence that the genes in the 15q14 band are imprinted; therefore, their potential contribution in this patient's expanded PWS phenotype must be a consequence of dosage sensitivity of the genes or due to altered expression of intact neighboring genes from a position effect. Copyright 2010 Wiley-Liss, Inc.

Comparison of perinatal factors in deletion versus uniparental disomy in Prader-Willi syndrome.

PubMed

Gold, June-Anne; Mahmoud, Ranim; Cassidy, Suzanne B; Kimonis, Virginia

2018-05-01

Prader-Willi syndrome (PWS) is caused by a deficiency of imprinted genes in the 15q11-q13 region and is characterized by prenatal onset of hypotonia, poor feeding, childhood-onset obesity, hyperphagia, short stature, facial dysmorphism, intellectual disability, and behavioral problems. We studied perinatal factors in a cohort of 64 people with PWS resulting from paternal deletion of 15q11-q13 and maternal uniparental disomy (UPD) for chromosome 15. We recruited 34 individuals with deletion and 30 with UPD. We compared the frequency of multiple prenatal and neonatal factors with the general population as well as between the two genetic subtypes. Of the 64 individuals with PWS, fetal movements were decreased in 82.8%, 31.7% were born prematurely, 42.1% by Cesarean section, and 35.9% required oxytocin induction. Apgar scores were low in 34.6%, 96.8% had feeding difficulty, 50% needed tube feeding, and 6.2% subsequently had gastrostomy tube placement. On comparing findings in the deletion versus the UPD groups, we did not find many significant differences. We, however, found a higher maternal age, and also later age at diagnosis in the UPD versus the deletion group. PWS subjects have higher rates of perinatal complications, especially Cesarean section rate, hypotonia, and low Apgar scores compared to the general population. We did not find many differences between the genetic subtypes, except for later age of diagnosis of the UPD 15 group suggesting a milder phenotype. We also found that the mothers in the UPD were older, supporting the hypothesis that UPD results from nondisjunction associated trisomy rescue. © 2018 Wiley Periodicals, Inc.

Impact of transitional care on endocrine and anthropometric parameters in Prader-Willi syndrome.

PubMed

Paepegaey, A C; Coupaye, M; Jaziri, A; Ménesguen, F; Dubern, B; Polak, M; Oppert, J M; Tauber, M; Pinto, G; Poitou, C

2018-05-01

The transition of patients with Prader-Willi syndrome (PWS) to adult life for medical care is challenging because of multiple comorbidities, including hormone deficiencies, obesity and cognitive and behavioral disabilities. To assess endocrine management, and metabolic and anthropometric parameters of PWS adults who received ( n  = 31) or not ( n  = 64) transitional care, defined as specialized pediatric care followed by a structured care pathway to a multidisciplinary adult team. Hormonal and metabolic parameters were retrospectively recorded in 95 adults with PWS (mean ± s.d. age 24.7 ± 8.2 years, BMI: 39.8 ± 12.1 kg/m²) referred to our Reference Center and compared according to transition. Among the entire cohort, 35.8% received growth hormone (GH) during childhood and 16.8% had a GH stimulation test after completion of growth. In adulthood, 14.7% were treated with GH, 56.8% received sex-hormone therapy, whereas 91.1% were hypogonadic and 37.9% had undergone valid screening of the corticotropic axis. The main reason for suboptimal endocrine management was marked behavioral disorders. Patients receiving transitional care were more likely to have had a GH stimulation test and hormonal substitutions in childhood. They also had a lower BMI, percentage of fat mass, improved metabolic parameters and fewer antidepressant treatments. Transitional care remained significantly associated with these parameters in multivariate analysis when adjusted on GH treatment. A coordinated care pathway with specialized pediatric care and transition to a multidisciplinary adult team accustomed to managing complex disability including psychiatric troubles are associated with a better health status in adults with PWS. © 2018 The authors.

Management of hypogonadism in adolescent girls and adult women with Prader-Willi syndrome.

PubMed

Eldar-Geva, Talia; Hirsch, Harry J; Pollak, Yehuda; Benarroch, Fortu; Gross-Tsur, Varda

2013-12-01

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder characterized by an insatiable appetite, dysmorphic features, cognitive and behavioral difficulties, and hypogonadism. The heterogeneous reproductive hormone profiles indicate that some PWS women may have symptoms of hypoestrogenism, while others may potentially be fertile. We describe our experience in the assessment and treatment of hypogonadism in adolescents and adult females with PWS. The study population consisted of 20 PWS females, age ≥16 years (27.3 ± 7.9 years), followed in our clinic (12 deletion, 7 uniparental disomy, 1 imprinting-center defect). General physical examination, pubertal assessment, body mass index (BMI), gynecological examination, ultrasonography, bone densitometry, and hormonal profiles [FSH, LH, inhibin B, estradiol, prolactin, and TSH] were performed. The relevant assessed factors were: FSH and inhibin B, menstrual cycles (oligo/amenorrhea or irregular bleeding), ultrasound findings (endometrial thickness, uterine/ovarian abnormalities), BMI, bone densitometry, and patient/caregivers attitude. We classified seven women with inhibin B >20 ng/ml as potentially fertile. Following the assessment of the above factors, we recommended the individual-specific treatment; contraceptive pills, intra-uterine device, estrogen/progesterone replacement, and cyclic progesterone, in 3, 1, 4, and 1 patients, respectively. Four patients did not follow our recommendations due to poor compliance or family refusal. We recommended contraception pills for one 26-year-old woman with inhibin B and FSH levels 53 ng/ml and 6.4 IU/L; however, she refused treatment, conceived spontaneously and had an abortion. Guidelines for hormonal replacement therapy in PWS need to be tailored individually depending on physical development, hormonal profiles, bone density, and emotional and social needs of each PWS adolescent and adult. © 2013 Wiley Periodicals, Inc.

Truncating Mutations of MAGEL2, a Gene within the Prader-Willi Locus, Are Responsible for Severe Arthrogryposis

PubMed Central

Mejlachowicz, Dan; Nolent, Flora; Maluenda, Jérome; Ranjatoelina-Randrianaivo, Hanitra; Giuliano, Fabienne; Gut, Ivo; Sternberg, Damien; Laquerrière, Annie; Melki, Judith

2015-01-01

Arthrogryposis multiplex congenita (AMC) is characterized by the presence of multiple joint contractures resulting from reduced or absent fetal movement. Here, we report two unrelated families affected by lethal AMC. By genetic mapping and whole-exome sequencing in a multiplex family, a heterozygous truncating MAGEL2 mutation leading to frameshift and a premature stop codon (c.1996delC, p.Gln666Serfs∗36) and inherited from the father was identified in the probands. In another family, a distinct heterozygous truncating mutation leading to frameshift (c.2118delT, p.Leu708Trpfs∗7) and occurring de novo on the paternal allele of MAGEL2 was identified in the affected individual. In both families, RNA analysis identified the mutated paternal MAGEL2 transcripts only in affected individuals. MAGEL2 is one of the paternally expressed genes within the Prader-Willi syndrome (PWS) locus. PWS is associated with, to varying extents, reduced fetal mobility, severe infantile hypotonia, childhood-onset obesity, hypogonadism, and intellectual disability. MAGEL2 mutations have been recently reported in affected individuals with features resembling PWS and called Schaaf-Yang syndrome. Here, we show that paternal MAGEL2 mutations are also responsible for lethal AMC, recapitulating the clinical spectrum of PWS and suggesting that MAGEL2 is a PWS-determining gene. PMID:26365340

A review of chemosensory perceptions, food preferences and food-related behaviours in subjects with Prader-Willi Syndrome.

PubMed

Martínez Michel, Lorelei; Haqq, Andrea M; Wismer, Wendy V

2016-04-01

Hyperphagia and obsessive preoccupation with food are hallmark characteristics of Prader-Willi Syndrome (PWS). Although hyperphagia in PWS is linked to hypothalamic dysfunction, the underlying mechanisms behind this problem are poorly understood. Moreover, our understanding of how chemosensory perceptions and food choice/preferences relate to hyperphagia in individuals with PWS is very limited. This narrative review synthesizes studies that assessed chemosensory perceptions, food choices and food-related behaviours in PWS individuals and highlights knowledge gaps in research for further exploration. Twenty seven publications from relevant databases met inclusion criteria and were organized thematically by study technique in the review. Results suggested that PWS individuals have consistent preferences for sweet tastes and in most studies have exhibited a preference for calorie-dense foods over lower calorie foods. No firm conclusions were drawn concerning the chemosensory perceptions of PWS individuals and their influence on food preferences or choices; chemosensation among PWS individuals is an understudied topic. Current evidence suggests that eating behaviour in PWS is a complex phenomenon that involves a dysfunctional satiation and not excessive hunger. Food preferences, choices, and related behaviours and the impact of these on obesity management in those with PWS remain poorly understood and require further study using validated tools and methodologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Does segmental body composition differ in women with Prader-Willi syndrome compared to women with essential obesity?

PubMed

Bedogni, G; Grugni, G; Tringali, G; Marazzi, N; Sartorio, A

2015-09-01

Subjects with Prader-Willi syndrome (PWS) have a higher fat mass and a lower fat-free mass compared to subjects with essential obesity. However, few data are presently available on the segmental body composition (BC) of PWS subjects. To evaluate whether women with PWS and women with essential obesity, matched for age and percent body fat, differ in segmental fat distribution and surrogate markers of cardiometabolic disease (CMD). 35 women with PWS and 50 women with essential obesity were matched for age and percent body fat using coarsened exact matching. BC was measured by dual-energy X-ray absorptiometry. Oral glucose tolerance testing and measurements of cholesterol, triglycerides, C-reactive protein, and blood pressure were performed. Comparisons between PWS and obese women were performed using generalized linear models. Trunk fat was lower in PWS than in obese women on both absolute [-7.3 (95% confidence interval -9.4 to -5.2) kg] and relative [-4.1 (-6.9 to -1.4)% of body fat] grounds. PWS and obese women had similar surrogate markers of CMD, with the exception of HDL-cholesterol, which was higher in PWS women. Trunk fat is lower in obese women with PWS than in those with essential obesity. Surrogate markers of CMD are, however, mostly similar in the two groups.

PET scan perfusion imaging in the Prader-Willi syndrome: new insights into the psychiatric and social disturbances.

PubMed

Mantoulan, Carine; Payoux, Pierre; Diene, Gwenaëlle; Glattard, Mélanie; Rogé, Bernadette; Molinas, Catherine; Sevely, Annick; Zilbovicius, Monica; Celsis, Pierre; Tauber, Maïthé

2011-01-01

The Prader-Willi syndrome (PWS), a rare multisystem genetic disease, leads to severe disabilities, such as morbid obesity, endocrine dysfunctions, psychiatric disorders, and social disturbances. We explored the whole brain of patients with PWS to detect abnormalities that might explain the behavioral and social disturbances, as well as the psychiatric disorders of these patients. Nine patients with PWS (six males, three females; mean age 16.4 years) underwent a positron emission tomography (PET) scan with H(2)(15)O as a tracer to measure regional cerebral blood flow (rCBF). The images were compared with those acquired from nine controls (six males, three females; mean age 21.2 years). A morphologic magnetic resonance imaging (MRI) was also performed in PWS patients, and their cognitive and behavioral skills were assessed with Wechsler Intelligence Scale for Children III and the Child Behavior Check List (CBCL). The MRI images showed no evident anatomic abnormalities, whereas PET scans revealed hypoperfused brain regions in PWS patients compared with controls, particularly in the anterior cingulum and superior temporal regions. We observed a significant relationship (P<0.05) between rCBF in the hypoperfused regions and CBCL scores. The functional consequences of these perfusion abnormalities in specific brain regions might explain the behavioral and social problems observed in these individuals.

A specific pathway can be identified between genetic characteristics and behaviour profiles in Prader-Willi syndrome via cognitive, environmental and physiological mechanisms.

PubMed

Woodcock, K A; Oliver, C; Humphreys, G W

2009-06-01

Behavioural phenotypes associated with genetic syndromes have been extensively investigated in order to generate rich descriptions of phenomenology, determine the degree of specificity of behaviours for a particular syndrome, and examine potential interactions between genetic predispositions for behaviour and environmental influences. However, relationships between different aspects of behavioural phenotypes have been less frequently researched and although recent interest in potential cognitive phenotypes or endophenotypes has increased, these are frequently studied independently of the behavioural phenotypes. Taking Prader-Willi syndrome (PWS) as an example, we discuss evidence suggesting specific relationships between apparently distinct aspects of the PWS behavioural phenotype and relate these to specific endophenotypic characteristics. The framework we describe progresses through biological, cognitive, physiological and behavioural levels to develop a pathway from genetic characteristics to behaviour with scope for interaction with the environment at any stage. We propose this multilevel approach as useful in setting out hypotheses in order to structure research that can more rapidly advance theory.

Growth hormone therapy, muscle thickness, and motor development in Prader-Willi syndrome: an RCT.

PubMed

Reus, Linda; Pillen, Sigrid; Pelzer, Ben J; van Alfen-van der Velden, Janielle A A E M; Hokken-Koelega, Anita C S; Zwarts, Machiel; Otten, Barto J; Nijhuis-van der Sanden, Maria W G

2014-12-01

To investigate the effect of physical training combined with growth hormone (GH) on muscle thickness and its relationship with muscle strength and motor development in infants with Prader-Willi syndrome (PWS). In a randomized controlled trial, 22 infants with PWS (12.9 ± 7.1 months) were followed over 2 years to compare a treatment group (n = 10) with a waiting-list control group (n = 12). Muscle thickness of 4 muscle groups was measured by using ultrasound. Muscle strength was evaluated by using the Infant Muscle Strength meter. Motor performance was measured with the Gross Motor Function Measurement. Analyses of variance were used to evaluate between-group effects of GH on muscle thickness at 6 months and to compare pre- and posttreatment (after 12 months of GH) values. Multilevel analyses were used to evaluate effects of GH on muscle thickness over time, and multilevel bivariate analyses were used to test relationships between muscle thickness, muscle strength, and motor performance. A significant positive effect of GH on muscle thickness (P < .05) was found. Positive relationships were found between muscle thickness and muscle strength (r = 0.61, P < .001), muscle thickness and motor performance (r = 0.81, P < .001), and muscle strength and motor performance (r = 0.76, P < .001). GH increased muscle thickness, which was related to muscle strength and motor development in infants with PWS. Catch-up growth was faster in muscles that are most frequently used in early development. Because this effect was independent of GH, it suggests a training effect. Copyright © 2014 by the American Academy of Pediatrics.

Repetitive and ritualistic behaviour in children with Prader-Willi syndrome and children with autism.

PubMed

Greaves, N; Prince, E; Evans, D W; Charman, T

2006-02-01

Recent research has shown that the range of repetitive behaviour seen in individuals with Prader-Willi syndrome (PWS) extends beyond food-related behaviour. The presence and intensity of repetitive, rigid and routinized behaviour in children with PWS was compared with that seen in children with another neurodevelopmental condition in which repetitive behaviour is common: children with autism. Parents completed the Childhood Routines Inventory (CRI). Contrary to our predictions, controlling for developmental level, children with PWS and children with autism showed similar levels of repetitive and ritualistic behaviour overall and on the two CRI factors measuring 'just right' and 'repetitive' behaviour. Indeed, the majority of the sample of parents of children with PWS endorsed most items on the CRI. However there was some specificity at the level of individual items with parents of children with PWS more frequently endorsing an item on 'collecting and storing objects' and parents of children with autism more frequently endorsing 'lining up objects', 'has a strong preference for certain foods' and 'seems aware of detail at home'. These findings confirm the range of repetitive behaviours that form part of the behavioural phenotype of PWS, including insistence on sameness and 'just right' behaviours, and uncover a surprising overlap with those seen in children with autism. Clinical management for children with PWS should include advice and education regarding management of repetitive and rigid behaviour. Future research should investigate whether the repetitive behaviours that form part of the behavioural phenotype of both PWS and autism are associated with a common neuropsychological, neurotransmitter or genetic origin.

Neural correlates of task switching in paternal 15q11-q13 deletion Prader-Willi syndrome.

PubMed

Woodcock, Kate A; Humphreys, Glyn W; Oliver, Chris; Hansen, Peter C

2010-12-02

We report a first study of brain activity linked to task switching in individuals with Prader-Willi syndrome (PWS). PWS individuals show a specific cognitive deficit in task switching which may be associated with the display of temper outbursts and repetitive questioning. The performance of participants with PWS and typically developing controls was matched in a cued task switching procedure, and brain activity was contrasted on switching and non-switching blocks using fMRI. Individuals with PWS did not show the typical frontal-parietal pattern of neural activity associated with switching blocks, with significantly reduced activation in regions of the posterior parietal and ventromedial prefrontal cortices. We suggest that this is linked to a difficulty in PWS in setting appropriate attentional weights to enable task-set reconfiguration. In addition to this, PWS individuals did not show the typical pattern of deactivation, with significantly less deactivation in an anterior region of the ventromedial prefrontal cortex. One plausible explanation for this is that individuals with PWS show dysfunction within the default mode network, which has been linked to attentional control. The data point to functional changes in the neural circuitry supporting task switching in PWS even when behavioural performance is matched to controls and thus highlight neural mechanisms that may be involved in a specific pathway between genes, cognition and behaviour. Copyright © 2010 Elsevier B.V. All rights reserved.

Clinical implications of gait analysis in the rehabilitation of adult patients with "Prader-Willi" Syndrome: a cross-sectional comparative study ("Prader-Willi" Syndrome vs matched obese patients and healthy subjects).

PubMed

Vismara, Luca; Romei, Marianna; Galli, Manuela; Montesano, Angelo; Baccalaro, Gabriele; Crivellini, Marcello; Grugni, Graziano

2007-05-10

Being severely overweight is a distinctive clinical feature of Prader-Willi Syndrome (PWS). PWS is a complex multisystem disorder, representing the most common form of genetic obesity. The aim of this study was the analysis of the gait pattern of adult subjects with PWS by using three-Dimensional Gait Analysis. The results were compared with those obtained in a group of obese patients and in a group of healthy subjects. Cross-sectional, comparative study: 19 patients with PWS (11 males and 8 females, age: 18-40 years, BMI: 29.3-50.3 kg/m2); 14 obese matched patients (5 males and 9 females, age: 18-40 years, BMI: 34.3-45.2 kg/m2); 20 healthy subjects (10 males and 10 females, age: 21-41 years, BMI: 19.3-25.4 kg/m2). Kinematic and kinetic parameters during walking were assessed by an optoelectronic system and two force platforms. PWS adult patients walked slower, had a shorter stride length, a lower cadence and a longer stance phase compared with both matched obese, and healthy subjects. Obese matched patients showed spatio-temporal parameters significantly different from healthy subjects.Furthermore, Range Of Motion (ROM) at knee and ankle, and plantaflexor activity of PWS patients were significantly different between obese and healthy subjects. Obese subjects revealed kinematic and kinetic data similar to healthy subjects. PWS subjects had a gait pattern significantly different from obese patients. Despite that, both groups had a similar BMI. We suggest that PWS gait abnormalities may be related to abnormalities in the development of motor skills in childhood, due to precocious obesity. A tailored rehabilitation program in early childhood of PWS patients could prevent gait pattern changes.

Clinical implications of gait analysis in the rehabilitation of adult patients with "Prader-Willi" Syndrome: a cross-sectional comparative study ("Prader-Willi" Syndrome vs matched obese patients and healthy subjects)

PubMed Central

Vismara, Luca; Romei, Marianna; Galli, Manuela; Montesano, Angelo; Baccalaro, Gabriele; Crivellini, Marcello; Grugni, Graziano

2007-01-01

Background Being severely overweight is a distinctive clinical feature of Prader-Willi Syndrome (PWS). PWS is a complex multisystem disorder, representing the most common form of genetic obesity. The aim of this study was the analysis of the gait pattern of adult subjects with PWS by using three-Dimensional Gait Analysis. The results were compared with those obtained in a group of obese patients and in a group of healthy subjects. Methods Cross-sectional, comparative study: 19 patients with PWS (11 males and 8 females, age: 18–40 years, BMI: 29.3–50.3 kg/m2); 14 obese matched patients (5 males and 9 females, age: 18–40 years, BMI: 34.3–45.2 kg/m2); 20 healthy subjects (10 males and 10 females, age: 21–41 years, BMI: 19.3–25.4 kg/m2). Kinematic and kinetic parameters during walking were assessed by an optoelectronic system and two force platforms. Results PWS adult patients walked slower, had a shorter stride length, a lower cadence and a longer stance phase compared with both matched obese, and healthy subjects. Obese matched patients showed spatio-temporal parameters significantly different from healthy subjects. Furthermore, Range Of Motion (ROM) at knee and ankle, and plantaflexor activity of PWS patients were significantly different between obese and healthy subjects. Obese subjects revealed kinematic and kinetic data similar to healthy subjects. Conclusion PWS subjects had a gait pattern significantly different from obese patients. Despite that, both groups had a similar BMI. We suggest that PWS gait abnormalities may be related to abnormalities in the development of motor skills in childhood, due to precocious obesity. A tailored rehabilitation program in early childhood of PWS patients could prevent gait pattern changes. PMID:17493259

The effects of muscle hypotonia and weakness on balance: a study on Prader-Willi and Ehlers-Danlos syndrome patients.

PubMed

Galli, Manuela; Cimolin, Veronica; Vismara, Luca; Grugni, Graziano; Camerota, Filippo; Celletti, Claudia; Albertini, Giorgio; Rigoldi, Chiara; Capodaglio, Paolo

2011-01-01

Prader-Willi syndrome (PWS) and Ehlers-Danlos syndrome (EDS) are two different genetical disorders both characterized, among other features, by muscular hypotonia. Postural control seems to be impaired in both conditions. The aim of the present study was to quantitatively compare postural control in adult PWS and EDS using stabilometric platform to unveil possible common determinants of impaired balance. We enrolled 11 PWS and 21 EDS adult patients and 20 age-matched controls. They were instructed to maintain an upright standing position for 30s with open eyes (OEs) focusing on a 6 cm black circle positioned at a distance of 1.5m. Both PWS and EDS patients were characterized by higher RANGEML, RANGEAP and trajectory length of CoP values as compared to CG. No statistically differences were found between PWS and EDS in terms of any of these parameters. The results demonstrated that both PWS and EDS are characterized by a severe postural instability. Muscle hypotonia and weakness may account for reduced balance capacity. Quantitative characterization of instability is important to identify, develop and enhance rehabilitation interventions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Multicentre study of maternal and neonatal outcomes in individuals with Prader-Willi syndrome.

PubMed

Singh, Preeti; Mahmoud, Ranim; Gold, June-Anne; Miller, Jennifer L; Roof, Elizabeth; Tamura, Roy; Dykens, Elisabeth; Butler, Merlin G; Driscoll, Dan J; Kimonis, Virginia

2018-05-18

Prader-Willi syndrome (PWS) is a complex genetic disorder associated with three different genetic subtypes: deletion of the paternal copy of 15q11-q13, maternal UPD for chromosome 15 and imprinting defect. Patients are typically diagnosed because of neonatal hypotonia, dysmorphism and feeding difficulties; however, data on the prenatal features of PWS are limited. The aim of the study was to identify and compare frequencies of prenatal and neonatal clinical features of PWS among the three genetic subtypes. Data from 355 patients with PWS from the Rare Diseases Clinical Research Network PWS registry were used to analyse multiple maternal and neonatal factors collected during an 8-year multisite study. Among our cohort of 355 patients with PWS (61% deletion, 36% UPD and 3% imprinting defect) 54% were born by caesarean section, 26% were born prematurely and 34% with a low birth weight (frequencies 32%, 9.6% and 8.1%, respectively, in the general population). Fetal movements were reported as decreased in 72%. All babies were hypotonic, and 99% had feeding difficulties. Low Apgar scores (<7) were noted in 17.7% and 5.6% of patients, respectively, compared with 1% and 1.4%, respectively, in the general population. Maternal age and pre-pregnancy weight were significantly higher in the UPD group (p=0.01 and <0.001, respectively). We found a higher rate of perinatal complications in PWS syndrome compared with the general population. No significant differences in the genetic subtypes were noted except for a higher maternal age and pre-pregnancy weight in the UPD subgroup. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Genetic subtype differences in neural circuitry of food motivation in Prader-Willi syndrome.

PubMed

Holsen, L M; Zarcone, J R; Chambers, R; Butler, M G; Bittel, D C; Brooks, W M; Thompson, T I; Savage, C R

2009-02-01

Differences in behavioral phenotypes between the two most common subtypes of Prader-Willi syndrome (PWS) (chromosome 15q deletions and maternal uniparental disomy 15 (UPD) indicate that distinct neural networks may be affected. Though both subtypes display hyperphagia, the deletion subgroup shows reduced behavioral inhibition around food, whereas those with UPD are generally more able to maintain cognitive control over food intake impulses. To examine the neural basis of phenotypic differences to better understand relationships between genetic subtypes and behavioral outcomes. We predicted greater food motivation circuitry activity in the deletion subtype and greater activity in higher order cognitive regions in the UPD group, especially after eating. Nine individuals with PWS due to UPD and nine individuals with PWS due to (type 2) deletion, matched for age, gender and body mass index, underwent functional magnetic resonance imaging (fMRI) while viewing food images during two food motivation states: one before (pre-meal) and one after (post-meal) eating a standardized 500 kcal meal. Both PWS subgroups showed greater activity in response to food pre- and post-meal compared with the healthy-weight group. Compared with UPD, the deletion subtype showed increased food motivation network activation both pre- and post-meal, especially in the medial prefrontal cortex (mPFC) and amygdala. In contrast, the UPD group showed greater activation than the deletion subtype post-meal in the dorsolateral prefrontal cortex (DLPFC) and parahippocampal gyrus (PHG). These preliminary findings are the first functional neuroimaging findings to support divergent neural mechanisms associated with behavioral phenotypes in genetic subtypes of PWS. Results are discussed within the framework of genetic mechanisms such as haploinsufficiency and gene dosage effects and their differential influence on deletion and UPD subtypes, respectively.

Does the Genetic Cause of Prader-Willi Syndrome Explain the Highly Variable Phenotype?

PubMed

Dobrescu, Andreea-Iulia; Chirita-Emandi, Adela; Andreescu, Nicoleta; Farcas, Simona; Puiu, Maria

2016-09-01

Prader-Willi syndrome (PWS) is characterized by extensive clinical and genetic variability caused by lack of expression of imprinted genes of the chromosomal region 15q11.2-q13. The genotye-phenotype correlation has not been yet fully elucidated. To analyze these correlations in order to determine the role of specifi c geneic alterations in the development of clinical symptoms in PWS. We retrospectively analyzed data routinely collected as part of the clinical care of 52 patients with clinical suspicion of PWS. FISH test was performed in all patients; in case of negative results, methylation test was performed. PWS was confi rmed in 35 patients that were divided in two groups according to the genetic cause of PWS: group A-21 patients with 15q11-q13 region deletion, mean age at evaluation 8.1 years (SD= 5.6) and mean of clinical score 9.4 ± 1.8; group B-14 patients with positive methylation test, with mean age at evaluation 6.7 years (SD= 4.6) and mean of clinical score 10.1 ± 1.9. Facial dysmorphism and neonatal hypotonia were present in all evaluated patients; while, higher frequency of major and minor PWS criteria were noted in the group A. Onset of hyperphagia, was around the age of 2 years in most patients, however one patient from group B had normal eating behavior and normal weight beyond age 5 years. In our study, the various genotypes did not seem to explain the diff erence in phenotype in PWS patients. We found a delayed time until diagnosis in these patients, although all had neonatal hypotonia and other suggestive phenotypic features, underlining once more the need for increased awareness of this syndrome, as well as easier accessibility to genetic counseling.

Paradoxical leanness in the imprinting-centre deletion mouse model for Prader-Willi syndrome.

PubMed

Golding, David M; Rees, Daniel J; Davies, Jennifer R; Relkovic, Dinko; Furby, Hannah V; Guschina, Irina A; Hopkins, Anna L; Davies, Jeffrey S; Resnick, James L; Isles, Anthony R; Wells, Timothy

2017-01-01

Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by loss of paternal gene expression from 15q11-q13, is characterised by growth retardation, hyperphagia and obesity. However, as single gene mutation mouse models for this condition display an incomplete spectrum of the PWS phenotype, we have characterised the metabolic impairment in a mouse model for 'full' PWS, in which deletion of the imprinting centre (IC) abolishes paternal gene expression from the entire PWS cluster. We show that PWS-IC del mice displayed postnatal growth retardation, with reduced body weight, hyperghrelinaemia and marked abdominal leanness; proportionate retroperitoneal, epididymal/omental and inguinal white adipose tissue (WAT) weights being reduced by 82%, 84% and 67%, respectively. PWS-IC del mice also displayed a 48% reduction in proportionate interscapular brown adipose tissue (isBAT) weight with significant 'beiging' of abdominal WAT, and a 2°C increase in interscapular surface body temperature. Maintenance of PWS-IC del mice under thermoneutral conditions (30°C) suppressed the thermogenic activity in PWS-IC del males, but failed to elevate the abdominal WAT weight, possibly due to a normalisation of caloric intake. Interestingly, PWS-IC del mice also showed exaggerated food hoarding behaviour with standard and high-fat diets, but despite becoming hyperphagic when switched to a high-fat diet, PWS-IC del mice failed to gain weight. This evidence indicates that, unlike humans with PWS, loss of paternal gene expression from the PWS cluster in mice results in abdominal leanness. Although reduced subcutaneous insulation may lead to exaggerated heat loss and thermogenesis, abdominal leanness is likely to arise from a reduced lipid storage capacity rather than increased energy utilisation in BAT. © 2017 The authors.

Patterns of habitual physical activity in youth with and without Prader-Willi Syndrome.

PubMed

Castner, Diobel M; Tucker, Jared M; Wilson, Kathleen S; Rubin, Daniela A

2014-11-01

Children classified as overweight or obese and those with disabilities are at a greater risk of not meeting the minimum recommendation of 60 min a day of moderate to vigorous physical activity (PA). Youth with Prader-Willi Syndrome (PWS) appear to participate in less PA compared to nonsyndromal children, likely due to syndrome-related factors. However, description of PA patterns in youth with PWS is lacking. The purpose of this study was to characterize PA in youth with PWS and to compare it to PA in children with nonsyndromal obesity. Twenty-four youth with PWS (ages 8-16 years) and 40 obese children without PWS (OB) (ages 8-11 years) wore accelerometers for eight consecutive days. Data were screened for compliance and classified into PA intensities: sedentary behavior (SED), light (LPA), moderate (MPA), vigorous (VPA) and moderate plus vigorous (MVPA). Youth with PWS spent 19.4% less time in weekly LPA (p=0.007) and 29.8% less time in weekly VPA compared to OB controls (p=0.036). All other intensities were similar between groups. In addition, PWS participated in less LPA and VPA during the weekends compared to OB, and less LPA on weekdays when compared to OB. There was also a trend towards PWS participating in less MVPA during the weekends and less VPA during the weekends than OB controls. There was a trend towards PWS participating in less VPA on weekends compared to weekdays, while OB participated similarly in VPA on weekdays and weekend days. On average, neither PWS nor OB children met minimum MVPA recommendations. The results suggest there is a need to design exercise programs for PWS youth that focus on integrating vigorous intensity activities, especially during the weekends when structured PA may not be available. Copyright © 2014 Elsevier Ltd. All rights reserved.

Genetic studies of Prader-Willi patients provide evidence for conservation of genomic architecture in proximal chromosome 15q.

PubMed

Hou, Aihua; Lin, Shuan-Pei; Ho, Shi Yun; Chen, Chi-Fung Jennifer; Lin, Hsiang-Yu; Chen, Yen-Juin; Huang, Chi-Yu; Chiu, Huei-Ching; Chuang, Chih-Kuang; Chen, Ken-Shiung

2011-03-01

Prader-Willi syndrome (PWS) is a neurogenetic disorder associated with recurrent genomic recombination involving low copy repeats (LCRs) located in the human chromosome 15q11-q13. Previous studies of PWS patients from Asia suggested that there is a higher incidence of deletion and lower incidence of maternal uniparental disomy (mUPD) compared to that of Western populations. In this report, we present genetic etiology of 28 PWS patients from Taiwan. Consistent with the genetic etiology findings from Western populations, the type II deletion appears to be the most common deletion subtype. Furthermore, the ratio of the two most common deletion subtypes and the ratio of the maternal heterodisomy to isodisomy cases observed from this study are in agreement with previous findings from Western populations. In addition, we identified and further mapped the deletion breakpoints in two patients with atypical deletions using array CGH (comparative genomic hybridization). Despite the relatively small numbers of patients in each subgroup, our findings suggest that the genomic architecture responsible for the recurrent recombination in PWS is conserved in Taiwanese of the Han Chinese heritage and Western populations, thereby predisposing chromosome 15q11-q13 to a similar risk of rearrangements. © 2010 The Authors Annals of Human Genetics © 2010 Blackwell Publishing Ltd/University College London.

The Prader-Willi syndrome proteins MAGEL2 and necdin regulate leptin receptor cell surface abundance through ubiquitination pathways.

PubMed

Wijesuriya, Tishani Methsala; De Ceuninck, Leentje; Masschaele, Delphine; Sanderson, Matthea R; Carias, Karin Vanessa; Tavernier, Jan; Wevrick, Rachel

2017-11-01

In Prader-Willi syndrome (PWS), obesity is caused by the disruption of appetite-controlling pathways in the brain. Two PWS candidate genes encode MAGEL2 and necdin, related melanoma antigen proteins that assemble into ubiquitination complexes. Mice lacking Magel2 are obese and lack leptin sensitivity in hypothalamic pro-opiomelanocortin neurons, suggesting dysregulation of leptin receptor (LepR) activity. Hypothalamus from Magel2-null mice had less LepR and altered levels of ubiquitin pathway proteins that regulate LepR processing (Rnf41, Usp8, and Stam1). MAGEL2 increased the cell surface abundance of LepR and decreased their degradation. LepR interacts with necdin, which interacts with MAGEL2, which complexes with RNF41 and USP8. Mutations in the MAGE homology domain of MAGEL2 suppress RNF41 stabilization and prevent the MAGEL2-mediated increase of cell surface LepR. Thus, MAGEL2 and necdin together control LepR sorting and degradation through a dynamic ubiquitin-dependent pathway. Loss of MAGEL2 and necdin may uncouple LepR from ubiquitination pathways, providing a cellular mechanism for obesity in PWS. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Cognitive and adaptive advantages of growth hormone treatment in children with Prader-Willi syndrome.

PubMed

Dykens, Elisabeth M; Roof, Elizabeth; Hunt-Hawkins, Hailee

2017-01-01

People with Prader-Willi syndrome (PWS) typically have mild to moderate intellectual deficits, compulsivity, hyperphagia, obesity, and growth hormone deficiencies. Growth hormone treatment (GHT) in PWS has well-established salutatory effects on linear growth and body composition, yet cognitive benefits of GHT, seen in other patient groups, have not been well studied in PWS. Study 1 included 96 children and youth with PWS aged 4-21 years who naturalistically varied in their exposures to GHT. Controlling for socioeconomic status, analyses compared cognitive and adaptive behavior test scores across age-matched treatment naïve versus growth hormone treated children. Study II assessed if age of treatment initiation or treatment duration was associated with subsequent cognition or adaptive behavior in 127, 4- to 21-year olds with PWS. Study III longitudinally examined cognitive and adaptive behavior in 168 participants who were either consistently on versus off GHT for up to 4-5 years. Compared to the treatment naïve group, children receiving GHT had significantly higher Verbal and Composite IQs, and adaptive communication and daily living skills. Children who began treatment before 12 months of age had higher Nonverbal and Composite IQs than children who began treatment between 1 and 5 years of age. Longitudinally, the groups differed in their intercepts, but not slopes, with each group showing stable IQ and adaptive behavior scores over time. Cognitive and adaptive advantages should be considered an ancillary benefit and additional justification for GHT in people with PWS. Future efforts need to target apparent socioeconomic inequities in accessing GHT in the PWS population. © 2016 Association for Child and Adolescent Mental Health.

Cognitive and adaptive advantages of growth hormone treatment in children with Prader-Willi syndrome

PubMed Central

Dykens, Elisabeth M; Roof, Elizabeth; Hunt-Hawkins, Hailee

2016-01-01

Background People with Prader-Willi syndrome (PWS) typically have mild to moderate intellectual deficits, compulsivity, hyperphagia, obesity, and growth hormone deficiencies. Growth hormone treatment (GHT) in PWS has well-established salutatory effects on linear growth and body composition, yet cognitive benefits of GHT, seen in other patient groups, have not been well studied in PWS. Methods Study 1 included 96 children and youth with PWS aged 4 to 21 years who naturalistically varied in their exposures to GHT. Controlling for socio-economic status, analyses compared cognitive and adaptive behavior test scores across age-matched treatment naïve versus growth hormone treated children. Study II assessed if age of treatment initiation or treatment duration was associated with subsequent cognition or adaptive behavior in 127, 4- to-21 year olds with PWS. Study III longitudinally examined cognitive and adaptive behavior in 168 participants who were either consistently on versus off GHT for up to 4–5 years. Results Compared to the treatment naïve group, children receiving growth hormone treatment had significantly higher Verbal and Composite IQs, and adaptive communication and daily living skills. Children who began treatment before 12 months of age had higher Nonverbal and Composite IQs than children who began treatment between 1 to 5 years of age. Longitudinally, the groups differed in their intercepts, but not slopes, with each group showing stable IQ and adaptive behavior scores over time. Conclusions Cognitive and adaptive advantages should be considered an ancillary benefit and additional justification for GHT in people with PWS. Future efforts need to target apparent socio-economic inequities in accessing GHT in the PWS population. PMID:27481444

A double-blind randomized controlled trial of oxytocin nasal spray in Prader Willi syndrome.

PubMed

Einfeld, Stewart L; Smith, Ellie; McGregor, Iain S; Steinbeck, Kate; Taffe, John; Rice, Lauren J; Horstead, Siân K; Rogers, Naomi; Hodge, M Antoinette; Guastella, Adam J

2014-09-01

Individuals with Prader-Willi syndrome (PWS) have a significant reduction in the number of oxytocin-producing neurons (42%) in the hypothalamic paraventricular nucleus. A number of animal studies and observations of humans show that lesions in this region can produce PWS-like symptoms. Given the evidence for potential oxytocin deficiency, we tested the effects of a course of intranasal oxytocin on PWS symptoms. Thirty individuals with PWS aged 12-30 years participated in an 18-week randomized double-blind placebo-controlled crossover trial. Participants received 8 weeks of oxytocin and 8 weeks of placebo with a minimum 2-week washout period. The first 11 participants received the following oxytocin doses: 24 IU (twice daily) B.I.D for participants 16 years and over and 18 IU B.I.D for participants 13-15 years. The dose was increased for the remaining 18 participants to 40 IU B.I.D for participants 16 years and over and 32 IU B.I.D for 13-15 years. Measures used to assess changes were standardized well-accepted measures, including the Developmental Behavior Checklist-Monitor, Parent, Teacher, and Adult; The Yale-Brown Obsessive Compulsive Scale; The Dykens Hyperphagia questionnaire; Reading The Mind in the Eyes Test; Epworth Sleepiness Scale and the Movie Stills. Oxytocin had little impact on any measure. The only significant difference found between the baseline, oxytocin, and placebo measures was an increase in temper outbursts (P = 0.023) with higher dose oxytocin. The lack of effect of oxytocin nasal spray may reflect the importance of endogenous release of oxytocin in response to exogenous oxytocin. © 2014 Wiley Periodicals, Inc.

Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome.

PubMed

Knani, Ibrahim; Earley, Brian J; Udi, Shiran; Nemirovski, Alina; Hadar, Rivka; Gammal, Asaad; Cinar, Resat; Hirsch, Harry J; Pollak, Yehuda; Gross, Itai; Eldar-Geva, Talia; Reyes-Capo, Daniela P; Han, Joan C; Haqq, Andrea M; Gross-Tsur, Varda; Wevrick, Rachel; Tam, Joseph

2016-12-01

Extreme obesity is a core phenotypic feature of Prader-Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB 1 R) blockade reverses obesity both in animals and humans. The first-in-class CB 1 R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. We studied eCB 'tone' in individuals with PWS and in the Magel2 -null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB 1 R antagonist, JD5037 in treating obesity in these mice. Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB 'tone', manifested by increased eCBs and upregulated CB 1 R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2 -null mice. Daily chronic treatment of obese Magel2 -null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Dysregulation of the eCB/CB 1 R system may contribute to hyperphagia and obesity in Magel2 -null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB 1 R antagonists may be an effective strategy for the management of severe obesity in PWS.

Macronutrient Regulation of Ghrelin and Peptide YY in Pediatric Obesity and Prader-Willi Syndrome.

PubMed

Gumus Balikcioglu, Pinar; Balikcioglu, Metin; Muehlbauer, Michael J; Purnell, Jonathan Q; Broadhurst, David; Freemark, Michael; Haqq, Andrea M

2015-10-01

The roles of macronutrients and GH in the regulation of food intake in pediatric obesity and Prader-Willi Syndrome (PWS) are poorly understood. We compared effects of high-carbohydrate (HC) and high-fat (HF) meals and GH therapy on ghrelin, insulin, peptide YY (PYY), and insulin sensitivity in children with PWS and body mass index (BMI) -matched obese controls (OCs). In a randomized, crossover study, 14 PWS (median, 11.35 y; BMI z score [BMI-z], 2.15) and 14 OCs (median, 11.97 y; BMI-z, 2.35) received isocaloric breakfast meals (HC or HF) on separate days. Blood samples were drawn at baseline and every 30 minutes for 4 hours. Mixed linear models were adjusted for age, sex, and BMI-z. Relative to OCs, children with PWS had lower fasting insulin and higher fasting ghrelin and ghrelin/PYY. Ghrelin levels were higher in PWS across all postprandial time points (P < .0001). Carbohydrate was more potent than fat in suppressing ghrelin levels in PWS (P = .028); HC and HF were equipotent in OCs but less potent than in PWS (P = .011). The increase in PYY following HF was attenuated in PWS (P = .037); thus, postprandial ghrelin/PYY remained higher throughout. A lesser increase in insulin and lesser decrease in ghrelin were observed in GH-treated PWS patients than in untreated patients; PYY responses were comparable. Children with PWS have fasting and postprandial hyperghrelinemia and an attenuated PYY response to fat, yielding a high ghrelin/PYY ratio. GH therapy in PWS is associated with increased insulin sensitivity and lesser postprandial suppression of ghrelin. The ratio Ghrelin/PYY may be a novel marker of orexigenic drive.

Prader-Willi-like syndrome in a patient with an Xq23q25 duplication.

PubMed

Monaghan, K G; Van Dyke, D L; Feldman, G L

1998-11-16

We report on a 24-year old woman with an Xq duplication and findings suggestive of Prader-Willi syndrome (PWS). Her birth weight was at the 3rd centile and her birth length was less than the 3rd centile. She was hypotonic and had a weak cry as an infant. There were no feeding difficulties, although her mother reports that as an infant, she was "small for her age." Excessive weight gain began between 3 and 4 years. The patient's development was delayed and she received special education. She has a history of hiding food. She has a sleep disturbance disorder and inappropriate social behavior. At the age of 24 years her height was below the 5th centile and weight >95th centile. She has physical findings typical of PWS, skin picking, and speech articulation defects. Cytogenetic analysis showed a 46,X,dup(X)(q23q25) karyotype. Fluorescent in situ hybridization (FISH) studies using a chromosome X painting probe demonstrated that the rearrangement was intrachromosomal. The X-chromosome fold scoring technique was used to determine the X inactivation pattern and indicated that some cells expressed the abnormal X chromosome. Results of FISH studies using the SNRPN probe localized to 15q11q13 and DNA studies using the PW71B and SNRPN probes were normal. The duplicated X chromosome, random X inactivation pattern, and the negative molecular studies for PWS indicate that the abnormal X chromosome is the basis of this patient's phenotype. This patient emphasizes the importance of obtaining a karyotype even when a syndrome diagnosable by molecular methods is strongly suspected.

Hormonal and metabolic responses to endurance exercise in children with Prader-Willi syndrome and non-syndromic obesity.

PubMed

Rubin, Daniela A; Clark, Susan J; Ng, Jason; Castner, Diobel M; Haqq, Andrea M; Judelson, Daniel A

2015-03-01

Excess adiposity affects endocrine and metabolic function at rest and during exercise. This study evaluated the endocrine and metabolic responses to exercise in syndromic (Prader-Willi syndrome) and non-syndromic pediatric obesity. Eleven PWS (10.9±1.6 y, 45.4±9.5% body fat), 12 lean (9.4±1.2 y, 17.5±4.6% body fat), and 12 obese (9.2±1.2 y, 39.9±6.8% body fat) children completed ten two-minute cycling exercise bouts, separated by one-minute rest. Blood samples were obtained at rest pre-exercise (PRE), immediately post-exercise (IP), and 15, 30 and 60 minutes into recovery. Samples were analyzed for hormones and metabolites. Growth hormone increased in response to exercise in lean and obese but not PWS (IP>PRE; IP: lean>obese). Epinephrine increased with exercise in lean (IP>PRE), while norepinephrine increased in lean and obese (IP>PRE) but not PWS; no differences were observed between lean and obese groups at IP. No other significant hormonal group interactions existed. Glucose, lactate, free fatty acid, glycerol and ketone responses were similar among groups. PWS children exhibited altered stress hormone responses to exercise. However, glucose-regulating hormones and metabolic responses to exercise appeared normal. Copyright © 2015 Elsevier Inc. All rights reserved.

Regional cerebral glucose metabolic abnormality in Prader-Willi syndrome: A 18F-FDG PET study under sedation.

PubMed

Kim, Sang Eun; Jin, Dong-Kyu; Cho, Sang Soo; Kim, Ji-Hae; Hong, Sungdo David; Paik, Kyung Hoon; Oh, Yoo Joung; Kim, An Hee; Kwon, Eun Kyung; Choe, Yon Ho

2006-07-01

Prader-Willi syndrome (PWS) is a genetic disorder caused by the nonexpression of paternal genes in the PWS region of chromosome 15q11-13 and is the most common cause of human syndromic obesity. We investigated regional brain metabolic impairment in children with PWS by 18F-FDG PET. Sixteen children with PWS (9 males, 7 females; mean age +/- SD, 4.2 +/- 1.1 y) and 7 healthy children (4 males, 3 females; mean age +/- SD, 4.0 +/- 1.7 y) underwent brain 18F-FDG PET in the resting state. The images of PWS children were compared using statistical parametric mapping analysis with those of healthy children in a voxelwise manner. Group comparison showed that children with PWS had decreased glucose metabolism in the right superior temporal gyrus and left cerebellar vermis, regions that are associated with taste perception/food reward and cognitive and emotional function, respectively. Metabolism was increased in the right orbitofrontal, bilateral middle frontal, right inferior frontal, left superior frontal, and bilateral anterior cingulate gyri, right temporal pole, and left uncus, regions that are involved in cognitive functions related to eating or obsessive-compulsive behavior. Interestingly, no significant metabolic abnormality was found in the hypothalamus, the brain region believed to be most involved in energy intake and expenditure. This study describes the neural substrate underlying the abnormal eating behavior and psychobehavioral problems of PWS.

High unacylated ghrelin levels support the concept of anorexia in infants with prader-willi syndrome.

PubMed

Beauloye, Veronique; Diene, Gwenaelle; Kuppens, Renske; Zech, Francis; Winandy, Coralie; Molinas, Catherine; Faye, Sandy; Kieffer, Isabelle; Beckers, Dominique; Nergårdh, Ricard; Hauffa, Berthold; Derycke, Christine; Delhanty, Patrick; Hokken-Koelega, Anita; Tauber, Maithé

2016-05-04

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder with different nutritional phases from suckling deficit with failure to thrive to early onset of obesity. Hyperghrelinemia has been described in PWS long before the development of obesity. Ghrelin is found in both acylated (AG) and unacylated (UAG) forms in the circulation. In contrast to AG, UAG has been shown to inhibit food intake and to be elevated in anorexia nervosa. The present project is aiming to determine the underlying mechanisms driving the different nutritional phases in PWS. Measurement of at least 4 h-fasting plasma acylated and unacylated ghrelin in 37 infants with a genetic diagnosis of PWS aged from 1 month to 4 years and in 100 age-matched controls without endocrine disorder recruited prior to minor surgery. One blood sampling was analysed for each patient/control and clinical data were recorded. Eleven PWS infants underwent repetitive blood samples at 3 or 6-month intervals during routine visits. In infants with PWS, AG is not elevated (p = 0.45), UAG is significantly higher (p = 0.0044; confidence interval 1.06;1.33) resulting in a low AG/UAG ratio (p = 0.0056; confidence interval 0.76;0.95) compared to controls. Unlike children and adults with PWS that have high AG and AG/UAG ratio, infants with PWS have elevated UAG that supports the concept of anorexia in the early phases of the disease. The change in AG/UAG ratio possibly drives the switch from failure to thrive to obesity. NCT02529085 .

Behavioural and cognitive abnormalities in an imprinting centre deletion mouse model for Prader-Willi syndrome.

PubMed

Relkovic, Dinko; Doe, Christine M; Humby, Trevor; Johnstone, Karen A; Resnick, James L; Holland, Anthony J; Hagan, Jim J; Wilkinson, Lawrence S; Isles, Anthony R

2010-01-01

The genes in the imprinted cluster on human chromosome 15q11-q13 are known to contribute to psychiatric conditions such as schizophrenia and autism. Major disruptions of this interval leading to a lack of paternal allele expression give rise to Prader-Willi syndrome (PWS), a neurodevelopmental disorder with core symptoms of a failure to thrive in infancy and, on emergence from infancy, learning disabilities and over-eating. Individuals with PWS also display a number of behavioural problems and an increased incidence of neuropsychiatric abnormalities, which recent work indicates involve aspects of frontal dysfunction. To begin to examine the contribution of genes in this interval to relevant psychological and behavioural phenotypes, we exploited the imprinting centre (IC) deletion mouse model for PWS (PWS-IC(+/-)) and the five-choice serial reaction time task (5-CSRTT), which is primarily an assay of visuospatial attention and response control that is highly sensitive to frontal manipulations. Locomotor activity, open-field behaviour and sensorimotor gating were also assessed. PWS-IC(+/-) mice displayed reduced locomotor activity, increased acoustic startle responses and decreased prepulse inhibition of startle responses. In the 5-CSRTT, the PWS-IC(+/-) mice showed deficits in discriminative response accuracy, increased correct reaction times and increased omissions. Task manipulations confirmed that these differences were likely to be due to impaired attention. Our data recapitulate several aspects of the PWS clinical condition, including findings consistent with frontal abnormalities, and may indicate novel contributions of the imprinted genes found in 15q11-q13 to behavioural and cognitive function generally.

Healthcare transition in persons with intellectual disabilities: general issues, the Maastricht model, and Prader-Willi syndrome.

PubMed

Schrander-Stumpel, Constance T R M; Sinnema, Margje; van den Hout, Lieke; Maaskant, Marian A; van Schrojenstein Lantman-de Valk, Henny M J; Wagemans, Annemieke; Schrander, Jaap J P; Curfs, Leopold M G

2007-08-15

In current healthcare, transitional healthcare is a very important and timely issue. Thanks to the major advances made in medical care and technology, many children with childhood onset diseases and/or genetic syndromes survive to adulthood. These children are at risk of not being provided with adequate healthcare as they reach adulthood. Healthcare transition is an essential part of healthcare provision, referred to as the shift from one type of healthcare to another. In Maastricht, we developed a transition/out clinic led by a medical doctor specialized in persons with intellectual disability (ID), together with a clinical geneticist. We aim to coordinate healthcare issues based on guidelines if available. Also questions concerning living, daily activities, relations, sexuality, and sterilization can be discussed. The aging process of persons with ID has been a topic of interest in recent years. Little is known about the aging process of people with specific syndromes, except for persons with Down syndrome. We present some data of a recent questionnaire study in persons with Prader-Willi syndrome. In only 50% in persons with a clinical diagnosis genetic test results could be reported. The majority of persons were obese. Diabetes mellitus, hypertension, skin problems, sleep apnea, and hormonal problems like osteoporosis and hypothyroidism were common. Psychiatric problems were frequent, especially in the persons with uniparental disomy. Osteoporosis and sleep apnoea seem to be underestimated. Further longitudinal research is necessary for a better understanding of the aging process in PWS. (c) 2007 Wiley-Liss, Inc.

Thyroid axis dysfunction in patients with Prader-Willi syndrome during the first 2 years of life.

PubMed

Vaiani, Elisa; Herzovich, Viviana; Chaler, Eduardo; Chertkoff, Lilien; Rivarola, Marco A; Torrado, Maria; Belgorosky, Alicia

2010-10-01

Prader-Willi syndrome (PWS) is a genetic disorder caused by the loss of expression of paternally transcribed genes in a highly imprinted region of chromosome 15q11-13. The clinical phenotype has been well characterized, mostly related to hypothalamic dysfunction. Even though central hypothyroidism has been documented in 20-30% of patients with PWS, thyroid function during the first 2 years of life has not been clearly defined. To evaluate hypothalamic-pituitary-thyroid function in infant PWS patients. Eighteen patients with PWS, aged 0.16-2 years, were included in a prospective study. PWS diagnosis was based on clinical features and molecular analysis. Serum total (T) T4, free (F) T4, T3 and thyroid-stimulating hormone (TSH) were evaluated in the patients with PWS included in the study. Serum hormone values were compared to those of a large reference population of the same age. In 13 of 18 patients with PWS (72.2%), serum TT4 and/or FT4 levels were below the 2.5th percentile of the reference population, while in only one PWS patient serum T3 was below this cut-off. The results of this study suggest that transient or definitive thyrotropin-releasing hormone (TRH)-TSH thyroid axis dysfunction may frequently be present in infant PWS patients. Paediatricians should be aware of this dysfunction in this critical period of thyroid hormone action on neurological development. © 2010 Blackwell Publishing Ltd.

Metabolic and adipose tissue signatures in adults with Prader-Willi syndrome: a model of extreme adiposity.

PubMed

Lacroix, Delphine; Moutel, Sandrine; Coupaye, Muriel; Huvenne, Hélène; Faucher, Pauline; Pelloux, Véronique; Rouault, Christine; Bastard, Jean-Philippe; Cagnard, Nicolas; Dubern, Béatrice; Clément, Karine; Poitou, Christine

2015-03-01

Prader-Willi syndrome (PWS), the most frequent syndrome of obesity, is a model of early fat mass (FM) development, but scarce data exist on adipose tissue characteristics. The objective of the study was to compare metabolic, fat distribution, and transcriptomic signatures of sc adipose tissue (scAT) in PWS adults, with matched obese adults with primary obesities. Hormonal and metabolic assessments, systemic inflammation, and gene expression in scAT were compared between PWS patients and obese controls (OCs). Each 42nd PWS patient was matched with one randomly paired control with primary obesity. Matching factors were age, gender, fat mass (percentage), and diabetic status. Compared with OCs, the PWS group had a decreased percentage of trunk FM and a better metabolic profile with decreased insulin and homeostasis model assessment, an index of insulin-resistance, and increased concentrations of serum adiponectin and ghrelin. Adipocyte size relative to body fat was significantly higher in PWS vs OCs. scAT in PWS patients was characterized by a transcriptomic functional signature with enrichment of themes related to immunoinflammation, the extracellular matrix, and angiogenesis. A RT-PCR targeted study revealed that candidate genes encoding proinflammatory markers and remodeling molecules, CD68, CD3e, IL-1β, chemokine (C-C motif) ligand 5, collagen type 4-α, and lysyl oxidase, were down-regulated. Matched for FM, PWS subjects have a better metabolic profile, a phenotype that could be linked to changes in scAT remodeling and promotion of adipocyte growth.

Gait initiation and termination strategies in patients with Prader-Willi syndrome.

PubMed

Cimolin, Veronica; Cau, Nicola; Galli, Manuela; Santovito, Cristina; Grugni, Graziano; Capodaglio, Paolo

2017-05-23

Gait Initiation (GI) is a functional task representing one of the first voluntary destabilizing behaviours observed in the development of a locomotor pattern as the whole body centre of mass transitions from a large to a small base of support. Conversely, Gait Termination (GT) consists in the transition from walking to standing which, in everyday life, is a very common movement. Compared to normal walking, it requires higher control of postural stability. For a safe GT, the forward movement of the body has to be slowed down to achieve a stable upright position. Stability requirements have to be fulfilled for safe GT. In individuals with Prader-Willi syndrome (PWS), excessive body weight negatively affects the movement, such as walking and posture, but there are no experimental studies about GI and GT in these individuals. The aim of this study was to quantitatively characterise the strategy of patients with PWS during GI and GT using parameters obtained by the Center of Pressure (CoP) track. Twelve patients with PWS, 20 obese (OG) and 19 healthy individuals (HG) were tested using a force platform during the GI and GT tasks. CoP plots were divided into different phases, and duration, length and velocity of the CoP trace in these phases were calculated and compared for each task. As for GI, the results showed a significant reduction of the task duration and lower velocity and CoP length parameters in PWS, compared to OG and HG. In PWS, those parameters were reduced to a higher degree with respect to the OG. During GT, longer durations, similar to OG, were observed in PWS than HG. Velocity is reduced when compared to OG and HG, especially in medio-lateral direction and in the terminal part of GT. From these data, GI appears to be a demanding task in most of its sub-phases for PWS individuals, while GT seems to require caution only towards the end of the task. Breaking the cycle of gait into the phases of GI and GT and implementing specific exercises focusing on weight

Irisin and the Metabolic Phenotype of Adults with Prader-Willi Syndrome

PubMed Central

Pollak, Yehuda; Eldar-Geva, Talia

2015-01-01

Context Hyperphagia, low resting energy expenditure, and abnormal body composition contribute to severe obesity in Prader Willi syndrome (PWS). Irisin, a circulating myokine, stimulates “browning” of white adipose tissue resulting in increased energy expenditure and improved insulin sensitivity. Irisin has not been previously studied in PWS. Objectives Compare plasma and salivary irisin in PWS adults and normal controls. Examine the relationship of irisin to insulin sensitivity and plasma lipids. Design and Study Participants A fasting blood sample for glucose, lipids, insulin, leptin, adinopectin, and irisin was obtained from 22 PWS adults and 54 healthy BMI-matched volunteers. Saliva was collected for irisin assay in PWS and controls. Results Fasting glucose (77±9 vs 83±7mg/dl, p = 0.004), insulin (4.1±2.0 vs 7.9±4.7μU/ml, p<0.001), and triglycerides (74±34 vs 109±71mg/dl, p = 0.007) were lower in PWS than in controls. Insulin resistance (HOMA-IR) was lower (0.79±0.041 vs 1.63±1.02, p<0.001) and insulin sensitivity (QUICKI) was higher (0.41±0.04 vs 0.36±0.03, p<0.001) in PWS. Plasma irisin was similar in both groups, but salivary irisin (64.5±52.0 vs 33.0±12.1ng/ml), plasma leptin (33.5±24.2 vs 19.7±19.3ng/ml) and plasma adinopectin (13.0±10.8 vs 7.6±4.5μg/ml) were significantly greater in PWS (p<0.001). In PWS, plasma irisin showed positive Pearson correlations with total cholesterol (r = 0.58, p = 0.005), LDL-cholesterol (r = 0.59, p = 0.004), and leptin (r = 0.43, p = 0.045). Salivary irisin correlated negatively with HDL-cholesterol (r = -0.50, p = 0.043) and positively with LDL-cholesterol (r = 0.51, p = 0.037) and triglycerides (r = 0.50, p = 0.041). Conclusions Salivary irisin was markedly elevated in PWS although plasma irisin was similar to levels in controls. Significant associations with plasma lipids suggest that irisin may contribute to the metabolic phenotype of PWS. PMID:26334732

Irisin and the Metabolic Phenotype of Adults with Prader-Willi Syndrome.

PubMed

Hirsch, Harry J; Gross, Itai; Pollak, Yehuda; Eldar-Geva, Talia; Gross-Tsur, Varda

2015-01-01

Hyperphagia, low resting energy expenditure, and abnormal body composition contribute to severe obesity in Prader Willi syndrome (PWS). Irisin, a circulating myokine, stimulates "browning" of white adipose tissue resulting in increased energy expenditure and improved insulin sensitivity. Irisin has not been previously studied in PWS. Compare plasma and salivary irisin in PWS adults and normal controls. Examine the relationship of irisin to insulin sensitivity and plasma lipids. A fasting blood sample for glucose, lipids, insulin, leptin, adinopectin, and irisin was obtained from 22 PWS adults and 54 healthy BMI-matched volunteers. Saliva was collected for irisin assay in PWS and controls. Fasting glucose (77 ± 9 vs 83 ± 7 mg/dl, p = 0.004), insulin (4.1 ± 2.0 vs 7.9 ± 4.7 μU/ml, p<0.001), and triglycerides (74 ± 34 vs 109 ± 71 mg/dl, p = 0.007) were lower in PWS than in controls. Insulin resistance (HOMA-IR) was lower (0.79 ± 0.041 vs 1.63 ± 1.02, p<0.001) and insulin sensitivity (QUICKI) was higher (0.41 ± 0.04 vs 0.36 ± 0.03, p<0.001) in PWS. Plasma irisin was similar in both groups, but salivary irisin (64.5 ± 52.0 vs 33.0 ± 12.1ng/ml), plasma leptin (33.5 ± 24.2 vs 19.7 ± 19.3 ng/ml) and plasma adinopectin (13.0 ± 10.8 vs 7.6 ± 4.5μg/ml) were significantly greater in PWS (p<0.001). In PWS, plasma irisin showed positive Pearson correlations with total cholesterol (r = 0.58, p = 0.005), LDL-cholesterol (r = 0.59, p = 0.004), and leptin (r = 0.43, p = 0.045). Salivary irisin correlated negatively with HDL-cholesterol (r = -0.50, p = 0.043) and positively with LDL-cholesterol (r = 0.51, p = 0.037) and triglycerides (r = 0.50, p = 0.041). Salivary irisin was markedly elevated in PWS although plasma irisin was similar to levels in controls. Significant associations with plasma lipids suggest that irisin may contribute to the metabolic phenotype of PWS.

Endocrine problems in children with Prader-Willi syndrome: special review on associated genetic aspects and early growth hormone treatment

PubMed Central

2012-01-01

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder characterized by hypothalamic-pituitary dysfunction. The main clinical features include neonatal hypotonia, distinctive facial features, overall developmental delay, and poor growth in infancy, followed by overeating with severe obesity, short stature, and hypogonadism later in development. This paper reviews recent updates regarding the genetic aspects of this disorder. Three mechanisms (paternal deletion, maternal disomy, and deficient imprinting) are recognized. Maternal disomy can arise because of 4 possible mechanisms: trisomy rescue (TR), gamete complementation (GC), monosomy rescue (MR), and postfertilization mitotic nondisjunction (Mit). Recently, TR/GC caused by nondisjunction at maternal meiosis 1 has been identified increasingly, as a result of advanced maternal childbearing age in Korea. We verified that the d3 allele increases the responsiveness of the growth hormone (GH) receptor to endogenous GH. This paper also provides an overview of endocrine dysfunctions in children with PWS, including GH deficiency, obesity, sexual development, hypothyroidism, and adrenal insufficiency, as well as the effects of GH treatment. GH treatment coupled with a strictly controlled diet during early childhood may help to reduce obesity, improve neurodevelopment, and increase muscle mass. A more active approach to correct these hormone deficiencies would benefit patients with PWS. PMID:22844316

Disruption of the mouse Necdin gene results in hypothalamic and behavioral alterations reminiscent of the human Prader-Willi syndrome.

PubMed

Muscatelli, F; Abrous, D N; Massacrier, A; Boccaccio, I; Le Moal, M; Cau, P; Cremer, H

2000-12-12

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with considerable clinical variability that is thought in large part to be the result of a hypothalamic defect. PWS results from the absence of paternal expression of imprinted genes localized in the 15q11-q13 region; however, none of the characterized genes has so far been shown to be involved in the etiology of PWS. Here, we provide a detailed investigation of a mouse model deficient for NECDIN: Linked to the mutation, a neonatal lethality of variable penetrance is observed. Viable NECDIN: mutants show a reduction in both oxytocin-producing and luteinizing hormone-releasing hormone (LHRH)-producing neurons in hypothalamus. This represents the first evidence of a hypothalamic deficiency in a mouse model of PWS. NECDIN:-deficient mice also display increased skin scraping activity in the open field test and improved spatial learning and memory in the Morris water maze. The latter features are reminiscent of the skin picking and improved spatial memory that are characteristics of the PWS phenotype. These striking parallels in hypothalamic structure, emotional and cognitive-related behaviors strongly suggest that NECDIN is responsible for at least a subset of the multiple clinical manifestations of PWS.

Promising effects of oxytocin on social and food-related behaviour in young children with Prader-Willi syndrome: a randomized, double-blind, controlled crossover trial.

PubMed

Kuppens, R J; Donze, S H; Hokken-Koelega, A C S

2016-12-01

Prader-Willi syndrome (PWS) is known for hyperphagia with impaired satiety and a specific behavioural phenotype with stubbornness, temper tantrums, manipulative and controlling behaviour and obsessive-compulsive features. PWS is associated with hypothalamic and oxytocinergic dysfunction. In humans without PWS, intranasal oxytocin administration had positive effects on social and eating behaviour, and weight balance. To evaluate the effects of intranasal oxytocin compared to placebo administration on social behaviour and hyperphagia in children with PWS. Randomized, double-blind, placebo-controlled, crossover study in a PWS Reference Center in the Netherlands. Crossover intervention with twice daily intranasal oxytocin (dose range 24-48 IU/day) and placebo administration, both during 4 weeks, in 25 children with PWS (aged 6 to 14 years). In the total group, no significant effects of oxytocin on social behaviour or hyperphagia were found, but in the 17 children younger than 11 years, parents reported significantly less anger (P = 0·001), sadness (P = 0·005), conflicts (P = 0·010) and food-related behaviour (P = 0·011), and improvement of social behaviour (P = 0·018) during oxytocin treatment compared with placebo. In the eight children older than 11 years, the items happiness (P = 0·039), anger (P = 0·042) and sadness (P = 0·042) were negatively influenced by oxytocin treatment compared to placebo. There were no side effects or adverse events. This randomized, double-blind, placebo-controlled study suggests that intranasal oxytocin administration has beneficial effects on social behaviour and food-related behaviour in children with PWS younger than 11 years of age, but not in those older than 11 years of age. © 2016 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.

Deactivation of the left dorsolateral prefrontal cortex in Prader-Willi syndrome after meal consumption

PubMed Central

Reinhardt, Martin; Parigi, Angelo Del; Chen, Kewei; Reiman, Eric M.; Thiyyagura, Pradeep; Krakoff, Jonathan; Hohenadel, Maximilian G.; Le, Duc Son N.T.; Weise, Christopher M.

2016-01-01

Background/Objectives Prader-Willi syndrome (PWS) a type of human genetic obesity may inform us about the physiology of non-syndromic obesity. Objective of this study was to investigate the functional correlates of hunger and satiety in individuals with PWS in comparison to healthy controls with obesity, hypothesizing that we would see significant differences in activation in the left dorsolateral prefrontal cortex (DLPFC) based on prior findings. Subjects/Methods This study compared the central effects of food consumption in 9 individuals with PWS (7 men, 2 women; body fat 35.3%±10.0) and 7 controls (7 men; body fat 28.8%±7.6), matched for percentage body fat. H215O PET scans were performed before and after consumption of a standardized liquid meal to obtain quantitative measures of regional cerebral blood flow (rCBF), a marker of neuronal activity. Results Compared with obese controls, PWS showed altered (p<0.05 FWE cluster-level corrected; voxelwise p<0.001) rCBF before and after meal consumption in multiple brain regions. There was a significant differential rCBF response within the left DLPFC after meal ingestion with decreases in DLPFC rCBF in PWS; in controls DLPFC rCBF tended to remain unchanged. In more liberal analyses (voxelwise p<0.005) rCBF of the right orbitofrontal cortex (OFC) increased in PWS and decreased in controls. In PWS, ΔrCBF of the right OFC was associated with changes in appetite ratings. Conclusion The pathophysiology of eating behavior in PWS is characterized by a paradoxical meal induced deactivation of the left DLPFC and activation in the right OFC, brain regions implicated in the central regulation of eating behavior. PMID:27121248

Divergent structural brain abnormalities between different genetic subtypes of children with Prader-Willi syndrome.

PubMed

Lukoshe, Akvile; White, Tonya; Schmidt, Marcus N; van der Lugt, Aad; Hokken-Koelega, Anita C

2013-10-22

Prader-Willi syndrome (PWS) is a complex neurogenetic disorder with symptoms that indicate not only hypothalamic, but also a global, central nervous system (CNS) dysfunction. However, little is known about developmental differences in brain structure in children with PWS. Thus, our aim was to investigate global brain morphology in children with PWS, including the comparison between different genetic subtypes of PWS. In addition, we performed exploratory cortical and subcortical focal analyses. High resolution structural magnetic resonance images were acquired in 20 children with genetically confirmed PWS (11 children carrying a deletion (DEL), 9 children with maternal uniparental disomy (mUPD)), and compared with 11 age- and gender-matched typically developing siblings as controls. Brain morphology measures were obtained using the FreeSurfer software suite. Both children with DEL and mUPD showed smaller brainstem volume, and a trend towards smaller cortical surface area and white matter volume. Children with mUPD had enlarged lateral ventricles and larger cortical cerebrospinal fluid (CSF) volume. Further, a trend towards increased cortical thickness was found in children with mUPD. Children with DEL had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes. Focal analyses revealed smaller white matter volumes in left superior and bilateral inferior frontal gyri, right cingulate cortex, and bilateral precuneus areas associated with the default mode network (DMN) in children with mUPD. Children with PWS show signs of impaired brain growth. Those with mUPD show signs of early brain atrophy. In contrast, children with DEL show signs of fundamentally arrested, although not deviant brain development and presented few signs of cortical atrophy. Our results of global brain measurements suggest divergent neurodevelopmental patterns in children with DEL and mUPD.

Strength characterization of knee flexor and extensor muscles in Prader-Willi and obese patients.

PubMed

Capodaglio, Paolo; Vismara, Luca; Menegoni, Francesco; Baccalaro, Gabriele; Galli, Manuela; Grugni, Graziano

2009-05-06

despite evidence of an obesity-related disability, there is a lack of objective muscle functional data in overweight subjects. Only few studies provide instrumental strength measurements in non-syndromal obesity, whereas no data about Prader-Willi syndrome (PWS) are reported. The aim of our study was to characterize the lower limb muscle function of patients affected by PWS as compared to non-syndromal obesity and normal-weight subjects. We enrolled 20 obese (O) females (age: 29.1 +/- 6.5 years; BMI: 38.1 +/- 3.1), 6 PWS females (age: 27.2 +/- 4.9 years; BMI: 45.8 +/- 4.4) and 14 healthy normal-weight (H) females (age: 30.1 +/- 4.7 years; BMI: 21 +/- 1.6). Isokinetic strength during knee flexion and extension in both lower limbs at the fixed angular velocities of 60 degrees /s, 180 degrees /s, 240 degrees /s was measured with a Cybex Norm dynamometer. the H, O and PWS populations appear to be clearly stratified with regard to muscle strength.: PWS showed the lowest absolute peak torque (PT) for knee flexor and extensor muscles as compared to O (-55%) and H (-47%) (P = 0.00001). O showed significantly higher strength values than H as regard to knee extension only (P = 0.0014). When strength data were normalised by body weight, PWS showed a 50% and a 70% reduction in PT as compared to O and H, respectively. Knee flexors strength values were on average half of those reported for extension in all of the three populations. the novel aspect of our study is the determination of objective measures of muscle strength in PWS and the comparison with O and H patients. The objective characterization of muscle function performed in this study provides baseline and outcome measures that may quantify specific strength deficits amendable with tailored rehabilitation programs and monitor effectiveness of treatments.

Macronutrient Regulation of Ghrelin and Peptide YY in Pediatric Obesity and Prader-Willi Syndrome

PubMed Central

Balikcioglu, Metin; Muehlbauer, Michael J.; Purnell, Jonathan Q.; Broadhurst, David; Freemark, Michael; Haqq, Andrea M.

2015-01-01

Background: The roles of macronutrients and GH in the regulation of food intake in pediatric obesity and Prader-Willi Syndrome (PWS) are poorly understood. Objective: We compared effects of high-carbohydrate (HC) and high-fat (HF) meals and GH therapy on ghrelin, insulin, peptide YY (PYY), and insulin sensitivity in children with PWS and body mass index (BMI) –matched obese controls (OCs). Methods: In a randomized, crossover study, 14 PWS (median, 11.35 y; BMI z score [BMI-z], 2.15) and 14 OCs (median, 11.97 y; BMI-z, 2.35) received isocaloric breakfast meals (HC or HF) on separate days. Blood samples were drawn at baseline and every 30 minutes for 4 hours. Mixed linear models were adjusted for age, sex, and BMI-z. Results: Relative to OCs, children with PWS had lower fasting insulin and higher fasting ghrelin and ghrelin/PYY. Ghrelin levels were higher in PWS across all postprandial time points (P < .0001). Carbohydrate was more potent than fat in suppressing ghrelin levels in PWS (P = .028); HC and HF were equipotent in OCs but less potent than in PWS (P = .011). The increase in PYY following HF was attenuated in PWS (P = .037); thus, postprandial ghrelin/PYY remained higher throughout. A lesser increase in insulin and lesser decrease in ghrelin were observed in GH-treated PWS patients than in untreated patients; PYY responses were comparable. Conclusion: Children with PWS have fasting and postprandial hyperghrelinemia and an attenuated PYY response to fat, yielding a high ghrelin/PYY ratio. GH therapy in PWS is associated with increased insulin sensitivity and lesser postprandial suppression of ghrelin. The ratio Ghrelin/PYY may be a novel marker of orexigenic drive. PMID:26259133

Deactivation of the left dorsolateral prefrontal cortex in Prader-Willi syndrome after meal consumption.

PubMed

Reinhardt, M; Parigi, A D; Chen, K; Reiman, E M; Thiyyagura, P; Krakoff, J; Hohenadel, M G; Le, D S N T; Weise, C M

2016-09-01

Prader-Willi syndrome (PWS) is a type of human genetic obesity that may give us information regarding the physiology of non-syndromic obesity. The objective of this study was to investigate the functional correlates of hunger and satiety in individuals with PWS in comparison with healthy controls with obesity, hypothesizing that we would see significant differences in activation in the left dorsolateral prefrontal cortex (DLPFC) based on prior findings. This study compared the central effects of food consumption in nine individuals with PWS (7 men, 2 women; body fat 35.3±10.0%) and seven controls (7 men; body fat 28.8±7.6%), matched for percentage body fat. H2(15)O-PET (positron emission tomography) scans were performed before and after consumption of a standardized liquid meal to obtain quantitative measures of regional cerebral blood flow (rCBF), a marker of neuronal activity. Compared with obese controls, PWS showed altered (P<0.05 family-wise error cluster-level corrected; voxelwise P<0.001) rCBF before and after meal consumption in multiple brain regions. There was a significant differential rCBF response within the left DLPFC after meal ingestion with decreases in DLPFC rCBF in PWS; in controls, DLPFC rCBF tended to remain unchanged. In more liberal analyses (P<0.05 family-wise error cluster-level corrected; voxelwise P<0.005), rCBF of the right orbitofrontal cortex (OFC) increased in PWS and decreased in controls. In PWS, ΔrCBF of the right OFC was associated with changes in appetite ratings. The pathophysiology of eating behavior in PWS is characterized by a paradoxical meal-induced deactivation of the left DLPFC and activation in the right OFC, brain regions implicated in the central regulation of eating behavior.

TPH2 polymorphisms and expression in Prader-Willi syndrome subjects with differing genetic subtypes.

PubMed

Henkhaus, Rebecca S; Bittel, Douglas C; Butler, Merlin G

2010-09-01

Prader-Willi syndrome (PWS) is a genetic imprinting disease that causes developmental and behavioral disturbances resulting from loss of expression of genes from the paternal chromosome 15q11-q13 region. In about 70% of subjects, this portion of the paternal chromosome is deleted, while 25% have two copies of the maternal chromosome 15, or uniparental maternal disomy (UPD; the remaining subjects have imprinting center defects. There are several documented physical and behavioral differences between the two major PWS genetic subtypes (deletion and UPD) indicating the genetic subtype plays a role in clinical presentation. Serotonin is known to be disturbed in PWS and affects both eating behavior and compulsion, which are reported to be abnormal in PWS. We investigated the tryptophan hydroxylase gene (TPH2), the rate-limiting enzyme in the production of brain serotonin, by analyzing three different TPH2 gene polymorphisms, transcript expression, and correlation with PWS genetic subtype. DNA and RNA from lymphoblastoid cell lines derived from 12 PWS and 12 comparison subjects were used for the determination of genetic subtype, TPH2 polymorphisms and quantitative RT-PCR analysis. A similar frequency of TPH2 polymorphisms was seen in the PWS and comparison subjects with PWS deletion subjects showing increased expression with one or more TPH2 polymorphism. Both PWS deletion and PWS UPD subjects had significantly lower TPH2 expression than control subjects and PWS deletion subjects had significantly lower TPH2 expression compared with PWS UPD subjects. PWS subjects with 15q11-q13 deletions had lower TPH2 expression compared with PWS UPD or control subjects, requiring replication and further studies to identify the cause including identification of disturbed gene interactions resulting from the deletion process.

Prader-Willi Syndrome due to an Unbalanced de novo Translocation t(15;19)(q12;p13.3).

PubMed

Dang, Vy; Surampalli, Abhilasha; Manzardo, Ann M; Youn, Stephanie; Butler, Merlin G; Gold, June-Anne; Kimonis, Virginia E

2016-01-01

Prader-Willi syndrome (PWS) is a complex, multisystem genetic disorder characterized by endocrine, neurologic, and behavioral abnormalities. We report the first case of an unbalanced de novo reciprocal translocation of chromosomes 15 and 19, 45,XY,-15,der(19)t(15;19)(q12;p13.3), resulting in monosomy for the PWS critical chromosome region. Our patient had several typical features of PWS including infantile hypotonia, a poor suck and feeding difficulties, tantrums, skin picking, compulsions, small hands and feet, and food seeking, but not hypopigmentation, a micropenis, cryptorchidism or obesity as common findings seen in PWS at the time of examination at 6 years of age. He had seizures noted from 1 to 3 years of age and marked cognitive delay. High-resolution SNP microarray analysis identified an atypical PWS type I deletion in chromosome 15 involving the proximal breakpoint BP1. The deletion extended beyond the GABRB3 gene but was proximal to the usual distal breakpoint (BP3) within the 15q11q13 region, and GABRA5, GABRG3, and OCA2 genes were intact. No deletion of band 19p13.3 was detected; therefore, the patient was not at an increased risk of tumors from the Peutz-Jeghers syndrome associated with a deletion of the STK11 gene. © 2016 S. Karger AG, Basel.

Attitudes toward prenatal genetic testing and therapeutic termination of pregnancy among parents of offspring with Prader-Willi syndrome.

PubMed

Even-Zohar Gross, Noa; Geva-Eldar, Talia; Pollak, Yehuda; Hirsch, Harry J; Gross, Itai; Gross-Tsur, Varda

2017-04-01

Prenatal diagnosis (PND) raises ethical dilemmas such as the option of termination of pregnancy (TOP) in cases with severe outcome. Prader-Willi Syndrome (PWS), a complex neurogenetic syndrome with high morbidity and mortality throughout life. Recently, a unique prenatal phenotype was reported and TOP becomes a possibility. To explore factors influencing the attitudes of parents of PWS children toward PND and TOP concerning a hypothetical pregnancy with a PWS fetus. All 85 parents of individuals with PWS were interviewed regarding their attitudes towards PND and TOP using semi-structured questionnaire. Fifty-seven parents were supportive of invasive PND and 28 of non-invasive tests only; none opposed PND. Thirty eight favored TOP, additional 31 supported TOP under certain conditions such as spiritual advice, 15 were categorically against TOP. Attitudes correlated with religiosity (p < 0.025), mother's education (p < 0.001), mother's work status (p < 0.001), current age of the child with PWS (p < 0.008). Couples had similar attitudes regarding PND and TOP. No correlation was found with gender, genetic subtype and parental age. Most parents of individuals with PWS support PND, however less than half support TOP. Religiosity was the most influential factor. Familial worldview should be taken into account during prenatal counseling. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

A 5-year-old white girl with Prader-Willi syndrome and a submicroscopic deletion of chromosome 15q11q13

DOE Office of Scientific and Technical Information (OSTI.GOV)

Butler, M.G.; Christian, S.L.; Kubota, T.

1996-10-16

We report on a 5-year-old white girl with Prader-Willi syndrome (PWS) and a submicroscopic deletion of 15q11q13 of approximately 100-200 kb in size. High resolution chromosome analysis was normal but fluorescence in situ hybridization (FISH), Southern hybridization, and microsatellite data from the 15q11q13 region demonstrated that the deletion was paternal in origin and included the SNRPN, PAR-5, and PAR-7 genes from the proximal to distal boundaries of the deletion segment. SNRPN and PW71B methylation studies showed an abnormal pattern consistent with the diagnosis of PWS and supported the presence of a paternal deletion of 15q11q13 or an imprinting mutation. Biparentalmore » (normal) inheritance of PW71B (D15S63 locus) and a deletion of the SNRPN gene were observed by microsatellite, quantitative Southern hybridization, and/or FISH analyses. Our patient met the diagnostic criteria for PWS, but has no reported behavior problems, hyperphagia, or hypopigmentation. Our patient further supports SNRPN and possibly other genomic sequences which are deleted as the cause of the phenotype recognized in PWS patients. 21 refs., 7 figs.« less

A 5-year-old white girl with Prader-Willi syndrome and a submicroscopic deletion of chromosome 15q11q13.

PubMed

Butler, M G; Christian, S L; Kubota, T; Ledbetter, D H

1996-10-16

We report on a 5-year-old white girl with Prader-Willi syndrome (PWS) and a submicroscopic deletion of 15q11q13 of approximately 100-200 kb in size. High resolution chromosome analysis was normal but fluorescence in situ hybridization (FISH), Southern hybridization, and microsatellite data from the 15q11q13 region demonstrated that the deletion was paternal in origin and included the SNRPN, PAR-5, and PAR-7 genes from the proximal to distal boundaries of the deletion segment. SNRPN and PW71B methylation studies showed an abnormal pattern consistent with the diagnosis of PWS and supported the presence of a paternal deletion of 15q11q13 or an imprinting mutation. Biparental (normal) inheritance of PW71B (D15S63 locus) and a deletion of the SNRPN gene were observed by microsatellite, quantitative Southern hybridization, and/or FISH analyses. Our patient met the diagnostic criteria for PWS, but has no reported behavior problems, hyperphagia, or hypopigmentation. Our patient further supports SNRPN and possibly other genomic sequences which are deleted as the cause of the phenotype recognized in PWS patients.

Comparative analysis of autistic traits and behavioral disorders in Prader-Willi syndrome and Asperger disorder.

PubMed

Song, Dae Kwang; Sawada, Masayuki; Yokota, Shingo; Kuroda, Kenji; Uenishi, Hiroyuki; Kanazawa, Tetsufumi; Ogata, Hiroyuki; Ihara, Hiroshi; Nagai, Toshiro; Shimoda, Kazutaka

2015-01-01

Prader-Willi syndrome (PWS) is a neuro-genetic disorder caused by the absence/loss of expression of one or more paternally expressed genes on chromosome 15 (q11-13). In this study, a comparative analysis of intelligence level and autistic traits was conducted between children with PWS (n = 30; 18 males, 12 females; age = 10.6 ± 2.8 years) and those with Asperger disorder (AD; n = 31; 24 males, 7 females; age = 10.5 ± 3.1 years). The children were compared by age group: lower elementary school age (6-8 years), upper elementary school age (9-12 years), and middle school age (13-15 years). As results, the intelligence levels of children with PWS were significantly lower than those with AD across all age groups. Autistic traits, assessed using the Pervasive Developmental Disorders Autism Society Japan Rating Scale (PARS), revealed that among elementary school age children, those with PWS had less prominent autistic traits than those with AD, however, among middle school age children, those with PWS and AD showed similar prominence. An analysis of the PARS subscale scores by age group showed that while the profiles of autistic traits for children with PWS differed from those of children with AD at elementary school age, the profiles showed no significant differences between the groups at middle school age. The findings suggest that autistic traits in PWS become gradually more prominent with increasing of age and that these autistic traits differ in their fundamental nature from those observed in AD. © 2014 Wiley Periodicals, Inc.

Hormonal and Metabolic Responses to a Single Bout of Resistance Exercise in Prader-Willi Syndrome
.

PubMed

Rubin, Daniela A; Clark, Susan J; Haqq, Andrea M; Castner, Diobel M; Ng, Jason; Judelson, Daniel A

2017-01-01

Prader-Willi syndrome (PWS) is characterized by excessive adiposity. Excess adiposity negatively affects hormonal and metabolic responses to aerobic exercise. This study determined whether PWS and/or adiposity affected hormonal and metabolic responses to resistance exercise. Eleven children with PWS (11.4 ± 3.1 years, 43.9 ± 7.5% body fat), 12 lean children (9.3 ± 1.4 years, 18.3 ± 4.9% body fat), and 13 obese children (9.6 ± 1.3 years, 40.3 ± 5.2% body fat) participated. The children stepped onto an elevated platform while wearing a weighted vest for 6 sets of 10 repetitions per leg (sets separated by 1 min of rest). For the children with PWS, the platform height was 23.0 cm and vest load was computed as (20% of stature × 50% of lean body mass)/23.0 cm. For the controls, the platform height was 20% of the stature and vest load 50% of the lean body mass. Blood samples were obtained before, immediately after, and during recovery from exercise (+15, +30, and +60 min). All groups had similar catecholamine, insulin, and glucagon responses. The groups showed no major differences in glucose and lactate levels. The PWS children demonstrated earlier increases in fatty acids during recovery and higher glycerol and ketone levels than the controls. The PWS children demonstrated largely intact hormonal, glycolytic, and lipolytic responses to lower-body resistance exercise. In PWS, elevated ketone levels suggest an incomplete fat oxidation.
. This is a work of the US Government and is not subject to copyright protection in the USA. Foreign copyrights may apply. Published by S. Karger AG, Basel.

Reduced gamma-aminobutyric acid is associated with emotional and behavioral problems in Prader-Willi syndrome.

PubMed

Rice, Lauren J; Lagopoulos, Jim; Brammer, Michael; Einfeld, Stewart L

2016-12-01

Prader-Willi syndrome (PWS) is characterized by infantile hypotonia, hypogonadism, small hands and feet, distinct facial features and usually intellectual impairment. The disorder is associated with severe behavioral disturbances which include hyperphagia leading to morbid obesity, temper outbursts, skin-picking, and compulsive behaviors. While the brain mechanisms that underpin these disturbances are unknown these behaviors suggest a lack of inhibition and thus gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter may be implicated. In the present study, we investigated in vivo brain GABA and its relationship with emotion and behavior in individuals with PWS. Single voxel proton magnetic resonance spectroscopy (1H-MRS) was performed on 15 individuals with PWS and 15 age- and gender-matched typically developing controls. GABA levels were measured in the parieto-occipital lobe. All other metabolite levels (N-acetyl aspartate, myo-Inositol, glutathione, glutamate, and glutamine + glutamate) were measured in the anterior cingulate cortex (ACC). GABA levels were significantly lower in the participants with PWS who had clinically significant emotional and behavioral problems relative to typically developing control participants and participants with PWS who did not have emotional and behavioral problems within the clinically significant range. GABA levels were negatively correlated with total behavioral problem scores as well as temper outbursts, skin-picking, depression, social relating difficulties, and a tendency to be self-absorbed. Our data suggests that alterations of the GABAergic system may play an important role in aspects of the pathophysiology of PWS. Pathological mechanism found in PWS may be relevant to understanding the control of similar behaviors in the general population. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Children with Prader-Willi syndrome vs. Williams syndrome: indirect effects on parents during a jigsaw puzzle task.

PubMed

Ly, T M; Hodapp, R M

2005-12-01

Genetic disorders predispose individuals to exhibit characteristic behaviours, which in turn elicit particular behaviours from others. In response to the strength of Prader-Willi syndrome (PWS) and weakness of Williams syndrome (WS) in visual-spatial tasks such as jigsaw puzzles, parents' behaviours can be affected by their child's level of puzzle ability or syndrome diagnosis. Children were asked to complete two jigsaw puzzles (one with the experimenter and the other with the parent) for 5 min each. Frequencies of parental helping and reinforcement behaviours, along with ratings of parental directiveness, were examined as parents interacted with their children on a jigsaw puzzle task. Within each aetiological group, correlates of parental behaviours with child characteristics were also examined. Compared to parents of children with PWS, parents of children with WS engaged in a more directive style of interaction, and provided more help and reinforcement. Relative to parents of children with higher puzzle abilities (from both aetiologies), parents of children with lower abilities also showed the same pattern. Both the child's aetiology and puzzle abilities were important in predicting parents' directiveness and helping and reinforcement behaviours. Within the PWS group, parents' behaviours correlated negatively with the child's puzzle abilities and general cognitive functioning; no such relations occurred in the WS group. Parents' behaviours were affected by both the child's diagnosis and actual puzzle abilities, suggesting important implications for understanding and intervening with parents and children with different genetic syndromes.

The relationship between compulsive behaviour and academic achievement across the three genetic subtypes of Prader-Willi syndrome.

PubMed

Zarcone, J; Napolitano, D; Peterson, C; Breidbord, J; Ferraioli, S; Caruso-Anderson, M; Holsen, L; Butler, M G; Thompson, T

2007-06-01

Prader-Willi syndrome (PWS) is a genetic syndrome associated with several physical, cognitive and behavioural characteristics. For many individuals with this syndrome, compulsive behaviour is often noted in both food and non-food situations. The focus of this paper is on the non-food-related compulsions in individuals with PWS and comparing differences across the three genetic subtypes of the syndrome. Compulsive behaviours in 73 people with PWS were assessed using the Yale-Brown Obsessive Compulsive Scale and the Compulsive Behavior Checklist. Compulsive behaviour and its relation to IQ and academic achievement also were evaluated. Phenotypic differences were characterized for the three most common genetic subtypes of the disorder: 16 individuals with the long Type I (TI) 15q deletion, 26 individuals with the short Type II (TII) 15q deletion and 31 individuals with maternal disomy 15. There appeared to be important differences between the two deletion subtypes. Specifically, individuals with the TI deletion had more compulsions regarding personal cleanliness (i.e. excessive bathing/grooming), and their compulsions were more difficult to interrupt and interfered with social activities more than the other subtypes. Individuals with the TII deletion were more likely to have compulsions related to specific academic areas (i.e. rereading, erasing answers and counting objects or numbers). These findings may help clinicians and researchers identify possible intervention strategies and supports based on the behavioural phenotype associated with genetic subtype in individuals with PWS.

Enhanced activation of reward mediating prefrontal regions in response to food stimuli in Prader-Willi syndrome.

PubMed

Miller, Jennifer L; James, G Andrew; Goldstone, Anthony P; Couch, Jessica A; He, Guojun; Driscoll, Daniel J; Liu, Yijun

2007-06-01

Individuals with Prader-Willi syndrome (PWS) exhibit severe disturbances in appetite regulation, including delayed meal termination, early return of hunger after a meal, seeking and hoarding food and eating of non-food substances. Brain pathways involved in the control of appetite in humans are thought to include the hypothalamus, frontal cortex (including the orbitofrontal, ventromedial prefrontal, dorsolateral prefrontal and anterior cingulate areas), insula, and limbic and paralimbic areas. We hypothesised that the abnormal appetite in PWS results from aberrant reward processing of food stimuli in these neural pathways. We compared functional MRI blood oxygen level dependent (BOLD) responses while viewing pictures of food in eight adults with PWS and eight normal weight adults after ingestion of an oral glucose load. Subjects with PWS demonstrated significantly greater BOLD activation in the ventromedial prefrontal cortex than controls when viewing food pictures. No significant differences were found in serum insulin, glucose or triglyceride levels between the groups at the time of the scan. Individuals with PWS had an increased BOLD response in the ventromedial prefrontal cortex compared with normal weight controls when viewing pictures of food after an oral glucose load. These findings suggest that an increased reward value for food may underlie the excessive hunger in PWS, and support the significance of the frontal cortex in modulating the response to food in humans. Our findings in the extreme appetite phenotype of PWS support the importance of the neural pathways that guide reward related behaviour in modulating the response to food in humans.

Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome patients with an imprinting mutation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Saitoh, S.; Cassidy, S.B.; Conroy, J.M.

Recent studies have identified a new class of Prader-Willi syndrome (PWS) and Angelman syndrome (AS) patients who have biparental inheritance, but neither the typical deletion nor uniparental disomy (UPD) or translocation. However, these patients have uniparental DNA methylation throughout 15q11-q13, and thus appear to have a mutation in the imprinting process for this region. Here we describe detailed clinical findings of five AS imprinting mutation patients (three families) and two PWS imprinting mutation patients (one new family). All these patients have essentially the classical clinical phenotype for the respective syndrome, except that the incidence of microcephaly is lower in imprintingmore » mutation AS patients than in deletion AS patients. Furthermore, imprinting mutation AS and PWS patients do not typically have hypopigmentation, which is commonly found in patients with the usual large deletion. Molecular diagnosis of these cases is initially achieved by DNA methylation analyses of the DN34/ZNF127, PW71 (D15S63), and SNRPN loci. The latter two probes have clear advantages in the simple molecular diagnostic analysis of PWS and AS patients with an imprinting mutation, as has been found for typical deletion or UPD PWS and AS cases. With the recent finding of inherited microdeletions in PWS and AS imprinting mutation families, our studies define a new class of these two syndromes. The clinical and molecular identification of these PWS and AS patients has important genetic counseling consequences. 49 refs., 4 figs., 3 tabs.« less

The characteristics of scoliosis in Prader-Willi syndrome (PWS): analysis of 58 scoliosis patients with PWS.

PubMed

Nakamura, Yutaka; Murakami, Nobuyuki; Iida, Takahiro; Ozeki, Satoru; Asano, Satoshi; Nohara, Yutaka; Nagai, Toshiro

2015-01-01

The purpose of this study was to compare the characteristics of scoliosis in Prader-Willi syndrome (PWS) patients versus idiopathic scoliosis (IS). We identified 193 PWS patients. Scoliosis was found in 58 PWS patients, 39 of whom were treated with GH. Fifty-five IS patients were consecutively selected from an outpatient clinic. We investigated 113 patients (58 PWS group, 55 IS group) followed for a minimum of 2 years. The mean age was 17.9 and 16.1 years, respectively. Deformity was measured using Lenke classification, Cobb angle, thoracic kyphosis at T2-5 and T5-12, lumbar lordosis at T12-S1, and sagittal alignment at the C7 plumb line. BMI was also recorded. According to the Lenke system, patients were classified as (PWS group/IS group): Type 1 (8/26), Type 2 (1/4), Type 3 (3/15), Type 4 (1/0), Type 5 (32/8), and Type 6 (13/2). The average Cobb angles were 32.6° in the PWS and 35.4° in the IS. No significant differences were found for the thoracic kyphosis (T2-5, T5-12), lumbar lordosis (T12-S1) or C7 plumb line between the two groups. BMI was increased in the PWS group not treated previously with GH as compared with the IS group and the PWS group with GH. Most PWS patients presented with lumbar or thoracolumbar curves (Type 5, 6), whereas IS patients typically had thoracic scoliosis (Type 1, 2, 3).

Hormonal and metabolic defects in a prader-willi syndrome mouse model with neonatal failure to thrive.

PubMed

Stefan, M; Ji, H; Simmons, R A; Cummings, D E; Ahima, R S; Friedman, M I; Nicholls, R D

2005-10-01

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.

The noncoding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome.

PubMed

Stelzer, Yonatan; Sagi, Ido; Yanuka, Ofra; Eiges, Rachel; Benvenisty, Nissim

2014-06-01

Parental imprinting is a form of epigenetic regulation that results in parent-of-origin differential gene expression. To study Prader-Willi syndrome (PWS), a developmental imprinting disorder, we generated case-derived induced pluripotent stem cells (iPSCs) harboring distinct aberrations in the affected region on chromosome 15. In studying PWS-iPSCs and human parthenogenetic iPSCs, we unexpectedly found substantial upregulation of virtually all maternally expressed genes (MEGs) in the imprinted DLK1-DIO3 locus on chromosome 14. Subsequently, we determined that IPW, a long noncoding RNA in the critical region of the PWS locus, is a regulator of the DLK1-DIO3 region, as its overexpression in PWS and parthenogenetic iPSCs resulted in downregulation of MEGs in this locus. We further show that gene expression changes in the DLK1-DIO3 region coincide with chromatin modifications rather than DNA methylation levels. Our results suggest that a subset of PWS phenotypes may arise from dysregulation of an imprinted locus distinct from the PWS region.

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

PubMed

Butler, Merlin G; Theodoro, Mariana F; Bittel, Douglas C; Donnelly, Joseph E

2007-03-01

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

Growth hormone therapy improves exercise capacity in adult patients with Prader-Willi syndrome.

PubMed

Gondoni, L A; Vismara, L; Marzullo, P; Vettor, R; Liuzzi, A; Grugni, G

2008-09-01

Prader-Willi syndrome (PWS) is associated with an inappropriate proportion of fat mass (FM) to non-FM compared to simple obesity. Altered body composition in PWS resembles that seen in subjects with GH deficiency, in which a reduction of lean body mass (LBM) is observed. The low LBM may contribute to the reduced motor skills seen in PWS patients. The objective of the study was to investigate the effects of GH therapy on exercise capacity and body composition in a group of adult subjects with PWS. Twelve PWS adults (7 males and 5 females, aged 26.4+/-4.4 yr, body mass index 44.3+/-4.6 kg/m2) participated in the study. Body composition analysis and exercise stress test were carried out throughout the 12 months GH therapy. Body composition was measured by Dual Energy X-ray Absorptiometry. Physical performance was evaluated using treadmill exercise test. Exercise intensity was expressed as metabolic equivalents (MET, 1 MET= 3.5 ml O2 kg(-1) min(-1)). Statistical analysis was performed by repeated-measures analysis of variance followed by post-hoc analysis with t test for paired data for comparisons among the different follow ups. Compared to baseline GH therapy increased LBM at 6 (p<0.0001) and 12 months (p<0.005) (45.3+/-7.7 kg vs 48.6+/-6.7 kg vs 48.2+/-7.5 kg). FM% was significantly reduced both after 6 and 12 months (p<0.02) (56.1+/-4.8% vs 53.7+/-4.2% vs 53.3+/-4.8%). Attained MET were found to be improved by 16% after 6 months and by 19% after 12 months of GH (p<0.001), while the small further rise between 6 and 12 months was not significant. Our findings seem to support the view that GH therapy has beneficial effects on physical activity and agility as well as on body composition of adult patients with PWS.

Effectiveness of a 6-month home-based training program in Prader-Willi patients.

PubMed

Vismara, Luca; Cimolin, Veronica; Grugni, Graziano; Galli, Manuela; Parisio, Cinzia; Sibilia, Olivia; Capodaglio, Paolo

2010-01-01

In addition to hypotonia and relative sarcopenia, patients with Prader-Willi syndrome (PWS) show reduced spontaneous physical activity and gait disorders. Scant evidence exists that daily muscle training increases their lean mass and physical activity levels. Whether adequate long-term physical training is feasible and effective in improving muscle function and gait in PWS is still unknown. Eleven adult PWS patients (mean age: 33.8±4.3 years; mean BMI: 43.3±5.9 kg/m(2)) admitted to our hospital were enrolled in this study. During their hospital stay they attended a 2-week rehabilitation program which included supervised exercise sessions. At discharge, Group 1 (6 patients) continued the same exercises at home for 6 months, while Group 2 (5 patients) did not continue home-based training. They were assessed at admission (PRE), at 2 weeks (POST1) and at 6 months (POST2). The assessment consisted of a clinical examination, 3D gait analysis and muscle strength measurement with an isokinetic dynamometer. After 2 weeks of supervised training (POST1), no significant changes in spatial-temporal gait parameters were observed, although significant improvements in ankle dorsal flexion during stance and swing and knee flexor strength were evidenced by 3D gait analysis and dynamometry in all patients. Following 6 months of home training (POST2), Group 1 had showed significant improvements in cadence and reduced knee hyperextension in mid-stance. Ankle plantar and dorsal flexors isokinetic strength had improved significantly at 120° s(-1), whereas Group 2 showed no changes in their spatial-temporal and kinematic parameters. The present study reinforces the idea that even in participants with PWS who present with a distinctive psychological profile, long-term group interventions are feasible and effective in improving their overall physical functioning. Providing an effective and simple home-based training program represents a continuum of the rehabilitation process outside the

Prevalence and Phenotype of Sleep Disorders in 60 Adults With Prader-Willi Syndrome.

PubMed

Ghergan, Adelina; Coupaye, Muriel; Leu-Semenescu, Smaranda; Attali, Valérie; Oppert, Jean-Michel; Arnulf, Isabelle; Poitou, Christine; Redolfi, Stefania

2017-12-01

Excessive sleepiness is a common symptom in Prader-Willi syndrome (PWS), and it negatively impacts the quality of life. Obstructive sleep apnea and narcolepsy phenotypes have been reported in PWS. We characterized sleep disorders in a large cohort of adults with PWS. All consecutive patients with genetically confirmed PWS unselected for sleep-related symptoms, underwent a clinical interview, polysomnography, and multiple sleep latency tests (MSLT, n = 60), followed by long-term (24 hours) polysomnography (n = 22/60). Among 60 adults evaluated (57% female, aged 25 ± 10 years, body mass index: 39 ± 12 kg/m2), 67% reported excessive sleepiness. According to the sleep study results, 43% had a previously unrecognized hypersomnia disorder, 15% had an isolated sleep breathing disorder, 12% had combined hypersomnia disorder and untreated breathing sleep disorder, and only 30% had normal sleep. Isolated hypersomnia disorder included narcolepsy in 35% (type 1, n = 1, and type 2, n = 8), hypersomnia in 12% (total sleep time >11 hours, n = 2, and MSLT <8 minutes, n = 1), and borderline phenotype in 53% (≥2 sleep onset in REM periods and MSLT >8 minutes, n = 10, and 8 minutes < MSLT < 10 minutes, n = 4). Sleep breathing disorders, isolated and combined, included obstructive sleep apnea (n = 14, already treated in seven), sleep hypoxemia (n = 1) and previously undiagnosed hypoventilation (n = 5). Modafinil was taken by 16 patients (well tolerated in 10), resulting in improved sleepiness over a mean 5-year follow-up period. Sleepiness affects more than half of adult patients with PWS, with a variety of hypersomnia disorder (narcolepsy, hypersomnia, and borderline phenotypes) and breathing sleep disorders. Earlier diagnosis and management of sleep disorders may improve sleepiness, cognition, and behavior in these patients. © Sleep Research Society 2017. Published by Oxford University Press [on behalf of the Sleep Research Society]. All rights reserved. For permissions, please

A neuropsychological assessment of frontal cognitive functions in Prader-Willi syndrome.

PubMed

Jauregi, J; Arias, C; Vegas, O; Alén, F; Martinez, S; Copet, P; Thuilleaux, D

2007-05-01

Prader-Willi syndrome (PWS) is associated with a characteristic behavioural phenotype whose main features are, alongside compulsive hyperphagia, deficits in social behaviour: social withdrawal, temper tantrums, perseverative speech and behaviour, mental rigidity, stereotyped behaviour, impulsiveness, etc. Similar symptoms may also be found in autistic spectrum disorders and lesional pathologies of the frontal lobe. In both cases, such symptoms have been related to dysfunctions in frontal cognitive processes such as attention, working memory and executive functions. This study uses standardized neuropsychological instruments to analyse the degree to which these processes are affected in PWS. The sample comprised 16 individuals with a genetically confirmed PWS diagnosis. Subjects' IQ (Wechsler Adult Intelligence Scale), academic level, laterality and body mass index (BMI) were calculated. Attention, memory and executive functions were analysed using standard, widely employed neuropsychological tests. We compared the results of the sample group with the general population. Correlation analyses were carried out with IQ, academic level and BMI. In all the neuropsychological measures focusing on attention, executive functions and visuoperceptual organization, the study sample scored significantly lower than the normative reference population. The scores of the tests used for measuring immediate memory were also significantly lower when trials required sequential processing, although not when they required simultaneous processing. In the memorization of a list of words, subjects showed an initial deficit which disappeared with repetition, enabling them to obtain scores similar to the reference population. No significant correlations were found with BMI, and a higher IQ or academic level did not improve scores in the majority of tests. The study shows a deficit in elementary frontal cognitive processes in PWS patients. This deficit may be involved in the social behaviour

Relationship between antipsychotics and weight in patients with Prader-Willi syndrome.

PubMed

Elliott, Jennifer Padden; Cherpes, Gregory; Kamal, Khalid; Chopra, Ishveen; Harrison, Chelsea; Riedy, Mary; Herk, Brandon; McCrossin, Matt; Kalarchian, Melissa

2015-03-01

Individuals with Prader-Willi Syndrome (PWS) are at increased risk for developing behavioral and psychiatric disorders, often requiring antipsychotics (APs). Contrary to significant AP-associated weight gain observed in the general population, existing literature suggests weight loss in patients with PWS. To evaluate the relationship between AP use and body mass index (BMI) at admission, change in BMI during inpatient stay, and length of stay (LOS) in patients admitted to an inpatient PWS treatment program. Retrospective case-control study. Hospital-based, inpatient PWS treatment program serving nationally and internationally referred children and adults with PWS. Cases consisted of 52 pediatric patients with PWS who were taking APs at admission and during their stay, 97 adults with PWS who were taking APs at admission and during their stay, and 11 pediatric and adult patients with PWS who were AP naïve at admission and subsequently started an AP during their stay; all cases were matched with patients with PWS who were AP naïve at admission and during their stay by age (yrs), sex, and race-ethnicity (controls). Between- and within-group differences in admission BMI, BMI change from admission to discharge, and LOS were analyzed. Admission BMI was lower (mean ± SD 36.8 ± 11.9 kg/m(2) vs 46.7 ± 12.5 kg/m(2) , p<0.001) and LOS longer (mean ± SD 75.9 ± 38.5 days vs 57.8 ± 23.2 days, p=0.005) for pediatric cases with AP exposure at admission and during their stay compared with matched controls. All groups experienced significant decreases in BMI from admission to discharge (p≤0.001 for all comparisons), except for pediatric cases with AP exposure at admission and during their stay. Cases that were AP naïve at admission and subsequently started an AP during their inpatient stay experienced a significantly smaller decrease in BMI from admission to discharge than matched controls (-3.011 vs -7.288 kg/m(2) , p=0.027). No other comparisons between

Syndromes with salivary dysfunction predispose to tooth wear: Case reports of congenital dysfunction of major salivary glands, Prader-Willi, congenital rubella, and Sjögren's syndromes.

PubMed

Young, W; Khan, F; Brandt, R; Savage, N; Razek, A A; Huang, Q

2001-07-01

Four cases-of congenital dysfunction of the major salivary glands as well as of Prader-Willi, congenital rubella, and Sjögren's syndromes-were identified in a series of 500 patients referred for excessive tooth wear. Although there was evidence of consumption of highly acidic drinks, some occlusal parafunction, and unacceptable toothbrushing habits, salivary dysfunction was the salient factor predisposing a patient to tooth wear in these syndromal cases. The 500 subjects have been characterized either as having medical conditions and medications that predispose them to xerostomia or lifestyles in which workplace- and sports-related dehydration lead to reduced salivary flow. Normal salivation, by buffering capacity, clearance by swallowing, pellicle formation, and capacity for remineralization of demineralized enamel, protects the teeth from extrinsic and intrinsic acids that initiate dental erosion. Thus, the syndromes, unrelated in many respects, underline the importance of normal salivation in the protection of teeth against tooth wear by erosion, attrition, and abrasion.

Disorders of glucose metabolism in Prader-Willi syndrome: Results of a multicenter Italian cohort study.

PubMed

Fintini, D; Grugni, G; Bocchini, S; Brufani, C; Di Candia, S; Corrias, A; Delvecchio, M; Salvatoni, A; Ragusa, L; Greggio, N; Franzese, A; Scarano, E; Trifirò, G; Mazzanti, L; Chiumello, G; Cappa, M; Crinò, A

2016-09-01

Prader-Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1-50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children <10 yrs; adolescents 10-18 yrs, and adults >18 yrs), Body Mass Index (BMI = kg/m(2)), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program. Copyright © 2016 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Lack of Postprandial Peak in Brain-Derived Neurotrophic Factor in Adults with Prader-Willi Syndrome

PubMed Central

Bueno, Marta; Esteba-Castillo, Susanna; Novell, Ramon; Giménez-Palop, Olga; Coronas, Ramon; Gabau, Elisabeth; Corripio, Raquel; Baena, Neus; Viñas-Jornet, Marina; Guitart, Míriam; Torrents-Rodas, David; Deus, Joan; Pujol, Jesús; Rigla, Mercedes

2016-01-01

Context Prader-Willi syndrome (PWS) is characterized by severe hyperphagia. Brain-derived neurotrophic factor (BDNF) and leptin are reciprocally involved in energy homeostasis. Objectives To analyze the role of BDNF and leptin in satiety in genetic subtypes of PWS. Design Experimental study. Setting University hospital. Subjects 90 adults: 30 PWS patients; 30 age-sex-BMI-matched obese controls; and 30 age-sex-matched lean controls. Interventions Subjects ingested a liquid meal after fasting ≥10 hours. Main Outcome Measures Leptin and BDNF levels in plasma extracted before ingestion and 30’, 60’, and 120’ after ingestion. Hunger, measured on a 100-point visual analogue scale before ingestion and 60’ and 120’ after ingestion. Results Fasting BDNF levels were lower in PWS than in controls (p = 0.05). Postprandially, PWS patients showed only a truncated early peak in BDNF, and their BDNF levels at 60' and 120' were lower compared with lean controls (p<0.05). Leptin was higher in PWS patients than in controls at all time points (p<0.001). PWS patients were hungrier than controls before and after eating. The probability of being hungry was associated with baseline BDNF levels: every 50-unit increment in BDNF decreased the odds of being hungry by 22% (OR: 0.78, 95%CI: 0.65–0.94). In uniparental disomy, the odds of being hungry decreased by 66% (OR: 0.34, 90%CI: 0.13–0.9). Postprandial leptin patterns did no differ among genetic subtypes. Conclusions Low baseline BDNF levels and lack of postprandial peak may contribute to persistent hunger after meals. Uniparental disomy is the genetic subtype of PWS least affected by these factors. PMID:27685845

Repetitive behavior profiles: Consistency across autism spectrum disorder cohorts and divergence from Prader-Willi syndrome.

PubMed

Flores, Cindi G; Valcante, Gregory; Guter, Steve; Zaytoun, Annette; Wray, Emily; Bell, Lindsay; Jacob, Suma; Lewis, Mark H; Driscoll, Daniel J; Cook, Edwin H; Kim, Soo-Jeong

2011-12-01

Restricted and repetitive behavior (RRB) is a group of heterogeneous maladaptive behaviors. RRB is one of the key diagnostic features of autism spectrum disorders (ASDs) and also commonly observed in Prader-Willi syndrome (PWS). In this study, we assessed RRB using the Repetitive Behavior Scale-Revised (RBS-R) in two ASD samples (University of Illinois at Chicago [UIC] and University of Florida [UF]) and one PWS sample. We compared the RBS-R item endorsements across three ASD cohorts (UIC, UF and an ASD sample from Lam, The Repetitive Behavior Scale-Revised: independent validation and the effect of subject variables, PhD thesis, 2004), and a PWS sample. We also compared the mean RBS-R subscale/sum scores across the UIC, UF and PWS samples; across the combined ASD (UIC + UF), PWS-deletion and PWS-disomy groups; and across the combined ASD sample, PWS subgroup with a Social Communication Questionnaire (SCQ) score ≥15, and PWS subgroup with a SCQ score <15. Despite the highly heterogeneous nature, the three ASD samples (UIC, UF and Lam's) showed a similar pattern of the RBS-R endorsements, and the mean RBS-R scores were not different between the UIC and UF samples. However, higher RRB was noted in the ASD sample compared with the PWS sample, as well as in the PWS subgroup with a SCQ score ≥15 compared with the PWS subgroup with a SCQ score <15. Study limitations include a small sample size, a wide age range of our participants, and not controlling for potential covariates. A future replication study using a larger sample and further investigation into the genetic bases of overlapping ASD and RRB phenomenology are needed, given the higher RRB in the PWS subgroup with a SCQ score ≥15.

Elevated plasma oxytocin levels in children with Prader-Willi syndrome compared with healthy unrelated siblings.

PubMed

Johnson, Lisa; Manzardo, Ann M; Miller, Jennifer L; Driscoll, Daniel J; Butler, Merlin G

2016-03-01

Prader-Willi syndrome (PWS) is a rare genetic disorder associated with distinct abnormal behaviors including hyperphagia, profound social deficits, and obsessive-compulsive tendencies. PWS males showed reduced oxytocin receptor (OTR) gene expression and density in the hypothalamic paraventricular nucleus that may play a role in PWS psychopathology. Oxytocin is an anorexigenic neuropeptide similar to vasopressin that is associated with social cognition and obsessive-compulsive behavior. To evaluate oxytocin biology in PWS, we examined overnight fasting plasma oxytocin levels in 23 children with PWS (mean ± SD age: 8.2 ± 2.0 year) having genetic confirmation and 18 age matched healthy unrelated siblings without PWS (mean ± SD age: 8.2 ± 2.3 year) and a similar gender ratio under the same clinical assessments, specimen processing and laboratory conditions. Multiplex immune assays were carried out using the Milliplex Human Neuropeptide Magnetic panel and the Luminex system. Natural log-transformed oxytocin levels were analyzed using general linear model adjusting for diagnosis, gender, age and body mass index (BMI). Oxytocin plasma levels were significantly elevated in children with PWS (168 ± 121 pg/ml) compared with unrelated and unaffected siblings without the diagnosis of PWS (64.8 ± 83.8 pg/ml, F = 8.8, P < 0.01) and the diagnosis of PWS predicted oxytocin level (F = 9.5, P < 0.003) in controlled regression analysis with an overall model fit R(2) = 0.33 (P < 0.01). The symptoms of hyperphagia, anxiety and repetitive behaviors classically seen in PWS may be related to the disruption of oxytocin responsivity or feedback in the hypothalamic paraventricular nucleus possibly influencing vasopressin signaling. Further study is needed to characterize oxytocin function in PWS. © 2015 Wiley Periodicals, Inc.

The relationship between IGF-I concentration, cognitive function and quality of life in adults with Prader-Willi syndrome.

PubMed

van Nieuwpoort, I C; Deijen, J B; Curfs, L M G; Drent, M L

2011-04-01

Mental retardation is one of the clinical characteristics of Prader-Willi syndrome (PWS) and in part of the patients growth hormone deficiency is demonstrable. Cognitive function seems to be influenced by insulin-like growth factor I (IGF-I); however, little is known about cognitive function in relation to IGF-I levels in PWS adults. The aim of the present study was to evaluate cognitive function in adult PWS patients in comparison to healthy siblings and to investigate whether there is a correlation between cognitive function and IGF-I levels. Anthropometric measurements, IGF-I levels, quality of life (QoL), Appetite Assessment Score, IQ (GIT and Raven) and cognitive function (by four subtests of the Cambridge Neuropsychological Automated Testing Battery, CANTAB) were evaluated in PWS patients and their healthy siblings served as control group. PWS patients had significantly lower IGF-I levels, IQ and QoL when compared to controls. Reaction times were longer and performance was worse on CANTAB subtests in PWS adults. IGF-I on one hand and IQ, Appetite Assessment Score and cognitive performance on the other hand seem to be correlated in PWS patients. In conclusion, IGF-I levels, IQ and QoL are significantly lower in PWS subjects when compared to healthy siblings. In PWS adults, temporal as well as prefrontal cognitive functions are impaired. Higher IGF-I levels appear to be related to better intellectual skills and faster temporal memory processing in PWS patients. Copyright © 2011 Elsevier Inc. All rights reserved.

Altered inflammation, paraoxonase-1 activity and HDL physicochemical properties in obese humans with and without Prader-Willi syndrome

PubMed Central

Ferretti, Gianna; Bacchetti, Tiziana; Masciangelo, Simona; Grugni, Graziano; Bicchiega, Virginia

2012-01-01

SUMMARY Prader-Willi syndrome (PWS) represents the most common form of genetic obesity. Several studies confirm that obesity is associated with inflammation, oxidative stress and impairment of antioxidant systems; however, no data are available concerning PWS subjects. We compared levels of plasma lipids and C-reactive protein (CRP) in 30 subjects of ‘normal’ weight (18.5–25 kg/m2), 15 PWS obese (>30 kg/m2) subjects and 13 body mass index (BMI)-matched obese subjects not affected by PWS. In all subjects, we evaluated the levels of lipid hydroperoxides and the activity of paraoxonase-1 (PON1), an enzyme involved in the antioxidant and anti-inflammatory properties exerted by high-density lipoproteins (HDLs). Furthermore, using the fluorescent molecule of Laurdan, we investigated the physicochemical properties of HDLs isolated from normal weight and obese individuals. Altogether, our results demonstrated, for the first time, higher levels of lipid hydroperoxides and a lower PON1 activity in plasma of obese individuals with PWS with respect to normal-weight controls. These alterations are related to CRP levels, with a lower PON1:CRP ratio in PWS compared with non-PWS obese subjects. The study of Laurdan fluorescence parameters showed significant modifications of physicochemical properties in HDLs from PWS individuals. Whatever the cause of obesity, the increase of adiposity is associated with inflammation, oxidative stress and alterations in HDL compositional and functional properties. PMID:22822045

QOL in caregivers of Japanese patients with Prader-Willi syndrome with reference to age and genotype.

PubMed

Ihara, Hiroshi; Ogata, Hiroyuki; Sayama, Masayuki; Kato, Aya; Gito, Masao; Murakami, Nobuyuki; Kido, Yasuhiro; Nagai, Toshiro

2014-09-01

This study aimed to measure quality of life (QOL) of the primary family caregivers for patients with Prader-Willi syndrome (PWS). Comparisons were made between caregivers' QOL in regard to their dependents' genotype and age group. The participants with PWS consisted of 22 children (aged from 6 to 12 years) and 23 adolescents (aged from 13 to 19 years), including 6 children and 7 adolescents with maternal uniparental disomy (mUPD) and 16 children and 16 adolescents with deletion (DEL). The QOL of the primary family caregiver for each patient was assessed using the Japanese version of the WHOQOL-BREF. To examine the effect that age (children vs. adolescents) and genotype (DEL vs. mUPD) have on the QOL of caregivers, a two-way ANOVA was conducted, followed by the Bonferroni procedure to test the simple main effects. The two age groups and the two genotypes of PWS were used as independent variables and the total QOL of caregivers as a dependent variable. The two-way ANOVA (F(1, 41) = 6.98, P < 0.05), followed by the Bonferroni procedure, showed the following: the total QOL of caregivers of DEL adolescents showed little difference from that with DEL children, but the QOL of caregivers for mUPD adolescents was shown to be lower than that with mUPD children along with that of caregivers with DEL adolescents. There is hence a growing tendency for the deterioration in the QOL of caregivers to manifest itself later in the patients' adolescence, found mainly with mUPD patients. © 2014 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader-Willi syndrome iPSCs

PubMed Central

Cruvinel, Estela; Budinetz, Tara; Germain, Noelle; Chamberlain, Stormy; Lalande, Marc; Martins-Taylor, Kristen

2014-01-01

Prader-Willi syndrome (PWS), a disorder of genomic imprinting, is characterized by neonatal hypotonia, hypogonadism, small hands and feet, hyperphagia and obesity in adulthood. PWS results from the loss of paternal copies of the cluster of SNORD116 C/D box snoRNAs and their host transcript, 116HG, on human chromosome 15q11-q13. We have investigated the mechanism of repression of the maternal SNORD116 cluster and 116HG. Here, we report that the zinc-finger protein ZNF274, in association with the histone H3 lysine 9 (H3K9) methyltransferase SETDB1, is part of a complex that binds to the silent maternal but not the active paternal alleles. Knockdown of SETDB1 in PWS-specific induced pluripotent cells (iPSCs) causes a decrease in the accumulation of H3K9 trimethylation (H3K9me3) at 116HG and corresponding accumulation of the active chromatin mark histone H3 lysine 4 dimethylation (H3K4me2). We also show that upon knockdown of SETDB1 in PWS-specific iPSCs, expression of maternally silenced 116HG RNA is partially restored. SETDB1 knockdown in PWS iPSCs also disrupts DNA methylation at the PWS-IC where a decrease in 5-methylcytosine is observed in association with a concomitant increase in 5-hydroxymethylcytosine. This observation suggests that the ZNF274/SETDB1 complex bound to the SNORD116 cluster may protect the PWS-IC from DNA demethylation during early development. Our findings reveal novel epigenetic mechanisms that function to repress the maternal 15q11-q13 region. PMID:24760766

A descriptive study of colorectal function in adults with Prader-Willi Syndrome: high prevalence of constipation.

PubMed

Kuhlmann, Louise; Joensson, Iben Moeller; Froekjaer, Jens Broendum; Krogh, Klaus; Farholt, Stense

2014-04-04

Some patients with Prader-Willi Syndrome (PWS) have symptoms of constipation, but bowel function in PWS has never been systematically evaluated. The aim of the present study was to describe colorectal function in PWS by means of validated techniques. Twenty-one patients with PWS (14 women, age 17-47 (median = 32)) were evaluated with the Rome III constipation criteria, stool diary, digital rectal examination, rectal diameter assessed from transabdominal ultrasound, and total gastrointestinal transit time (GITT) determined with radio-opaque markers. Results were compared with those of healthy controls. Among PWS patients able to provide information for Rome III criteria, 8/20 (40%) fulfilled the criteria for constipation. Most commonly reported symptoms were a feeling of obstructed defecation (8/19, 42%), <3 defecations per week (8/17, 47%), straining during defecation (7/19, 37%) and lumpy or hard stools (6/19, 32%). Rectal diameter did not differ between PWS (median 3.56 centimeters, range 2.24-5.36) and healthy controls (median 3.42 centimeters, range 2.67-4.72) (p = 0.96), but more PWS patients (13/20; 65%) than healthy controls (3/25; 12%) (p < 0.001) had fecal mass in the rectum. Median GITT was 2.0 days (range 0.5-4.4) in PWS versus 1.6 (range 0.7-2.5) in the control group (p = 0.26). However, GITT was >3 days in 5/21 (24%) of PWS and none of the controls (p = 0.047). Constipation is very common in PWS. Patients with PWS have an increased prevalence of prolonged GITT and palpable stools in the rectum at digital rectal examination.

Social/economic costs and health-related quality of life in patients with Prader-Willi syndrome in Europe.

PubMed

López-Bastida, Julio; Linertová, Renata; Oliva-Moreno, Juan; Posada-de-la-Paz, Manuel; Serrano-Aguilar, Pedro; Kanavos, Panos; Taruscio, Domenica; Schieppati, Arrigo; Iskrov, Georgi; Baji, Petra; Delgado, Claudia; von der Schulenburg, Johann Matthias Graf; Persson, Ulf; Chevreul, Karine; Fattore, Giovanni

2016-04-01

The aim of this study was to determine the economic burden from a societal perspective and health-related quality of life (HRQOL) of patients with Prader-Willi syndrome (PWS) in Europe. We conducted a cross-sectional study of patients with PWS from Spain, Bulgaria, Hungary, Germany, Italy, the UK, Sweden and France. Data on demographic characteristics, healthcare resource utilisation, informal care, labour productivity losses and HRQOL were collected from questionnaires completed by patients or their caregivers. HRQOL was measured with the EuroQol 5-domain (EQ-5D) questionnaire. A total of 261 patients completed the questionnaire. The average annual costs ranged from € 3937 to € 67,484 between countries; the reference year for unit prices was 2012. Direct healthcare costs ranged from € 311 to € 18,760, direct non-healthcare costs ranged from € 1269 to € 44,035, and loss of labour productivity ranged from € 0 to € 2255. Costs were also shown to differ between children and adults. The mean EQ-5D index score for adult PWS patients ranged between 0.40 and 0.81 and the mean EQ-5D visual analogue scale score ranged between 51.25 and 90.00. The main strengths of this study lie in our bottom-up approach to costing and in the evaluation of PWS patients from a broad societal perspective. This type of analysis is very scarce in the international literature on rare diseases in comparison with other illnesses. We conclude that PWS patients incur considerable societal costs and experience substantial deterioration in HRQOL.

Successful early dietary intervention avoids obesity in patients with Prader-Willi syndrome: a ten-year follow-up.

PubMed

Schmidt, H; Pozza, S Bechtold-Dalla; Bonfig, W; Schwarz, H P; Dokoupil, K

2008-07-01

Hyperphagia is a frequent symptom in patients with Prader-Willi syndrome (PWS) and results in marked obesity with the risk of metabolic and cardiovascular complications. To investigate whether early diagnosis of PWS and strict dietary intervention prevents excessive weight gain in patients with PWS. A strict fat reduced and modified carbohydrate diet consisting of 10 kcal/ cm height was provided to nine patients (seven female, two male) diagnosed early with PWS (group A). Patients were prospectively followed at our center with follow-up visits every three months. Eight patients with late diagnosis of PWS served as controls (group B). Body mass index (BMI) SDS and height SDS were compared between these two groups over a ten-year period. At the age of two years height SDS and BMI SDS were significantly lower in group A (-2.9 vs -1.2, p <0.05, and BMI SDS -0.1 vs +1.8, p < 0.05). After ten years BMI SDS increased significantly to +1.2 SDS in group A, but was still significantly lower than in group B (BMI SDS +2.4), p <0.005. Patients without restrictive diet were significantly taller than patients on the diet (height SDS group A -2.8 vs group B -1.3, p < 0.05). Early dietary treatment starting at the second year of life and continued until the age of ten years is effective in avoiding excessive weight gain in patients with PWS, but results in shorter stature. Therefore growth hormone may be a useful additional treatment in these patients.

Methylation-Specific Multiplex Ligation-Dependent Probe Amplification and Identification of Deletion Genetic Subtypes in Prader-Willi Syndrome

PubMed Central

Henkhaus, Rebecca S.; Kim, Soo-Jeong; Kimonis, Virginia E.; Gold, June-Anne; Dykens, Elisabeth M.; Driscoll, Daniel J.

2012-01-01

Purpose: Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are complex neurodevelopmental disorders caused by loss of expression of imprinted genes from the 15q11-q13 region depending on the parent of origin. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) kits from MRC-Holland (Amsterdam, The Netherlands) were used to detect PWS and AS deletion subtypes. We report our experience with two versions of the MS-MLPA-PWS/AS kit (original A1 and newer B1) in determining methylation status and deletion subtypes in individuals with PWS. Methods: MS-MLPA analysis was performed on DNA isolated from a large cohort of PWS subjects with the MS-MLPA-PWS/AS-A1 and -B1 probe sets. Results: Both MS-MLPA kits will identify deletions in the 15q11-q13 region but the original MS-MLPA-A1 kit has a higher density of probes at the telomeric end of the 15q11-q13 region, which is more useful for identifying individuals with atypical deletions. The newer B1 kit contains more probes in the imprinting center (IC) and adjoining small noncoding RNAs useful in identifying small microdeletions. Conclusion: The A1 kit identified the typical deletions and smaller atypical deletions, whereas the B1 kit was more informative for identifying microdeletions including the IC and SNORD116 regions. Both kits should be made available for accurate characterization of PWS/AS deletion subtypes as well as evaluating for IC and SNORD116 microdeletions. PMID:21977908

Prader-Willi syndrome and atypical submicroscopic 15q11-q13 deletions with or without imprinting defects.

PubMed

Hassan, Maaz; Butler, Merlin G

2016-11-01

We report a 20 year follow up on a Caucasian female, now 26 years of age, with Prader-Willi syndrome (PWS) harboring an atypical 15q11-q13 submicroscopic deletion of 100-200 kb in size first detected in 1996 involving the imprinting center, SNRPN gene and surrounding region. PWS is a rare complex disorder caused by the loss of paternally expressed genes in the 15q11-q13 region. With high resolution chromosomal microarray and methylation - specific MLPA analysis, we updated the genetic findings on our patient and found a 209,819bp deletion including the SNURF-SNRPN gene complex which includes the imprinting center and the SNORD116 region. We compared with four other similarly reported individuals in the literature with atypical submicroscopic deletions within this region but without imprinting center involvement to better characterize the specific genetic lesions causing PWS clinical findings. Clinically, our patient met the diagnostic criteria of PWS including infantile hypotonia, a poor suck with feeding difficulties, global developmental delays and later food foraging, childhood obesity, small hands and skin picking. Small atypical deletions of comparable sizes were seen in the 15q11-q13 region in all five cases and similar behavioral/physical characteristics were found despite an imprinting defect in our patient. These results further support an overlapping critical deletion region involving the non-coding snoRNA SNORD116 in common in the five individuals playing a key role in contributing to the PWS phenotype. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Higher plasma orexin a levels in children with Prader-Willi syndrome compared with healthy unrelated sibling controls.

PubMed

Manzardo, Ann M; Johnson, Lisa; Miller, Jennifer L; Driscoll, Daniel J; Butler, Merlin G

2016-09-01

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder associated with maladaptive social behavior, hyperphagia and morbid obesity. Orexin A is a hypothalamic neuropeptide important as a homeostatic regulator of feeding behavior and in energy metabolism through actions in the lateral hypothalamus. Dysregulation of orexin signaling may contribute to behavioral problems and hyperphagia seen in PWS and we sought to assess orexin A levels in PWS relative to controls children. Morning fasting plasma orexin A levels were analyzed in 23 children (aged 5-11 years) with genetically confirmed PWS and 18 age and gender matched healthy unrelated siblings without PWS. Multiplex immune assays utilized the Milliplex Human Neuropeptide Magnetic panel and the Luminex platform. Natural log-transformed orexin A data were analyzed using general linear model adjusting for diagnosis, gender, age, total body fat, and body mass index (BMI). Plasma orexin A levels were significantly higher (P < 0.006) in children with PWS (average ±SD = 1,028 pg/ml ± 358) compared with unrelated siblings (average ±SD = 609 pg/ml ± 351; P < 0.001). Orexin A levels correlated with age in females and were significantly elevated in PWS even after these effects were controlled. These findings support the hypothesis that dysregulation of orexin signaling may contribute to behavioral problems and hyperphagia in PWS. Further studies are warranted to better understand the complex relationship between orexin A levels and the problematic behaviors consistently found in individuals with PWS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Higher plasma orexin A levels in children with Prader-Willi syndrome compared with healthy unrelated sibling controls.

PubMed

Manzardo, Ann M; Johnson, Lisa; Miller, Jennifer L; Driscoll, Daniel J; Butler, Merlin G

2016-08-01

Prader-Willi syndrome (PWS) is a rare genetic neurodevelopmental disorder associated with maladaptive social behavior, hyperphagia, and morbid obesity. Orexin A is a hypothalamic neuropeptide important as a homeostatic regulator of feeding behavior and in energy metabolism through actions in the lateral hypothalamus. Dysregulation of orexin signaling may contribute to behavioral problems and hyperphagia seen in PWS and we sought to assess orexin A levels in PWS relative to controls children. Morning fasting plasma orexin A levels were analyzed in 23 children (aged 5-11 years) with genetically confirmed PWS and 18 age and gender matched healthy unrelated siblings without PWS. Multiplex immune assays utilized the Milliplex Human Neuropeptide Magnetic panel and the Luminex platform. Natural log-transformed orexin A data were analyzed using general linear model adjusting for diagnosis, gender, age, total body fat and body mass index (BMI). Plasma orexin A levels were significantly higher (P < 0.006) in children with PWS (average ±SD = 1028 pg/ml ± 358) compared with unrelated siblings (average ±SD = 609 pg/ml ± 351; P < 0.001). Orexin A levels correlated with age in females and were significantly elevated in PWS even after these effects were controlled. These findings support the hypothesis that dysregulation of orexin signaling may contribute to behavioral problems and hyperphagia in PWS. Further studies are warranted to better understand the complex relationship between orexin A levels and the problematic behaviors consistently found in individuals with PWS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Response to growth hormone treatment in Prader-Willi syndrome: auxological criteria versus genetic diagnosis.

PubMed

Scheermeyer, Elly; Hughes, Ian; Harris, Mark; Ambler, Geoff; Crock, Patricia; Verge, Charles F; Craig, Maria E; Bergman, Phil; Werther, George; van Driel, Mieke; Davies, Peter Sw; Choong, Catherine S Y

2013-12-01

The Australian Prader-Willi Syndrome (PWS) database was established to monitor the efficacy and safety of growth hormone (GH) treatment in PWS. This study aims to compare response to GH based on eligibility criteria. Comparative study: 72 children received GH on the basis of short stature or evidence of GH deficiency (pre-2009: PWS-SS) and 94 on a genetic diagnosis (post-2009: PWS-Dx). We report on mandatory patient data for GH prescription: median and standard deviation score (SDS) for height and body mass index (BMI), waist/height ratio, bone age/chronological age ratio and adverse events. Comparisons were made using non-parametric tests. At baseline, the PWS-SS cohort was shorter (height SDS: -2.6 vs. -1.1, P < 0.001), had a lower BMI (0.6 vs. 1.5 SDS, P < 0.05) and greater bone age delay (bone age/chronological age: 0.7 vs. 0.9, P < 0.05) than the PWS-Dx cohort. PWS-SS parents were shorter (mid-parental height SDS: -0.13 vs. 0.28, P < 0.005). Mean change in height over 2 years was 0.9 SDS and in BMI using PWS reference standards -0.3 SDSPWS (n = 106) (year 2, height SDS: PWS-SS = -1.7, PWS-Dx = 0.1; BMI SDSPWS : PWS-SS = -1.0, PWS-Dx = -0.6). The waist/height ratio reduced (PWS-Dx: 0.60 vs. 0.56, P < 0.05) and bone age delay was unchanged over this period. No serious adverse events were reported. The PWS-SS cohort represents a subgroup of the wider PWS-Dx population; however both cohorts improved height SDS with normalisation of height in the PWS-Dx cohort and lowering of BMI relative to PWS standards supporting the efficacy of treatment under the current Australian GH programme. © 2013 The Authors. Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians).

Behavioral profile of adults with Prader-Willi syndrome: correlations with individual and environmental variables.

PubMed

Jauregi, Joseba; Laurier, Virginie; Copet, Pierre; Tauber, Maithé; Thuilleaux, Denise

2013-08-06

Maladaptive behavior has been reported as a phenotypical feature in Prader-Willi syndrome (PWS). It severely limits social adaptation and the quality of life of children and adults with the syndrome. Different factors have been linked with the intensity and form of these behavioral disturbances but there is no consensus about the cause. Consequently, there is still controversy regarding management strategies and there is a need for new data. The behavior of 100 adults with PWS attending a dedicated center was assessed using the Developmental Behavior Checklist for Adults (DBC-A) and the PWS-specific Hyperphagia Questionnaire. The DBC-A was completed separately by trained caregivers at the center and relatives or caregivers in a natural setting. Genotype, gender, age, degree of obesity and cognitive impairment were analyzed as variables with a hypothetical influence on behavioral features. Patients showed a relatively high rate of behavioral disturbances other than hyperphagia. Disruptive and social relating were the highest scoring DBC-A subscales whereas anxiety/antisocial and self-absorbed were the lowest. When hospital caregiver and natural caregiver scores were compared, scores for the latter were higher for all subscales except for disruptive and anxiety/antisocial. These effects of institutional management were underlined. In the DBC-A, 22 items have descriptive indications of PWS behavior and were used for further comparisons and correlation analysis. In contrast to previous reports, rates of disturbed behavior were lower in patients with a deletion genotype. However, the behavioral profile was similar for both genotypes. No differences were found in any measurement when comparing type I and type II deletions. The other analyzed variables showed little relevance. Significant rates of behavioral disorders were highlighted and their typology described in a large cohort of adults with PWS. The deletion genotype was related to a lower severity of symptoms. Some

Strength characterization of knee flexor and extensor muscles in Prader-Willi and obese patients

PubMed Central

Capodaglio, Paolo; Vismara, Luca; Menegoni, Francesco; Baccalaro, Gabriele; Galli, Manuela; Grugni, Graziano

2009-01-01

Background despite evidence of an obesity-related disability, there is a lack of objective muscle functional data in overweight subjects. Only few studies provide instrumental strength measurements in non-syndromal obesity, whereas no data about Prader-Willi syndrome (PWS) are reported. The aim of our study was to characterize the lower limb muscle function of patients affected by PWS as compared to non-syndromal obesity and normal-weight subjects. Methods We enrolled 20 obese (O) females (age: 29.1 ± 6.5 years; BMI: 38.1 ± 3.1), 6 PWS females (age: 27.2 ± 4.9 years; BMI: 45.8 ± 4.4) and 14 healthy normal-weight (H) females (age: 30.1 ± 4.7 years; BMI: 21 ± 1.6). Isokinetic strength during knee flexion and extension in both lower limbs at the fixed angular velocities of 60°/s, 180°/s, 240°/s was measured with a Cybex Norm dynamometer. Results the H, O and PWS populations appear to be clearly stratified with regard to muscle strength.: PWS showed the lowest absolute peak torque (PT) for knee flexor and extensor muscles as compared to O (-55%) and H (-47%) (P = 0.00001). O showed significantly higher strength values than H as regard to knee extension only (P = 0.0014). When strength data were normalised by body weight, PWS showed a 50% and a 70% reduction in PT as compared to O and H, respectively. Knee flexors strength values were on average half of those reported for extension in all of the three populations. Conclusion the novel aspect of our study is the determination of objective measures of muscle strength in PWS and the comparison with O and H patients. The objective characterization of muscle function performed in this study provides baseline and outcome measures that may quantify specific strength deficits amendable with tailored rehabilitation programs and monitor effectiveness of treatments. PMID:19419559

The Developmental Trajectory of Self-Injurious Behaviours in Individuals with Prader Willi Syndrome, Autism Spectrum Disorder and Intellectual Disability.

PubMed

Rice, Lauren J; Gray, Kylie M; Howlin, Patricia; Taffe, John; Tonge, Bruce J; Einfeld, Stewart L

2016-02-06

In the present study we examined the nature and developmental trajectory of self-injurious behaviour in Prader Willi syndrome (PWS) and autism spectrum disorder (ASD). The development of interventions is greatly aided by understanding gene to behaviour pathways, and this requires an accurate description of the behaviour phenotype, that is, which types and natural history of self-injurious behaviour are more common in PWS and ASD and which are shared with other forms of developmental disability. Self-injury displayed by individuals with PWS and individuals with ASD was compared with that reported in a group of individuals with intellectual disability due to mixed aetiology (ID group). Three self-injurious behaviours (head banging, skin-picking and hitting and/or biting self) were measured on five occasions over 18 years using the Developmental Behaviour Checklist (DBC) a well-validated caregiver report measure. Rates of skin picking were higher in individuals with PWS and hitting and/or biting self was higher in individuals with ASD compared to the ID group. Rates of head banging were similar across the three groups. Over time, skin-picking and head banging increased with age for individuals with ASD and hitting and/or biting self increased for the PWS group. In the PWS and mixed ID groups head banging decreased with age. These findings suggest that the typology and developmental trajectories of self-injurious behaviours differ between those with PWS and ASD.

The Developmental Trajectory of Self-Injurious Behaviours in Individuals with Prader Willi Syndrome, Autism Spectrum Disorder and Intellectual Disability

PubMed Central

Rice, Lauren J.; Gray, Kylie M.; Howlin, Patricia; Taffe, John; Tonge, Bruce J.; Einfeld, Stewart L.

2016-01-01

In the present study we examined the nature and developmental trajectory of self-injurious behaviour in Prader Willi syndrome (PWS) and autism spectrum disorder (ASD). The development of interventions is greatly aided by understanding gene to behaviour pathways, and this requires an accurate description of the behaviour phenotype, that is, which types and natural history of self-injurious behaviour are more common in PWS and ASD and which are shared with other forms of developmental disability. Self-injury displayed by individuals with PWS and individuals with ASD was compared with that reported in a group of individuals with intellectual disability due to mixed aetiology (ID group). Three self-injurious behaviours (head banging, skin-picking and hitting and/or biting self) were measured on five occasions over 18 years using the Developmental Behaviour Checklist (DBC) a well-validated caregiver report measure. Rates of skin picking were higher in individuals with PWS and hitting and/or biting self was higher in individuals with ASD compared to the ID group. Rates of head banging were similar across the three groups. Over time, skin-picking and head banging increased with age for individuals with ASD and hitting and/or biting self increased for the PWS group. In the PWS and mixed ID groups head banging decreased with age. These findings suggest that the typology and developmental trajectories of self-injurious behaviours differ between those with PWS and ASD. PMID:28933389

Physical activity and maximal oxygen uptake in adults with Prader-Willi syndrome.

PubMed

Gross, Itai; Hirsch, Harry J; Constantini, Naama; Nice, Shachar; Pollak, Yehuda; Genstil, Larry; Eldar-Geva, Talia; Tsur, Varda Gross

2017-03-16

Prader-Willi Syndrome (PWS) is the most common genetic syndrome causing life-threatening obesity. Strict adherence to a low-calorie diet and regular physical activity are needed to prevent weight gain. Direct measurement of maximal oxygen uptake (VO 2 max), the "gold standard" for assessing aerobic exercise capacity, has not been previously described in PWS. Assess aerobic capacity by direct measurement of VO 2 max in adults with PWS, and in age and BMI-matched controls (OC), and compare the results with values obtained by indirect prediction methods. Seventeen individuals (12 males) age: 19-35 (28.6 ± 4.9) years, BMI: 19.4-38.1 (27.8 ± 5) kg/m 2 with genetically confirmed PWS who exercise daily, and 32 matched OC (22 males) age: 19-36 (29.3 ± 5.2) years, BMI: 21.1-48.1 (26.3 ± 4.9) kg/m 2 . All completed a medical questionnaire and performed strength and flexibility tests. VO 2 max was determined by measuring oxygen consumption during a graded exercise test on a treadmill. VO 2 max (24.6 ± 3.4 vs 46.5 ± 12.2 ml/kg/min, p < 0.001) and ventilatory threshold (20 ± 2 and 36.2 ± 10.5 ml/kg/min, p < 0.001), maximal strength of both hands (36 ± 4 vs 91.4 ± 21.2 kg, p < 0.001), and flexibility (15.2 ± 9.5 vs 26 ± 11.1 cm, p = 0.001) were all significantly lower for PWS compared to OC. Predicted estimates and direct measurements of VO 2 max were almost identical for the OC group (p = 0.995), for the PWS group, both methods for estimating VO 2 max gave values which were significantly greater (p < 0.001) than results obtained by direct measurements. Aerobic capacity, assessed by direct measurement of VO 2 max, is significantly lower in PWS adults, even in those who exercise daily, compared to OCs. Indirect estimates of VO 2 max are accurate for OC, but unreliable in PWS. Direct measurement of VO 2 should be used for designing personal training programs and in clinical studies of exercise

Multiple forms of hypogonadism of central, peripheral or combined origin in males with Prader-Willi syndrome.

PubMed

Radicioni, A F; Di Giorgio, G; Grugni, G; Cuttini, M; Losacco, V; Anzuini, A; Spera, S; Marzano, C; Lenzi, A; Cappa, M; Crinò, A

2012-01-01

Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect, but pathophysiology is still unclear. To investigate the aetiology of hypothalamic-pituitary-gonadal axis dysfunction in PWS males. Clinical examination and blood sampling for luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, inhibin B and sexhormone-binding globulin (SHBG) were performed in 34 PWS patients, age 5·1-42·7 years, and in 125 healthy males of same age range. All participants were divided into two groups : < or ≥13·5 years. Pubertal PWS patients showed an arrest of pubertal development. Patients <13·5 years had normal LH, FSH, testosterone and 7/10 had low inhibin B. Among those ≥13·5 years, 8/24 patients had normal LH and testosterone, high FSH and low inhibin B. 5/24 had low FSH, LH, testosterone and inhibin B; one showed normal LH and FSH despite low testosterone and inhibin B; 4/24 had low testosterone and LH but normal FSH despite low inhibin B; 6/24 showed high FSH, low inhibin B and normal LH despite low testosterone. Compared with controls, patients <13·5 years had lower LH, inhibin B, similar FSH, testosterone, SHBG levels and testicular volume; those ≥13·5 years had smaller testicular volume, near-significantly lower LH, testosterone, SHBG, inhibin B and higher FSH. PWS patients display heterogeneity of hypogonadism: (i) hypogonadotropic hypogonadism of central origin for LH and/or FSH; (ii) early primary testicular dysfunction (Sertoli cells damage); and (iii) a combined hypogonadism (testicular origin for FSH-inhibin B axis and central origin for LH-T axis). © 2011 Blackwell Publishing Ltd.

Long-term echocardiographic and cardioscintigraphic effects of growth hormone treatment in adults with Prader-Willi syndrome.

PubMed

Marzullo, Paolo; Marcassa, Claudio; Minocci, Alessandro; Campini, Riccardo; Eleuteri, Ermanno; Gondoni, Luca Alessandro; Aimaretti, Gianluca; Sartorio, Alessandro; Scacchi, Massimo; Grugni, Graziano

2015-05-01

In Prader-Willi syndrome (PWS), an altered GH secretion has been related to reduced cardiac mass and systolic function compared to controls. The objective was to evaluate the cardiovascular response to a 4-year GH therapy in adult PWS patients. Study participants were nine severely obese PWS adults (three females, six males) and 13 age-, gender-, and body mass index-matched obese controls. In an open-label prospective study, assessment of endocrine parameters and metabolic outcome, whole-body and abdominal fat scans, echocardiography, and radionuclide angiography in unstimulated and dobutamine-stimulated conditions were conducted at baseline and after 1 and 4 years of GH treatment. GH treatment increased IGF-1 (P < .0001), decreased C-reactive protein levels (P < .05), improved visceral fat mass (P < .05), and achieved near-significant changes of fat and fat-free body mass in PWS patients. Left ventricle mass indexed by fat mass increased significantly after 1 and 4 years of GH therapy (P < .05) without evident abnormalities of diastolic function, while a trend toward a reduction of the ejection fraction was documented by echocardiography (P = .054). Radionuclide angiography revealed stable values throughout the study of both the left and right ventricle ejection fractions, although this was accompanied by a statistically nonsignificant reduction of the left ventricle filling rate. A positive association between lean body mass and left ventricle ejection fraction was evident during the study (P < .05). GH therapy increased the cardiac mass of PWS adults without causing overt abnormalities of systolic and diastolic function. Although the association between lean mass and left ventricle ejection fraction during GH therapy corroborates a favorable systemic outcome of long-term GH treatment in adults with PWS, subtle longitudinal modifications of functional parameters advocate appropriate cardiac monitoring in the long-term therapeutic strategy for PWS.

Impaired theory of mind and symptoms of Autism Spectrum Disorder in children with Prader-Willi syndrome.

PubMed

Lo, Sin Ting; Siemensma, Elbrich; Collin, Philippe; Hokken-Koelega, Anita

2013-09-01

In order to evaluate the social cognitive functioning in children with Prader-Willi syndrome (PWS), Theory of Mind (ToM) and symptoms of Autism Spectrum Disorder were evaluated. Sixty-six children with PWS aged 7-17 years were tested using the Theory of Mind test-R and the Diagnostic Interview for Social Communication disorders. We tested the correlation between Total ToM Standard Deviation Score (Total ToM SDS) and genetic subtype of paternal deletion or maternal uniparental disomy, and total IQ, verbal IQ and performal IQ. Prevalence and symptoms of Autism Spectrum Disorder were assessed. Median (interquartile range) of total ToM SDS of those aged 7-17 years was -3.84 (-5.73, -1.57). Their Total ToM SDS correlated with total IQ (β=0.662, p<0.001, adj.R(2)=0.407), in particular with verbal IQ (β=0.502, p=0.001, adj.R(2)=0.409), but not with performal IQ (β=0.241, p>0.05, adj.R(2)=0.259). No difference in Total ToM SDS was found between children with deletion and maternal uniparental disomy (β=-0.143, p>0.05, adj.R(2)=-0.016). Compared to the reference group of healthy children aged 7-12 years, children with PWS in the same age group had a median ToM developmental delay of 4 (3-5) years. One third of children with PWS scored positive for Autism Spectrum Disorder. Most prominent aberrations in Autism Spectrum Disorder were focused on maladaptive behavior. Our findings demonstrate a markedly reduced level of social cognitive functioning, which has consequences for the approach of children with PWS, i.e. adjustment to the child's level of social cognitive functioning. Copyright © 2013 Elsevier Ltd. All rights reserved.

Psychiatric illness and intellectual disability in the Prader-Willi syndrome with different molecular defects--a meta analysis.

PubMed

Yang, Lin; Zhan, Guo-dong; Ding, Jun-jie; Wang, Hui-jun; Ma, Duan; Huang, Guo-ying; Zhou, Wen-hao

2013-01-01

Several studies have suggested a difference in clinical features of intellectual ability and psychiatric illness in the Prader-Willi syndrome (PWS) with the 15q11-q13 paternal deletion and maternal uniparental disomy (mUPD). Our objective was to appraise evidence on this association through a meta-analysis. The electronic records PubMed and EMBASE from 1956 to 2012 were extracted for meta-analysis. Meta-analyses were performed by using fixed effect model. Mean difference, odds ratio, and 95% confidence interval were calculated. We retrieved a total of 744 PWS cases from 13 studies. These include 423 cases with paternal 15q11-q13 deletions and 318 cases of mUPD. Compare to the PWS cases with mUPD, PWS patients with the paternal 15q11-q13 deletion associated with significantly lower full scale IQ (FSIQ) [mean difference (MD), -2.69; 95%CI, -4.86 to -0.52; p=0.02] and verbal IQ (VIQ) (MD, -7.5; 95%CI, -9.75 to -5.26; p<0.00001) but higher performance IQ (PIQ) (MD, 4.02; 95%CI, 1.13 to 6.91; p=0.006). In contrast, PWS patients with mUPD are associated with significantly higher risk of psychiatric illness [odds rate (OR), 0.14; 95%CI, 0.08 to 0.23; p<0.00001] and higher risk of bipolar disorder (OR, 0.04; 95%CI, 0.01 to 0.23; p=0.0002). Significant different clinical features of cognitive development and psychiatric illness are associated with PWS with different molecular defects. These findings provide support for evidence based practice to evaluate and manage the PWS syndrome with different molecular defects.

TPH2 G/T polymorphism is associated with hyperphagia, IQ, and internalizing problems in Prader-Willi syndrome

PubMed Central

Dykens, Elisabeth M.; Roof, Elizabeth; Bittel, Douglas; Butler, Merlin G.

2010-01-01

Background Prader-Willi syndrome (PWS) is a genetic, neurodevelopmental disorder characterized by intellectual disabilities, growth hormone dysregulation, hyperphagia, increased risks of morbid obesity, compulsive behaviors, and irritability. As aberrant serotonergic functioning is strongly implicated in PWS, we examined associations between the PWS phenotype and polymorphisms in tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in the biosynthesis of serotonin in the brain. Methods 92 individuals with PWS aged 4 to 50 years (M = 21.97) were genotyped for the TPH2 G703-T polymorphism. IQ testing was conducted in offspring, and parents completed questionnaires that tapped their child’s compulsivity, hyperphagia, and other behavior problems. Results As expected, the frequency of G/T or T/T polymorphisms in participants with PWS (39%) was similar to rates found in the general population (38%). Compared to those with a homozygous (G/G) genotype, individuals with a T allele had significantly higher hyperphagic behavior, drive, and severity scores, and they also had a younger age of onset of hyperphagia. Those with a T allele also had higher IQ scores than their counterparts. Females with a T allele had significantly higher internalizing symptoms, primarily anxiety and depression, than all others. Conclusions TPH2 G/T polymorphisms, and presumed loss of enzyme function, were associated with specific aspects of the PWS phenotype. Aberrant serotonergic functioning is strongly implicated in hyperphagia in PWS, and females with TPH2 T alleles may be at higher risk for affective or mood disorders. Findings hold promise for examining other serotonin-altering genes in PWS, and for future serotonin-altering treatment trials. PMID:21418060

TPH2 G/T polymorphism is associated with hyperphagia, IQ, and internalizing problems in Prader-Willi syndrome.

PubMed

Dykens, Elisabeth M; Roof, Elizabeth; Bittel, Douglas; Butler, Merlin G

2011-05-01

Prader-Willi syndrome (PWS) is a genetic, neurodevelopmental disorder characterized by intellectual disabilities, growth hormone dysregulation, hyperphagia, increased risks of morbid obesity, compulsive behaviors, and irritability. As aberrant serotonergic functioning is strongly implicated in PWS, we examined associations between the PWS phenotype and polymorphisms in tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme in the biosynthesis of serotonin in the brain. Ninety-two individuals with PWS aged 4 to 50 years (M = 21.97) were genotyped for the TPH2 G703-T polymorphism. IQ testing was conducted in offspring, and parents completed questionnaires that tapped their child's compulsivity, hyperphagia, and other behavior problems. As expected, the frequency of G/T or T/T polymorphisms in participants with PWS (39%) was similar to rates found in the general population (38%). Compared to those with a homozygous (G/G) genotype, individuals with a T allele had significantly higher hyperphagic behavior, drive, and severity scores, and they also had a younger age of onset of hyperphagia. Those with a T allele also had higher IQ scores than their counterparts. Females with a T allele had significantly higher internalizing symptoms, primarily anxiety and depression, than all others. TPH2 G/T polymorphisms, and presumed loss of enzyme function, were associated with specific aspects of the PWS phenotype. Aberrant serotonergic functioning is strongly implicated in hyperphagia in PWS, and females with TPH2 T alleles may be at higher risk for affective or mood disorders. Findings hold promise for examining other serotonin-altering genes in PWS, and for future serotonin-altering treatment trials. © 2011 The Authors. Journal of Child Psychology and Psychiatry © 2011 Association for Child and Adolescent Mental Health.

A polymorphism in the growth hormone receptor is associated with height in children with Prader-Willi syndrome.

PubMed

Park, Sung Won; Lee, Seung-Tae; Sohn, Young Bae; Kim, Se Hwa; Cho, Sung-Yoon; Ko, Ah-Ra; Ji, Sun-Tae; Kwon, Jeong-Yi; Yeau, Sunghee; Paik, Kyung-Hoon; Kim, Jong-Won; Jin, Dong-Kyu

2011-12-01

The exon-3 deletion polymorphism (d3, Database of Genomic Variants ID: Variation_64191) in the growth hormone receptor (GHR) gene is associated with increased growth response to growth hormone (GH) therapy in GH-deficient patients. However, an association of the GHR genotype with height has not yet been reported in Prader-Willi syndrome (PWS). The aim of this study was to assess the association of GHR alleles with height before starting GH therapy in patients with PWS. Seventy-four patients with PWS were genotyped and their medical records were retrospectively reviewed (45 males and 29 females, median age 8.7 years). One hundred normal controls, with known final height, were also genotyped. The GH-exon 3 locus was genotyped using a PCR multiplex assay. The distribution of alleles in the patients with PWS was not different from controls [(fl/fl n = 53 (72%), fl/d3 n = 21 (28%)) in PWS vs. (fl/fl n = 72(72%), fl/d3 n = 26(26%), and d3/d3 n = 2(2%)]. However, patients with PWS carrying a d3 allele had significantly greater height standard deviation scores (SDS) (P = 0.025) and higher insulin-like growth factor I (IGF-I) level (P = 0.041), although the age at the start of GH therapy, weight, BMI, and body fat were not different. The d3 allele was associated with height and IGF-I levels before GH therapy and suggests that even before GH therapy, d3 allele may influence height through GH secretion. Copyright © 2011 Wiley Periodicals, Inc.

A daily comprehensive muscle training programme increases lean mass and spontaneous activity in children with Prader-Willi syndrome after 6 months.

PubMed

Schlumpf, Michael; Eiholzer, Urs; Gygax, Muriel; Schmid, Silvia; van der Sluis, Inge; l'Allemand, Dagmar

2006-01-01

The reduction of spontaneous physical activity (PA) and of muscle tissue are thought to be major causes of fat accretion and metabolic deterioration in Prader-Labhart-Willi syndrome (PWS). We investigated whether a generalized physical training programme in a home setting improves these parameters. The prospective study included 11 prepubertal children (mean age 8.7 years, range 5.9-11.8) with documented PWS and under continuous growth hormone treatment for at least 2.8 years. Seven children were enrolled in a training programme for several muscle groups during 4-10 minutes daily. Twelve matched children with PWS served as controls (average age 8.8 years, 6.1-11.3). Before and after training, at 6 months, PA was assessed by measuring walking distance by pedometer registration and by an activity score, and body composition by DEXA expressed as standard deviation scores (SDS) related to height. After training, lean mass (LM) increased from -1.83 to -1.48 SDS, p <0.05, whereas the controls showed no change. In the training group, walking distance and PA increased from 4.2 to 4.7 km/d and from 255 to 266 points, respectively, and these rises significantly exceeded those observed in controls. Children with PWS can be motivated by their families to follow a short daily training, which has general effects on PA and does increase, but not normalize LM.

Rapid Birth-and-Death Evolution of Imprinted snoRNAs in the Prader-Willi Syndrome Locus: Implications for Neural Development in Euarchontoglires

PubMed Central

Zhang, Yi-Jun; Yang, Jian-Hua; Shi, Qiao-Su; Zheng, Ling-Ling; Liu, Jun; Zhou, Hui; Zhang, Hui; Qu, Liang-Hu

2014-01-01

Imprinted small nucleolar RNAs (snoRNAs) are only found in eutherian genomes and closely related to brain functions. A complex human neurological disease, Prader-Willi syndrome (PWS), is primarily attributed to the deletion of imprinted snoRNAs in chromosome 15q11-q13. Here we investigated the snoRNA repertoires in the PWS locus of 12 mammalian genomes and their evolution processes. A total of 613 imprinted snoRNAs were identified in the PWS homologous loci and the gene number was highly variable across lineages, with a peak in Euarchontoglires. Lineage-specific gene gain and loss events account for most extant genes of the HBII-52 (SNORD115) and the HBII-85 (SNORD116) gene family, and remarkable high gene-birth rates were observed in the primates and the rodents. Meanwhile, rapid sequence substitution occurred only in imprinted snoRNA genes, rather than their flanking sequences or the protein-coding genes located in the same imprinted locus. Strong selective constraints on the functional elements of these imprinted snoRNAs further suggest that they are subjected to birth-and-death evolution. Our data suggest that the regulatory role of HBII-52 on 5-HT2CR pre-mRNA might originate in the Euarchontoglires through adaptive process. We propose that the rapid evolution of PWS-related imprinted snoRNAs has contributed to the neural development of Euarchontoglires. PMID:24945811

Delayed peak response of cortisol to insulin tolerance test in patients with Prader-Willi syndrome.

PubMed

Oto, Yuji; Matsubara, Keiko; Ayabe, Tadayuki; Shiraishi, Masahisa; Murakami, Nobuyuki; Ihara, Hiroshi; Matsubara, Tomoyo; Nagai, Toshiro

2018-06-01

Deaths among children with Prader-Willi syndrome (PWS) are often related to only mild or moderate upper respiratory tract infections, and many causes of death remain unexplained. Several reports have hypothesized that patients with PWS may experience latent central adrenal insufficiency. However, whether PWS subjects suffer from alteration of the hypothalamus-pituitary-adrenal (HPA) axis remains unclear. This study aimed to explore the HPA axis on PWS. We evaluated the HPA axis in 36 PWS patients (24 males, 12 females; age range, 7 months to 12 years; median age 2.0 years; interquartile range [IQR], 1.5-3.4 years) using an insulin tolerance test (ITT) in the morning between 08:00 and 11:00. For comparison, ITT results in 37 age-matched healthy children evaluated for short stature were used as controls. In PWS patients, basal levels of adrenocorticotropic hormone (ACTH) were 13.5 pg/ml (IQR, 8.3-27.5 pg/ml) and basal levels of cortisol were 18.0 μg/dl (IQR, 14.2-23.7 μg/dl). For all patients, cortisol levels at 60 min after stimulation were within the reference range (>18.1 μg/dl), with a median peak of 41.5 μg/dl (IQR, 32.3-48.6 μg/dl). Among control children, basal level of ACTH and basal and peak levels of cortisol were 10.9 (IQR, 8.5-22.0 pg/ml), 15.6 (IQR, 11.9-21.6 μg/dl), and 27.8 μg/dl (IQR, 23.7-30.5 μg/dl), respectively. Basal and peak levels of cortisol were all within normal ranges, but peak response of cortisol to ITT was delayed in the majority of PWS patients (64%). Although the mechanism remains unclear, this delay may signify the existence of central obstacle in adjustment of the HPA axis. © 2018 Wiley Periodicals, Inc.

Parent training education program: a pilot study, involving families of children with Prader-Willi syndrome.

PubMed

Kodra, Yllka; Kondili, Loreta A; Ferraroni, Alessia; Serra, Maria Antonietta; Caretto, Flavia; Ricci, Maria Antonietta; Taruscio, Domenica

2016-01-01

Prader-Willi syndrome (PWS) is a rare genetic disorder characterized by severe hypotonia during the neonatal period and the first two years of life, the onset of hyperphagia with a risk of obesity during infancy and adulthood, learning difficulties and behavioral or severe psychiatric problems. This complex disease has severe consequences and difficult management issues also for patients' families. Parents of children with PWS need appropriate psychoeducational intervention in order to better manage their children with PWS. The purpose of this study was the implementation and evaluation of a PWS psychoeducational parent training program. The Italian National Center for Rare Diseases implemented a pilot parent training program offered to parents of children with PWS. The intervention's effects was evaluated using questionnaires comprised of 11 items rated on a 7 point Likert scale. The intervention was offered to 43 parents. The behavior problems management, dietary restrictions, autonomy and relationships were indicated by parents as the priority topics which needed to be addressed. Evaluations, immediately post-intervention and after 6 months, were reported by parents, fulfilling specific questionnaires. 90% of parents involved in the study, appreciated the methodology, 86% felt more informed about PWS, 47-62% felt more capable to better approach behaviour's problems, 20-25% felt better about the child's health situation and future expectations. Feeling more capable to help the child autonomy and relationships were reported in 62% and 63% of parents respectively, which decreased significantly (p < 0.05) according to the evaluation 6 months after the intervention. Younger age of parents (< 44 years of age) was significantly correlated with better understanding on how to help the child's autonomy (OR: 0.05; CI: 0.04-0.8) and to better collaborate with the child's teachers (OR: 0.02; CI: 0.001-0.9). Parent training is a promising intervention for parents of children

Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome.

PubMed

Whittington, J; Holland, A; Webb, T; Butler, J; Clarke, D; Boer, H

2004-02-01

Prader-Willi syndrome (PWS) is characterized by extreme floppiness at birth, impaired sexual development, short stature, severe over-eating, characteristic physical features and learning disabilities (LD). Impaired social cognition, literal mindedness and cognitive inflexibility are also present. The syndrome has two main genetic subtypes that both result in the failure of expression of maternally imprinted genes on chromosome 15 at the locus q11-13. Through multiple sources, we attempted to identify all people with PWS living in one health region in the UK. Additional people with PWS identified in other regions were also recruited to augment the study sample. A comparison group of people with LD as a result of aetiologies other than PWS was also identified. All people from these three groups, over age three, who gave their consent, were assessed using tests of ability and attainment. In addition, their main carers were interviewed using a semistructured interview. Blood samples for genetic diagnosis were obtained from all consenting participants. The IQ distribution of the population sample was approximately normal with a mean IQ 40 points below that of the general population. There were systematic differences between the two main genetic subtypes. Those with disomies differed in cognitive profiles from both those with deletions and the comparison LD group (the latter two groups were very similar) in terms of better verbal abilities and impaired coding ability. Some people with PWS deletions had strong visuospatial skills. We propose that the normal distribution of IQ, shifted downwards relative to that of the general population, is the result of a global effect on IQ of the PWS gene(s), and that the different cognitive profile seen in those with chromosome 15 maternal disomies is a specific effect of a gene, or genes, on chromosome 15 which is differentially either expressed or not expressed in those with disomies relative to those with deletions. One hypothesis

An Unexpected Function of the Prader-Willi Syndrome Imprinting Center in Maternal Imprinting in Mice

PubMed Central

Wu, Mei-Yi; Jiang, Ming; Zhai, Xiaodong; Beaudet, Arthur L.; Wu, Ray-Chang

2012-01-01

Genomic imprinting is a phenomenon that some genes are expressed differentially according to the parent of origin. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders caused by deficiency of imprinted gene expression from paternal and maternal chromosome 15q11–q13, respectively. Imprinted genes at the PWS/AS domain are regulated through a bipartite imprinting center, the PWS-IC and AS-IC. The PWS-IC activates paternal-specific gene expression and is responsible for the paternal imprint, whereas the AS-IC functions in the maternal imprint by allele-specific repression of the PWS-IC to prevent the paternal imprinting program. Although mouse chromosome 7C has a conserved PWS/AS imprinted domain, the mouse equivalent of the human AS-IC element has not yet been identified. Here, we suggest another dimension that the PWS-IC also functions in maternal imprinting by negatively regulating the paternally expressed imprinted genes in mice, in contrast to its known function as a positive regulator for paternal-specific gene expression. Using a mouse model carrying a 4.8-kb deletion at the PWS-IC, we demonstrated that maternal transmission of the PWS-IC deletion resulted in a maternal imprinting defect with activation of the paternally expressed imprinted genes and decreased expression of the maternally expressed imprinted gene on the maternal chromosome, accompanied by alteration of the maternal epigenotype toward a paternal state spread over the PWS/AS domain. The functional significance of this acquired paternal pattern of gene expression was demonstrated by the ability to complement PWS phenotypes by maternal inheritance of the PWS-IC deletion, which is in stark contrast to paternal inheritance of the PWS-IC deletion that resulted in the PWS phenotypes. Importantly, low levels of expression of the paternally expressed imprinted genes are sufficient to rescue postnatal lethality and growth retardation in two PWS mouse models. These findings

Oxytocin treatment in children with Prader-Willi syndrome: A double-blind, placebo-controlled, crossover study.

PubMed

Miller, Jennifer L; Tamura, Roy; Butler, Merlin G; Kimonis, Virginia; Sulsona, Carlos; Gold, June-Anne; Driscoll, Daniel J

2017-05-01

Prader-Willi syndrome (PWS) is a rare, complex multisystem genetic disorder which includes hypothalamic dysfunction, hyperphagia, cognitive and behavioral problems, increased anxiety, and compulsive behaviors. Individuals with PWS have a deficit of oxytocin producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin plays a role in regulation of feeding behaviors, social interactions, and emotional reactivity, which are all issues that significantly affect the quality of life for individuals with this syndrome. We performed a double-blind, placebo-controlled, crossover study in 24 children with PWS at three academic institutions using 5 days of intranasal oxytocin (IN-OT) or 5 days of intranasal placebo spray, followed by a 4 week washout period, and then patients returned for 5 days of treatment with the alternate source. Questionnaires, including the Aberrant Behavior Checklist, Social Responsiveness Scale, Repetitive Behavior Scale - Revised, and the Hyperphagia Questionnaire, as well as Clinical Global Impression scales were administered. Blood testing for sodium, potassium, and glucose levels on days 2, 4, and 6, and a 24 hr diet recall. All scales factor improvement from Day 3 to Day 6 favored oxytocin over placebo. No single factor showed a statistically significant difference (P < 0.05) between groups at Day 6. The drug effect appeared to be diminished at Day 14. There was no evidence of a difference between oxytocin and placebo in safety lab parameters, 60 min post dose vital signs, weight, or diet parameters. The results from this study suggest that low dose intranasal oxytocin is safe for individuals with PWS and may result in reduction in appetite drive, and improvements in socialization, anxiety, and repetitive behaviors. Further, long-term studies with a larger population of participants are necessary to confirm these findings. The results of this study are encouraging that oxytocin may be a safe and effective treatment for

Caralluma Fimbriata Supplementation Improves the Appetite Behavior of Children and Adolescents with Prader-Willi Syndrome

PubMed Central

Griggs, Joanne L.; Su, Xiao Q.; Mathai, Michael L.

2015-01-01

Background: Prader-Willi syndrome (PWS) results from a deletion of the paternal genes in the region of chromosome 15q11-q13. PWS develops hyperphagia, which when left unmanaged, leads to an excessive ingestion of food. To date there is inadequate pharmacological treatment or supplementation for modification of the PWS hyperphagia and/or the associated behaviors. Therefore, the best practice is familial supervision and restriction of diet and environment. Aim: We aimed to determine if the natural supplement of Caralluma fimbriata extract (CFE) could attenuate hyperphagia or the associated appetite behaviors in children and adolescents with PWS over the 4-week pilot trial period. Materials and Methods: We conducted a placebo-controlled, double-blind, randomized crossover trial over a 10-week period to investigate the effects of CFE on hunger control, in a cohort of children and adolescents with confirmed PWS (n =15, mean age 9.27 ± 3.16 years, body weight 43.98 ± 23.99 kg). Participants from Australia and New Zealand ingested CFE or a placebo of maltodextrin/cabbage leaf over a 4-week period, with a 2-week washout before the crossover to the other treatment. Weekly comparisons in appetite behavior, severity, and drive were recorded by parents, as scaled time-point measures on a hyperphagia questionnaire validated for PWS. Results: CFE administration was found to induce a significant accumulative easing of hyperphagia (P = 0.05), with decreases evident in one-third of the participants. Furthermore due to CFE supplementation, a significant decrease (P ≤ 0.05) was recorded in the category of behavior and a decrease in hyperphagia (n = 8, P = 0.009) was observed at the highest dose 1,000 mg/day (recommended adult dose). There were no reported adverse effects at any dose. Conclusion: We demonstrate that an extract of the Indian cactus succulent Caralluma fimbriata eases hyperphagic appetite behavior within a cohort of children and adolescents (n = 15) with PWS without

An unexpected function of the Prader-Willi syndrome imprinting center in maternal imprinting in mice.

PubMed

Wu, Mei-Yi; Jiang, Ming; Zhai, Xiaodong; Beaudet, Arthur L; Wu, Ray-Chang

2012-01-01

Genomic imprinting is a phenomenon that some genes are expressed differentially according to the parent of origin. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders caused by deficiency of imprinted gene expression from paternal and maternal chromosome 15q11-q13, respectively. Imprinted genes at the PWS/AS domain are regulated through a bipartite imprinting center, the PWS-IC and AS-IC. The PWS-IC activates paternal-specific gene expression and is responsible for the paternal imprint, whereas the AS-IC functions in the maternal imprint by allele-specific repression of the PWS-IC to prevent the paternal imprinting program. Although mouse chromosome 7C has a conserved PWS/AS imprinted domain, the mouse equivalent of the human AS-IC element has not yet been identified. Here, we suggest another dimension that the PWS-IC also functions in maternal imprinting by negatively regulating the paternally expressed imprinted genes in mice, in contrast to its known function as a positive regulator for paternal-specific gene expression. Using a mouse model carrying a 4.8-kb deletion at the PWS-IC, we demonstrated that maternal transmission of the PWS-IC deletion resulted in a maternal imprinting defect with activation of the paternally expressed imprinted genes and decreased expression of the maternally expressed imprinted gene on the maternal chromosome, accompanied by alteration of the maternal epigenotype toward a paternal state spread over the PWS/AS domain. The functional significance of this acquired paternal pattern of gene expression was demonstrated by the ability to complement PWS phenotypes by maternal inheritance of the PWS-IC deletion, which is in stark contrast to paternal inheritance of the PWS-IC deletion that resulted in the PWS phenotypes. Importantly, low levels of expression of the paternally expressed imprinted genes are sufficient to rescue postnatal lethality and growth retardation in two PWS mouse models. These findings

Caralluma Fimbriata Supplementation Improves the Appetite Behavior of Children and Adolescents with Prader-Willi Syndrome.

PubMed

Griggs, Joanne L; Su, Xiao Q; Mathai, Michael L

2015-11-01

Prader-Willi syndrome (PWS) results from a deletion of the paternal genes in the region of chromosome 15q11-q13. PWS develops hyperphagia, which when left unmanaged, leads to an excessive ingestion of food. To date there is inadequate pharmacological treatment or supplementation for modification of the PWS hyperphagia and/or the associated behaviors. Therefore, the best practice is familial supervision and restriction of diet and environment. We aimed to determine if the natural supplement of Caralluma fimbriata extract (CFE) could attenuate hyperphagia or the associated appetite behaviors in children and adolescents with PWS over the 4-week pilot trial period. We conducted a placebo-controlled, double-blind, randomized crossover trial over a 10-week period to investigate the effects of CFE on hunger control, in a cohort of children and adolescents with confirmed PWS (n =15, mean age 9.27 ± 3.16 years, body weight 43.98 ± 23.99 kg). Participants from Australia and New Zealand ingested CFE or a placebo of maltodextrin/cabbage leaf over a 4-week period, with a 2-week washout before the crossover to the other treatment. Weekly comparisons in appetite behavior, severity, and drive were recorded by parents, as scaled time-point measures on a hyperphagia questionnaire validated for PWS. CFE administration was found to induce a significant accumulative easing of hyperphagia (P = 0.05), with decreases evident in one-third of the participants. Furthermore due to CFE supplementation, a significant decrease (P ≤ 0.05) was recorded in the category of behavior and a decrease in hyperphagia (n = 8, P = 0.009) was observed at the highest dose 1,000 mg/day (recommended adult dose). There were no reported adverse effects at any dose. We demonstrate that an extract of the Indian cactus succulent Caralluma fimbriata eases hyperphagic appetite behavior within a cohort of children and adolescents (n = 15) with PWS without notable adverse effects. The outcomes of this study will

An analysis of the topography, severity, potential sources of reinforcement, and treatments utilized for skin picking in Prader-Willi syndrome.

PubMed

Hustyi, Kristin M; Hammond, Jennifer L; Rezvani, Ava B; Hall, Scott S

2013-09-01

We examined the topography, severity, potential sources of reinforcement, and treatments utilized for skin-picking behavior shown by individuals with Prader-Willi syndrome (PWS). The parents of 55 individuals with PWS, aged 6-25 years, were interviewed about their child's skin-picking behavior using the Self-Injury Trauma Scale (SIT; Iwata, Pace, Kissel, Nau, & Farber, 1990) and the Functional Analysis Screening Tool (FAST; Iwata, DeLeon, & Roscoe, 2013). Results showed that skin picking in PWS occurred on the extremities (i.e., arms, legs, hands, and feet) for 75% of cases and resulted in bodily injury for 83.7% cases. Skin picking posed a high risk to the individual concerned in 41.8% of cases. Automatic sensory stimulation was identified as a potential source of reinforcement in the majority of cases (52.7%) followed by access to social attention or preferred items (36.4%). Treatments utilized by parents were primarily behavioral strategies (56.3%) followed by basic first aid (54.5%). There were no differences in the topography, severity or potential source of reinforcement between those with the deletion (DEL) subtype and those with the uniparental disomy (UPD) subtype. Taken together, these data indicate that skin picking shown by individuals with PWS is a particularly severe and intractable behavioral issue that may be maintained by (as yet unknown) sensory consequences. Further studies to identify the determinants of skin picking in PWS are therefore needed. The implications for interventions are discussed. Copyright © 2013 Elsevier Ltd. All rights reserved.

Behavioural phenotypes associated with specific genetic disorders: evidence from a population-based study of people with Prader-Willi syndrome.

PubMed

Holland, A J; Whittington, J E; Butler, J; Webb, T; Boer, H; Clarke, D

2003-01-01

Prader-Willi syndrome (PWS) is a genetic disorder resulting in obesity, short stature, cryptorchidism, learning disabilities (mental retardation) and severe neonatal hypotonia. Associated with the syndrome are a number of behaviours that are sufficiently distinctive that the syndrome is considered to have a specific 'behavioural phenotype'. Through multiple sources we attempted to identify all people with PWS living in one region in the U K. This cohort was augmented by people with PWS from other regions, and a contrast group of people with learning disabilities of varied aetiologies. The main carers were interviewed, using structured and semi-structured interview schedules, to establish the presence and severity of specific behaviours, and PWS diagnostic criteria. The intellectual functioning and attainments of all were determined. Blood samples were obtained for genetic diagnosis from all consenting participants. Although excessive eating was recognized as a potentially severe problem in those with PWS, it was almost universally controlled by food restriction, and therefore not seen as a 'problem behaviour'. Those with PWS differed from a learning disabled group of other aetiologies in the prevalence rates of skin picking, temper tantrums, compulsive behaviours and mood fluctuations, and also in the profile of their adaptive behaviours. The study confirms the distinct behavioural phenotype of PWS. Specific behaviours occurred significantly more frequently in PWS, compared with an age and BMI matched learning disabled comparison group. A factor analysis of the behaviours involved resulted in three factors that we hypothesized to be independent, and to arise from different mechanisms.

Expression and imprinting of MAGEL2 suggest a role in Prader-willi syndrome and the homologous murine imprinting phenotype.

PubMed

Lee, S; Kozlov, S; Hernandez, L; Chamberlain, S J; Brannan, C I; Stewart, C L; Wevrick, R

2000-07-22

Prader-Willi syndrome (PWS) is caused by the loss of expression of imprinted genes in chromosome 15q11-q13. Affected individuals exhibit neonatal hypotonia, developmental delay and childhood-onset obesity. Necdin, a protein implicated in the terminal differentiation of neurons, is the only PWS candidate gene to reduce viability when disrupted in a mouse model. In this study, we have characterized MAGEL2 (also known as NDNL1), a gene with 51% amino acid sequence similarity to necdin and located 41 kb distal to NDN in the PWS deletion region. MAGEL2 is expressed predominantly in brain, the primary tissue affected in PWS and in several fetal tissues as shown by northern blot analysis. MAGEL2 is imprinted with monoallelic expression in control brain, and paternal-only expression in the central nervous system as demonstrated by its lack of expression in brain from a PWS-affected individual. The orthologous mouse gene (Magel2) is located within 150 kb of NDN:, is imprinted with paternal-only expression and is expressed predominantly in late developmental stages and adult brain as shown by northern blotting, RT-PCR and whole-mount RNA in situ hybridization. Magel2 distribution partially overlaps that of NDN:, with strong expression being detected in the central nervous system in mid-gestation mouse embryos by in situ hybridization. We hypothesize that, although loss of necdin expression may be important in the neonatal presentation of PWS, loss of MAGEL2 may be critical to abnormalities in brain development and dysmorphic features in individuals with PWS.

[Neonatal presentation of Prader-Willi syndrome: A report of five cases].

PubMed

Richard-De Ceaurriz, B; Leymarie, C; Godefroy, A; Collignon, P; Sigaudy, S; Truc, P

2017-11-01

Prader-Willi syndrome (PWS) is a fingerprint disease caused by the loss of paternally inherited chromosome 15q11.2-q13. In several populations studied, prevalence is estimated to be from 1/10,000 to 1/25,000 births. The disease initially manifests by neonatal hypotonia associated with orality disorders. Secondly, hyperphagia appears with significant obesity and hypogonadism. Motor milestones and language development are delayed, and all individuals have variable degrees of cognitive disability during childhood. Frequently, the most prominent features do not become evident until the later childhood stage, which can lead to underdiagnosis or late diagnosis in early childhood. Because of the long-term implications of this syndrome, it is important to recognize its features as soon as possible so that early counseling of parents and the affected child is possible. The diagnosis is suspected on clinical grounds and confirmed by genetic analysis. Prenatal diagnosis is possible and can be considered in polyhydramnios, decreased fetal active movements, malpresentation, oddly positioned hands and feet, and abnormal fetal heart rhythm. Since PWS can also lead to complications in both pregnancy and labor, proper prenatal diagnosis can also help optimize perinatal care for affected children. We report a series of five newborns for whom PWS was diagnosed in the neonatal period over 6 years. During this period, no prenatal signs of PWS were detected. The incidence in our population was 1/7937 births. The disease was diagnosed on clinical criteria: severe hypotonia, failure to thrive with poor sucking, and dysmorphic and abnormalities of the genitalia. Polyhydramnios was observed in only one case. The delivery was normal for only one patient. All except one were term newborns. There were three males and two females. We noted abnormal fetal heart rate for 80 % of the patients. The birth weight was close to the 10th percentile for two patients, less than the 3rd

Calorie seeking, but not hedonic response, contributes to hyperphagia in a mouse model for Prader-Willi syndrome.

PubMed

Davies, Jennifer R; Humby, Trevor; Dwyer, Dominic M; Garfield, Alastair S; Furby, Hannah; Wilkinson, Lawrence S; Wells, Timothy; Isles, Anthony R

2015-08-01

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13, the most recognised feature of which is hyperphagia. This is thought to arise as a consequence of abnormalities in both the physiological drive for food and the rewarding properties of food. Although a number of mouse models for PWS exist, the underlying variables dictating maladaptive feeding remain unknown. Here, feeding behaviour in a mouse model in which the imprinting centre (IC) of the syntenic PWS interval has been deleted (PWS(ICdel) mice) is characterised. It is demonstrated that PWS(ICdel) mice show hyperghrelinaemia and increased consumption of food both following overnight fasting and when made more palatable with sucrose. However, hyperphagia in PWS(ICdel) mice was not accompanied by any changes in reactivity to the hedonic properties of palatable food (sucrose or saccharin), as measured by lick-cluster size. Nevertheless, overall consumption by PWS(ICdel) mice for non-caloric saccharin in the licking test was significantly reduced. Combined with converging findings from a continuous reinforcement schedule, these data indicate that PWS(ICdel) mice show a marked heightened sensitivity to the calorific value of food. Overall, these data indicate that any impact of the rewarding properties of food on the hyperphagia seen in PWS(ICdel) mice is driven primarily by calorie content and is unlikely to involve hedonic processes. This has important implications for understanding the neural systems underlying the feeding phenotype of PWS and the contribution of imprinted genes to abnormal feeding behaviour more generally. © 2015 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Gait pattern in two rare genetic conditions characterized by muscular hypotonia: Ehlers-Danlos and Prader-Willi syndrome.

PubMed

Cimolin, Veronica; Galli, Manuela; Vismara, Luca; Grugni, Graziano; Camerota, Filippo; Celletti, Claudia; Albertini, Giorgio; Rigoldi, Chiara; Capodaglio, Paolo

2011-01-01

This study aimed to quantify and compare the gait pattern in Ehlers-Danlos (EDS) and Prader-Willi syndrome (PWS) patients to provide data for developing evidence-based rehabilitation strategies. Twenty EDS and 19 PWS adult patients were evaluated with an optoelectronic system and force platforms for measuring kinematic and kinetic parameters during walking. The results were compared with those obtained in a group of 20 normal-weight controls (CG). The results showed that PWS patients walked with longer stance duration and reduced velocity than EDS, close to CG. Both EDS and PWS showed reduced anterior step length than CG. EDS kinematics evidenced a physiological position at proximal joints (pelvis and hip joint) while some deficits were displayed at knee (reduced flexion in swing phase) and ankle level (plantar flexed position in stance and reduced dorsal flexion in swing). PWS showed a forward tilted pelvis in the sagittal plane, excessive hip flexion during the whole gait cycle and an increased hip movement in the frontal plane. Their knees were flexed at initial contact with reduced range of motion while ankle joints showed a plantar flexed position during stance. No differences were found in terms of ankle kinetics and joint stiffness. Our data showed that EDS and PWS patients were characterized by a different gait strategy: PWS showed functional limitations at every level of the lower limb joints, whereas in EDS limitations, greater than PWS, were reported mainly at the distal joints. PWS patients should be encouraged to walk for its positive impact on muscle mass and strength and energy balance. For EDS patients the rehabilitation program should be focused on ankle strategy improvement. Copyright © 2011 Elsevier Ltd. All rights reserved.

Energy Metabolism Profile in Individuals with Prader-Willi Syndrome and Implications for Clinical Management: A Systematic Review.

PubMed

Alsaif, Maha; Elliot, Sarah A; MacKenzie, Michelle L; Prado, Carla M; Field, Catherine J; Haqq, Andrea M

2017-11-01

Prader-Willi syndrome (PWS) is a rare genetic disorder associated with excessive weight gain. Hyperphagia associated with PWS may result in higher energy intake, but alterations in energy expenditure may also contribute to energy imbalance. The purpose of this critical literature review is to determine the presence of alterations in energy expenditure in individuals with PWS. Ten studies that measured total energy expenditure (TEE), resting energy expenditure (REE), sleep energy expenditure (SEE), activity energy expenditure (AEE), and diet induced thermogenesis (DIT) were included in this review. The studies provided evidence that absolute TEE, REE, SEE, and AEE are lower in individuals with PWS than in age-, sex-, and body mass index-matched individuals without the syndrome. Alterations in lean body mass and lower physical activity amounts appear to be responsible for the lower energy expenditure in PWS rather than metabolic differences. Regardless of the underlying mechanism for lower TEE, the estimation of energy requirements with the use of equations derived for the general population would result in weight gain in individuals with PWS. The determination of energy requirements for weight management in individuals with PWS requires a more comprehensive understanding of energy metabolism. Future studies should aim to comprehensively profile all specific components of energy expenditure in individuals with PWS with the use of appropriately matched controls and gold standard methods to measure energy metabolism and body composition. One component of energy expenditure that is yet to be explored in detail in PWS is DIT. A reduced DIT (despite differences in fat free mass), secondary to hormonal dysregulation, may be present in PWS individuals, leading to a reduced overall energy expenditure. Further research exploring DIT in PWS needs to be conducted. Dietary energy recommendations for weight management in PWS have not yet been clearly established. © 2017 American

Prader-Willi syndrome and early-onset morbid obesity NIH rare disease consortium: A review of natural history study.

PubMed

Butler, Merlin G; Kimonis, Virginia; Dykens, Elisabeth; Gold, June A; Miller, Jennifer; Tamura, Roy; Driscoll, Daniel J

2018-02-01

We describe the National Institutes of Health rare disease consortium for Prader-Willi syndrome (PWS) developed to address concerns regarding medical care, diagnosis, growth and development, awareness, and natural history. PWS results from errors in genomic imprinting leading to loss of paternally expressed genes due to 15q11-q13 deletion, maternal disomy 15 or imprinting defects. The 8 year study was conducted at four national sites on individuals with genetically confirmed PWS and early-onset morbid obesity (EMO) with data accumulated to gain a better understanding of the natural history, cause and treatment of PWS. Enrollment of 355 subjects with PWS and 36 subjects with EMO began in September 2006 with study completion in July 2014. Clinical, genetic, cognitive, behavior, and natural history data were systematically collected along with PWS genetic subtypes, pregnancy and birth history, mortality, obesity, and cognitive status with study details as important endpoints in both subject groups. Of the 355 individuals with PWS, 217 (61%) had the 15q11-q13 deletion, 127 (36%) had maternal disomy 15, and 11 (3%) had imprinting defects. Six deaths were reported in our PWS cohort with 598 cumulative years of study exposure and one death in the EMO group with 42 years of exposure. To our knowledge, this description of a longitudinal study in PWS represents the largest and most comprehensive cohort useful for investigators in planning comparable studies in other rare disorders. Ongoing studies utilizing this database should have a direct impact on care and services, diagnosis, treatment, genotype-phenotype correlations, and clinical outcomes in PWS. © 2017 Wiley Periodicals, Inc.

Cognition and behavior in pre-pubertal children with Prader-Willi syndrome and associations with sleep-related breathing disorders.

PubMed

Festen, Dederieke A M; Wevers, Maaike; de Weerd, Al W; van den Bossche, Renilde A S; Duivenvoorden, Hugo J; Hokken-Koelega, Anita C S

2008-12-01

Prader-Willi syndrome (PWS) is characterized by hypotonia, hypogonadism, obesity, and short stature. Neurobehavioral abnormalities, cognitive impairment, and sleep-related breathing disorders (SRBD) are common. In the general population associations between neurobehavioral and cognitive abnormalities and SRBD have been found. We investigated cognition, behavior, and SRBD in children with PWS. Thirty-one pre-pubertal PWS children were evaluated (5 with paternal deletion, 14 with maternal disomy, 4 with imprinting-center mutation, and in 8 the defect was not specified). Cognition was assessed by Wechsler scale subtests, and behavior by parent-questionnaires. Polysomnography was performed. Cognition, behavior, and associations with SRBD were evaluated. All cognitive subtests were significantly below O SDS, with the lowest median (interquartile range) scores for the Block design subtest (-2.7 SDS (-3.0 to -0.3)). In 60%, verbal subtests were less affected than performance subtests. Parents reported problem behavior related to "emotions/behavior not adapted to the social situation" and "insensitivity to social information." All children had SRBD, with an Apnea Hypopnea Index of 4.1/hr (2.6-7.9). One performance subtest score was significantly higher in children with better sleep efficiency, and daytime sleepiness was associated with more autistic-like social impairment. In contrast to our expectations, behavior was worse in children with better sleep-related breathing. In pre-pubertal PWS children, cognition is impaired. Neurobehavioral abnormalities are common, particularly autistic-like social impairment. Sleep efficiency was associated with better performance on one of the performance subtests, and neurobehavioral abnormalities were associated with daytime sleepiness. In contrast, we could not confirm a positive association of neurobehavioral abnormalities with SRBD in PWS. Copyright (c) 2008 Wiley-Liss, Inc.

Diagnoses and characteristics of autism spectrum disorders in children with Prader-Willi syndrome.

PubMed

Dykens, Elisabeth M; Roof, Elizabeth; Hunt-Hawkins, Hailee; Dankner, Nathan; Lee, Evon Batey; Shivers, Carolyn M; Daniell, Christopher; Kim, Soo-Jeong

2017-01-01

A small percentage of people with autism spectrum disorders (ASD) have alterations in chromosome 15q11.2-q3, the critical region for Prader-Willi syndrome (PWS). Data are limited, however, on the rates and characteristics of ASD in PWS. Previous estimates of ASD in PWS (25 to 41%) are questionable as they are based solely on autism screeners given to parents. Inaccurate diagnoses of ASD in PWS can mislead intervention and future research. One hundred forty-six children and youth with PWS aged 4 to 21 years ( M  = 11) were assessed with the Autism Diagnostic Observation Schedule-2 (ADOS-2). An expert clinical team-made best-estimate ASD diagnoses based on ADOS-2 videotapes, calibrated severity scores, and children's developmental histories and indices of current functioning. Children were also administered the Kaufman Brief Intelligence Test-2, and parents completed the Repetitive Behavior Scale-Revised and Vineland Adaptive Behavior Scales. Scores were compared across children with PWS + ASD versus PWS only. The performance of an ASD screener, the Social Communication Questionnaire (SCQ) and the ADOS-2 were evaluated in relation to best-estimate diagnoses. Best-estimate diagnoses of ASD were made in 18 children, or 12.3% of the sample, and the majority of them had the maternal uniparental disomy (mUPD) PWS genetic subtype. Compared to the PWS-only group, children with PWS + ASD had lower verbal and composite IQ's and adaptive daily living and socialization skills, as well as elevated stereotypies and restricted interests. Regardless of ASD status, compulsivity and insistence on sameness in routines or events were seen in 76-100% of children and were robustly correlated with lower adaptive functioning. The SCQ yielded a 29-49% chance that screen-positive cases will indeed have ASD. The ADOS-2 had higher sensitivity, specificity and predictive values. Communication problems were seen in children who were ADOS-2 positive but deemed not to have ASD by the clinical

Efficacy and safety of long-term continuous growth hormone treatment in children with Prader-Willi syndrome.

PubMed

de Lind van Wijngaarden, Roderick F A; Siemensma, Elbrich P C; Festen, Dederieke A M; Otten, Barto J; van Mil, Edgar G A H; Rotteveel, Joost; Odink, Roelof J H; Bindels-de Heus, G C B Karen; van Leeuwen, Mariëtte; Haring, Danny A J P; Bocca, Gianni; Houdijk, E C A Mieke; Hoorweg-Nijman, J J Gera; Vreuls, René C F M; Jira, Petr E; van Trotsenburg, A S Paul; Bakker, Boudewijn; Schroor, Eelco J; Pilon, Jan Willem; Wit, Jan M; Drop, Stenvert L S; Hokken-Koelega, Anita C S

2009-11-01

Children with Prader-Willi syndrome (PWS) have abnormal body composition and impaired growth. Short-term GH treatment has beneficial effects. The aim of the study was to investigate effects of long-term continuous GH treatment on body composition, growth, bone maturation, and safety parameters. We conducted a multicenter prospective trial. Fifty-five children with a mean +/- sd age of 5.9 +/- 3.2 yr were followed during 4 yr of continuous GH treatment (1 mg/m(2) . d). Data were annually obtained in one center: fat percentage (fat%) and lean body mass (LBM) by dual-energy x-ray absorptiometry, height, weight, head circumference, bone age, blood pressure, and fasting IGF-I, IGF binding protein-3, glucose, insulin, glycosylated hemoglobin, total cholesterol, high-density lipoprotein, and low-density lipoprotein. sd scores (SDS) were calculated according to Dutch and PWS reference values (SDS and SDS(PWS)). Fat%SDS was significantly lower after 4 yr of GH treatment (P < 0.0001). LBMSDS significantly increased during the first year (P = 0.02) but returned to baseline values the second year and remained unchanged thereafter. Mean +/- sd height normalized from -2.27 +/- 1.2 SDS to -0.24 +/- 1.2 SDS (P < 0.0001). Head circumference SDS increased from -0.79 +/- 1.0 at start to 0.07 +/- 1.1 SDS after 4 yr. BMISDS(PWS) significantly decreased. Mean +/- sd IGF-I and the IGF-I/IGF binding protein-3 ratio significantly increased to 2.08 +/- 1.1 and 2.32 +/- 0.9 SDS, respectively. GH treatment had no adverse effects on bone maturation, blood pressure, glucose homeostasis, and serum lipids. Our study in children with PWS shows that 4 yr of continuous GH treatment (1 mg/m(2) . d) improves body composition by decreasing fat%SDS and stabilizing LBMSDS and head circumference SDS and normalizes heightSDS without adverse effects. Thus, long-term continuous GH treatment is an effective and safe therapy for children with PWS.

Importance of reward and prefrontal circuitry in hunger and satiety: Prader-Willi syndrome vs simple obesity.

PubMed

Holsen, L M; Savage, C R; Martin, L E; Bruce, A S; Lepping, R J; Ko, E; Brooks, W M; Butler, M G; Zarcone, J R; Goldstein, J M

2012-05-01

The majority of research on obesity (OB) has focused primarily on clinical features (eating behavior, adiposity measures) or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions that are associated with appetite-regulatory hormones are also involved in the development and maintenance of OB. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic OB. Simple (non-PWS) OB represents an OB-control state. This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (that is, hypothalamus, amygdala) and prefrontal regions associated with cognitive control (that is, dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC) after eating. A total of 14 individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC and DLPFC. Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in the hypothalamus and hippocampus in response to food (vs non-food) images pre-meal. Post meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared with OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory control. In PWS, compared with OB per se, results suggest

Importance of Reward and Prefrontal Circuitry in Hunger and Satiety: Prader-Willi Syndrome vs. Simple Obesity

PubMed Central

Holsen, Laura M.; Savage, Cary R.; Martin, Laura E.; Bruce, Amanda S.; Lepping, Rebecca J.; Ko, Eunice; Brooks, William M.; Butler, Merlin G.; Zarcone, Jennifer R.; Goldstein, Jill M.

2011-01-01

Background The majority of research on obesity has focused primarily on clinical features (eating behavior, adiposity measures), or peripheral appetite-regulatory peptides (leptin, ghrelin). However, recent functional neuroimaging studies have demonstrated that some reward circuitry regions which are associated with appetite-regulatory hormones are also involved in the development and maintenance of obesity. Prader-Willi syndrome (PWS), characterized by hyperphagia and hyperghrelinemia reflecting multi-system dysfunction in inhibitory and satiety mechanisms, serves as an extreme model of genetic obesity. Simple (non-PWS) obesity (OB) represents an obesity control state. Objective This study investigated subcortical food motivation circuitry and prefrontal inhibitory circuitry functioning in response to food stimuli before and after eating in individuals with PWS compared with OB. We hypothesized that groups would differ in limbic regions (i.e., hypothalamus, amygdala) and prefrontal regions associated with cognitive control [i.e., dorsolateral prefrontal cortex (DLPFC), orbitofrontal cortex (OFC)] after eating. Design and Participants Fourteen individuals with PWS, 14 BMI- and age-matched individuals with OB, and 15 age-matched healthy-weight controls (HWC) viewed food and non-food images while undergoing functional MRI before (pre-meal) and after (post-meal) eating. Using SPM8, group contrasts were tested for hypothesized regions: hypothalamus, nucleus accumbens (NAc), amygdala, hippocampus, OFC, medial PFC, and DLPFC. Results Compared with OB and HWC, PWS demonstrated higher activity in reward/limbic regions (NAc, amygdala) and lower activity in hypothalamus and hippocampus, in response to food (vs. non-food) images pre-meal. Post-meal, PWS exhibited higher subcortical activation (hypothalamus, amygdala, hippocampus) compared to OB and HWC. OB showed significantly higher activity versus PWS and HWC in cortical regions (DLPFC, OFC) associated with inhibitory

Long-term health outcomes in patients with Prader-Willi Syndrome: a nationwide cohort study in Denmark.

PubMed

Hedgeman, E; Ulrichsen, S P; Carter, S; Kreher, N C; Malobisky, K P; Braun, M M; Fryzek, J; Olsen, M S

2017-10-01

Prader-Willi syndrome (PWS) is a rare congenital disease that affects growth, sexual development, cognitive function and behavior. Individuals exhibit food preoccupation and hyperphagia, which may lead to obesity with premature morbidity and mortality. The aim of this work was to evaluate the risk of venous thromboembolisms (VTEs), myocardial infarction, pulmonary hypertension, sleep apnea, depression, anxiety and all-cause mortality among persons with PWS as compared with an age- and sex-matched general-population cohort. All persons diagnosed with PWS (n=155) were identified in the Danish Health Registries; an age- and sex-matched comparison group was selected from the general population of Denmark (n=15 500); diseases of interest were identified through the health registry and cause of death register. Follow-up began on date of birth or first medical record availability through to first occurrence of an outcome of interest; follow-up ceased at emigration from Denmark or end of study. Incidence rates (IRs) were calculated and Cox's proportional hazards models were used to understand the relative risk (RR) of disease. The IRs for VTE among patients with PWS was 144 (60-347) per 100 000 person-years. Risks for VTE events and all-cause mortality were 9.4 times (95% confidence interval (CI): 3.7-23.5) and 11.0 times (95% CI: 5.7-21.1) higher, respectively, for patients with PWS versus the general population. Increased risks were also found individually for deep venous thromboses (DVTs) (RR: 9.1; 95% CI: 3.2-25.2), pulmonary embolisms (RR: 11.0; 95% CI: 1.4-86.9), myocardial infarction (RR: 7.2; 95% CI: 1.7-30.2) and anxiety (RR: 2.8; 95% CI: 1.0-7.5). No cases of pulmonary hypertension, sleep apnea or depressive disorders were identified within this PWS cohort. Multiple cardiovascular and behavioral illnesses are more likely to occur among patients with PWS than within the general population. These increased risks may provide an impetus for enhanced disease

Regulatory Elements Associated with Paternally-Expressed Genes in the Imprinted Murine Angelman/Prader-Willi Syndrome Domain

PubMed Central

Khadake, Jyoti; Heggestad, Arnold D.; Ma, Xiaojie; Johnstone, Karen A.; Resnick, James L.; Yang, Thomas P.

2013-01-01

The Angelman/Prader-Willi syndrome (AS/PWS) domain contains at least 8 imprinted genes regulated by a bipartite imprinting center (IC) associated with the SNRPN gene. One component of the IC, the PWS-IC, governs the paternal epigenotype and expression of paternal genes. The mechanisms by which imprinting and expression of paternal genes within the AS/PWS domain – such as MKRN3 and NDN – are regulated by the PWS-IC are unclear. The syntenic region in the mouse is organized and imprinted similarly to the human domain with the murine PWS-IC defined by a 6 kb interval within the Snrpn locus that includes the promoter. To identify regulatory elements that may mediate PWS-IC function, we mapped the location and allele-specificity of DNase I hypersensitive (DH) sites within the PWS-IC in brain cells, then identified transcription factor binding sites within a subset of these DH sites. Six major paternal-specific DH sites were detected in the Snrpn gene, five of which map within the 6 kb PWS-IC. We postulate these five DH sites represent functional components of the murine PWS-IC. Analysis of transcription factor binding within multiple DH sites detected nuclear respiratory factors (NRF's) and YY1 specifically on the paternal allele. NRF's and YY1 were also detected in the paternal promoter region of the murine Mrkn3 and Ndn genes. These results suggest that NRF's and YY1 may facilitate PWS-IC function and coordinately regulate expression of paternal genes. The presence of NRF's also suggests a link between transcriptional regulation within the AS/PWS domain and regulation of respiration. 3C analyses indicated Mkrn3 lies in close proximity to the PWS-IC on the paternal chromosome, evidence that the PWS-IC functions by allele-specific interaction with its distal target genes. This could occur by allele-specific co-localization of the PWS-IC and its target genes to transcription factories containing NRF's and YY1. PMID:23390487

Hypotonia

MedlinePlus

... can be seen in Down syndrome, muscular dystrophy, cerebral palsy, Prader-Willi syndrome, myotonic dystrophy, and Tay-Sachs ... can be seen in Down syndrome, muscular dystrophy, cerebral palsy, Prader-Willi syndrome, myotonic dystrophy, and Tay-Sachs ...

Individuals with Smith-Magenis syndrome display profound neurodevelopmental behavioral deficiencies and exhibit food-related behaviors equivalent to Prader-Willi syndrome.

PubMed

Alaimo, Joseph T; Barton, Laura V; Mullegama, Sureni V; Wills, Rachel D; Foster, Rebecca H; Elsea, Sarah H

2015-12-01

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder associated with intellectual disability, sleep disturbances, early onset obesity and vast behavioral deficits. We used the Behavior Problems Inventory-01 to categorize the frequency and severity of behavioral abnormalities in a SMS cohort relative to individuals with intellectual disability of heterogeneous etiology. Self-injurious, stereotyped, and aggressive/destructive behavioral scores indicated that both frequency and severity were significantly higher among individuals with SMS relative to those with intellectual disability. Next, we categorized food behaviors in our SMS cohort across age using the Food Related Problems Questionnaire (FRPQ) and found that problems began to occur in SMS children as early as 5-11 years old, but children 12-18 years old and adults manifested the most severe problems. Furthermore, we evaluated the similarities of SMS adult food-related behaviors to those with intellectual disability and found that SMS adults had more severe behavioral problems. Many neurodevelopmental disorders exhibit syndromic obesity including SMS. Prader-Willi syndrome (PWS) is the most frequent neurodevelopmental disorder with syndromic obesity and has a well-established management and treatment plan. Using the FRPQ we found that SMS adults had similar scores relative to PWS adults. Both syndromes manifest weight gain early in development, and the FRPQ scores highlight specific areas in which behavioral similarities exist, including preoccupation with food, impaired satiety, and negative behavioral responses. SMS food-related behavior treatment paradigms are not as refined as PWS, suggesting that current PWS treatments for prevention of obesity may be beneficial for individuals with SMS. Copyright © 2015 Elsevier Ltd. All rights reserved.

Growth Hormone Research Society Workshop Summary: Consensus Guidelines for Recombinant Human Growth Hormone Therapy in Prader-Willi Syndrome

PubMed Central

Tony, Michèle; Höybye, Charlotte; Allen, David B.; Tauber, Maïthé; Christiansen, Jens Sandahl; Ambler, Geoffrey R.; Battista, Renaldo; Beauloye, Véronique; Berall, Glenn; Biller, Beverly M. K.; Butler, Merlin G.; Cassidy, Suzanne B.; Chihara, Kazuo; Cohen, Pinchas; Craig, Maria; Farholt, Stense; Goetghebeur, Mireille; Goldstone, Anthony P.; Greggi, Tiziana; Grugni, Graziano; Hokken-Koelega, Anita C.; Johannsson, Gudmundur; Johnson, Keegan; Kemper, Alex; Kopchick, John J.; Malozowski, Saul; Miller, Jennifer; Mogul, Harriette R.; Muscatelli, Françoise; Nergårdh, Ricard; Nicholls, Robert D.; Radovick, Sally; Rosenthal, M. Sara; Sipilä, Ilkka; Tarride, Jean-Eric; Vogels, Annick; Waters, Michael J.

2013-01-01

Context: Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. Objective: The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. Evidence: We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥ 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Methodology: Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Conclusions: Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as

Transcranial direct current stimulation reduces food-craving and measures of hyperphagia behavior in participants with Prader-Willi syndrome.

PubMed

Bravo, Gabriela L; Poje, Albert B; Perissinotti, Iago; Marcondes, Bianca F; Villamar, Mauricio F; Manzardo, Ann M; Luque, Laura; LePage, Jean F; Stafford, Diane; Fregni, Felipe; Butler, Merlin G

2016-03-01

Prader-Willi syndrome (PWS) is a neurodevelopmental genetic disorder characterized by intellectual disabilities and insatiable appetite with compulsive eating leading to severe obesity with detrimental health consequences. Transcranial direct current stimulation (tDCS) has been shown to modulate decision-making and cue-induced food craving in healthy adults. We conducted a pilot double blind, sham-controlled, multicenter study of tDCS modulation of food drive and craving in 10 adult PWS participants, 11 adult obese (OB) and 11 adult healthy-weight control (HWC) subjects. PWS and OB subjects received five consecutive daily sessions of active or sham tDCS over the right dorsolateral prefrontal cortex (DLPFC), while HWC received a single sham and active tDCS in a crossover design. Standardized psychometric instruments assessed food craving, drive and hyperphagia by self-report and caregiver assessment over 30 days. Robust baseline differences were observed in severity scores for the Three-Factor Eating Questionnaire (TFEQ) and Dykens Hyperphagia Questionnaire (DHQ) for PWS compared to HWC while obese participants were more similar to HWC. Active tDCS stimulation in PWS was associated with a significant change from baseline in TFEQ Disinhibition (Factor II) (Ƶ = 1.9, P < 0.05, 30 days) and Total Scores (Ƶ = 2.3, P < 0.02, 30 days), and participant ratings of the DHQ Severity (Ƶ = 1.8, P < 0.06, 5 days) and Total Scores (Ƶ = 1.9, P < 0.05, 15 days). These findings support sustained neuromodulatory effects and efficacy of tDCS to reduce food drive and behaviors impacting hyperphagia in PWS. Transcranial direct current stimulation may represent a straight-forward, low risk and low cost method to improve care, management and quality of life in PWS. © 2015 Wiley Periodicals, Inc.

Reduced cortical complexity in children with Prader-Willi Syndrome and its association with cognitive impairment and developmental delay.

PubMed

Lukoshe, Akvile; Hokken-Koelega, Anita C; van der Lugt, Aad; White, Tonya

2014-01-01

Prader-Willi Syndrome (PWS) is a complex neurogenetic disorder with symptoms involving not only hypothalamic, but also a global, central nervous system dysfunction. Previously, qualitative studies reported polymicrogyria in adults with PWS. However, there have been no quantitative neuroimaging studies of cortical morphology in PWS and no studies to date in children with PWS. Thus, our aim was to investigate and quantify cortical complexity in children with PWS compared to healthy controls. In addition, we investigated differences between genetic subtypes of PWS and the relationship between cortical complexity and intelligence within the PWS group. High-resolution structural magnetic resonance images were acquired in 24 children with genetically confirmed PWS (12 carrying a deletion (DEL), 12 with maternal uniparental disomy (mUPD)) and 11 age- and sex-matched typically developing siblings as healthy controls. Local gyrification index (lGI) was obtained using the FreeSurfer software suite. Four large clusters, two in each hemisphere, comprising frontal, parietal and temporal lobes, had lower lGI in children with PWS, compared to healthy controls. Clusters with lower lGI also had significantly lower cortical surface area in children with PWS. No differences in cortical thickness of the clusters were found between the PWS and healthy controls. lGI correlated significantly with cortical surface area, but not with cortical thickness. Within the PWS group, lGI in both hemispheres correlated with Total IQ and Verbal IQ, but not with Performance IQ. Children with mUPD, compared to children with DEL, had two small clusters with lower lGI in the right hemisphere. lGI of these clusters correlated with cortical surface area, but not with cortical thickness or IQ. These results suggest that lower cortical complexity in children with PWS partially underlies cognitive impairment and developmental delay, probably due to alterations in gene networks that play a prominent role in

Differences in behavioural phenotype between parental deletion and maternal uniparental disomy in Prader-Willi syndrome: an ERP study.

PubMed

Stauder, Johannes E A; Boer, Harm; Gerits, Rolf H A; Tummers, Anke; Whittington, Joyce; Curfs, Leopold M G

2005-06-01

Paternal deletion and maternal uniparental disomy are the principal genetic subtypes associated with Prader-Willi syndrome (PWS). Recent clinical findings suggest differences in phenotype between these subtypes. The present experimental study addresses this issue using a cognitive psycho-physiological setup. Behaviour and event-related brain activity (ERP) was recorded by a continuous performance response inhibition task (CPT-AX) in adults with paternal deletion PWS (n=11), maternal uniparental disomy PWS (n=11) and normal controls (n=11). The dependent behavioural variables of the CPT-AX task were reaction time and correct scores. For the ERPs the N200 and P300 components were included which are related to early modality-specific inhibition and late general inhibition, respectively. The disomy group had fewer correct scores and increased reaction times as compared to the CPT-AX task than the control and deletion group. Both PWS subgroups differed significantly from the control group for the N200 amplitude. Only the control group showed the typical task modulation for the N200 amplitude. The amplitude of the P300 component was considerably smaller in the uniparental disomy group than in the deletion and control groups. The ERP results suggest that early modality specific inhibition is impaired in both PWS genetic subtypes. Late general inhibition is impaired in the uniparental disomy group only. Thus, although the ERP data suggests a common impairment in early visual inhibition processing, uniparental disomy and parental deletion genetic PWS subtypes clearly differ in their behavioural and brain activation phenotypes. The present study is the first experimental demonstration which explains the two principal genetic mechanisms that hinder the expression of the genes at 15q11-q13g in PWS result in different behavioural phenotype.

Associations between repetitive questioning, resistance to change, temper outbursts and anxiety in Prader-Willi and Fragile-X syndromes.

PubMed

Woodcock, K; Oliver, C; Humphreys, G

2009-03-01

The behavioural phenotypes of Prader-Willi (PWS) and Fragile-X (FraX) syndromes both comprise repetitive behaviours with differences between the profiles. In this study we investigated the context and antecedents to the repetitive behaviours and the association with other behavioural phenotypic characteristics in order to generate testable hypotheses regarding the cause of the behaviours. The parents or carers of 46 children with PWS (mean age 14.1 years; 20 girls), and 33 boys with FraX (mean age 13.11 years) were interviewed about their children's repetitive behaviour in a semi-structured format. Children showed negative emotional behaviour (PWS: 87.0%; FraX: 79.4%) and repetitive questions (PWS: 78.3%; FraX: 73.5%) following changes in routine or expectations. Significantly more temper outbursts were reported to follow changes in children with PWS (89.1%) compared with boys with FraX (41.2%) (chi(2) = 20.93; P < 0.001). Anxiety that was frequently associated with repetitive and self-injurious behaviours in boys with FraX, followed changes in significantly more boys with FraX (76.5%) compared with children with PWS (6.5%) (chi(2) = 43.19, P < 0.001). On the basis of these reports and existing literature, we hypothesise that decreases in predictability are aversive to children with PWS and FraX. We also hypothesise that these children have a propensity to show a syndrome-related pattern of behaviour (temper outbursts in PWS and displays of anxiety in FraX) when an event in the environment has this aversive property. We hypothesise that questions may be reinforcing to children in their own right by increasing the predictability of the environment. We outline how a specific cognitive deficit in the endophenotypes associated with both PWS and FraX could be investigated as a potential explanation for the hypothesised aversive properties of decreased predictability.

GrowthHormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome.

PubMed

Deal, Cheri L; Tony, Michèle; Höybye, Charlotte; Allen, David B; Tauber, Maïthé; Christiansen, Jens Sandahl

2013-06-01

Recombinant human GH (rhGH) therapy in Prader-Willi syndrome (PWS) has been used by the medical community and advocated by parental support groups since its approval in the United States in 2000 and in Europe in 2001. Its use in PWS represents a unique therapeutic challenge that includes treating individuals with cognitive disability, varied therapeutic goals that are not focused exclusively on increased height, and concerns about potential life-threatening adverse events. The aim of the study was to formulate recommendations for the use of rhGH in children and adult patients with PWS. We performed a systematic review of the clinical evidence in the pediatric population, including randomized controlled trials, comparative observational studies, and long-term studies (>3.5 y). Adult studies included randomized controlled trials of rhGH treatment for ≥ 6 months and uncontrolled trials. Safety data were obtained from case reports, clinical trials, and pharmaceutical registries. Forty-three international experts and stakeholders followed clinical practice guideline development recommendations outlined by the AGREE Collaboration (www.agreetrust.org). Evidence was synthesized and graded using a comprehensive multicriteria methodology (EVIDEM) (http://bit.ly.PWGHIN). Following a multidisciplinary evaluation, preferably by experts, rhGH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental, and lifestyle interventions. Cognitive impairment should not be a barrier to treatment, and informed consent/assent should include benefit/risk information. Exclusion criteria should include severe obesity, uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer, or psychosis. Clinical outcome priorities should vary depending upon age and the presence of physical, mental, and social disability, and treatment should be continued for as long as demonstrated benefits outweigh the risks.

The metabolic phenotype of Prader-Willi syndrome (PWS) in childhood: heightened insulin sensitivity relative to body mass index.

PubMed

Haqq, Andrea M; Muehlbauer, Michael J; Newgard, Christopher B; Grambow, Steven; Freemark, Michael

2011-01-01

Insulin sensitivity is higher in patients with Prader-Willi syndrome (PWS) than in body mass index-matched obese controls (OCs). Factors contributing to the heightened insulin sensitivity of PWS remain obscure. We compared the fasting levels of various hormones, cytokines, lipids, and liver function tests in 14 PWS patients and 14 OCs with those in 14 age- and gender-matched lean children (LC). We hypothesized that metabolic profiles of children with PWS are comparable with those of LC, but different from those of OCs. Leptin levels were comparable in PWS patients and OCs, suggesting comparable degrees of adiposity. Glucose levels were comparable among groups. However, fasting insulin concentrations and homeostasis model assessment insulin resistance index were lower in PWS patients than in OCs (P < 0.05) and similar to LC. Moreover, high-density lipoprotein levels were lower and triglycerides higher in OCs (P < 0.05) but not PWS patients. Total adiponectin, high-molecular-weight (HMW) adiponectin and the HMW to total adiponectin ratio were higher in PWS patients (P < 0.05) than in OCs and similar to LC. High-sensitivity C-reactive protein and IL-6 levels were higher in OCs than in PWS patients or LC (P < 0.05). Nevertheless, PAI-1 levels were elevated in both OC and PWS patients. There were no group differences in glucagon-like peptide-1, macrophage chemoattractant protein-1, TNFα, IL-2, IL-8, IL-10, IL-12p40, IL-18, resistin, total or low-density lipoprotein cholesterol, aspartate aminotransferase, or alanine aminotransferase. The heightened insulin sensitivity of PWS patients relative to OCs is associated with higher levels of adiponectin and lower levels of high-sensitivity C-reactive protein and IL-6. Future studies will determine whether PWS children are protected from obesity comorbidities such as type 2 diabetes, hyperlipidemia, and nonalcoholic fatty liver disease.

EVALUATION OF PLASMA SUBSTANCE P AND BETA-ENDORPHIN LEVELS IN CHILDREN WITH PRADER-WILLI SYNDROME.

PubMed

Butler, M G; Nelson, T A; Driscoll, D J; Manzardo, A M

2015-09-01

Prader-Willi syndrome (PWS) is a rare obesity-related genetic disorder often caused by a deletion of the chromosome 15q11-q13 region inherited from the father or by maternal disomy 15. Growth hormone deficiency with short stature, hypogonadism, cognitive and behavioral problems, analgesia, decreased gastric motility and decreased ability to vomit with hyperphagia are common in PWS leading to severe obesity in early childhood, if not controlled. Substance P (SP) and beta-endorphin (BE) are neuropeptides involved with centrally and peripherally mediated pain perception, emotional regulation, and gastric motility impacting nausea, emesis and feeding patterns. The goal of this study was to investigate potential mechanisms for PWS symptom development for pain, emotion and gastric motility and plasma levels of substance P and beta-endorphin between PWS and unrelated unaffected children. Plasma samples were collected from 23 Caucasian children with PWS and 18 unrelated, unaffected siblings with an average age of 8.2 ±2.0 years and age range of 5 to 11 years following an overnight fast and neuropeptide substance p and beta-endorphin levels were assessed using Multiplex sandwich immunoassays using the Luminex magnetic-bead based platform. Linear regression analysis was carried out on log-transformed values adjusted for age, sex, and body mass index (BMI). The mean plasma SP (57 ± 23 pg/ml) and BE (592 ± 200 pg/ml) levels in PWS were significantly higher than SP (35 ± 20 pg/ml, F=10.5, P <0.01) and BE (402 ± 162 pg/ml, F=10.8, P <0.01) levels found in unrelated, unaffected siblings suggesting a previously uncharacterized neuroendocrine pathophysiology in PWS. The increased BE and SP plasma levels relative to unrelated, unaffected siblings may contribute to hyperphagia, abnormal pain sensation and adrenal insufficiency seen in PWS. Increases in SP levels may be modulated by central and/or peripheral actions of BE on opioid, GABA or POMC precursors and may reflect loss of

Effect of Genotype and Previous GH Treatment on Adiposity in Adults With Prader-Willi Syndrome.

PubMed

Coupaye, Muriel; Tauber, Maithé; Cuisset, Laurence; Laurier, Virginie; Bieth, Eric; Lacorte, Jean-Marc; Oppert, Jean-Michel; Clément, Karine; Poitou, Christine

2016-12-01

Adults with Prader-Willi syndrome (PWS) have an increased proportion of sc fat mass compared with body mass index (BMI)-matched controls, but whether the genotype influences body composition and metabolic profile remains controversial. To assess body composition and metabolic features in adults with PWS, according to genetic subtype. In addition, the effect of previous GH treatment was assessed. Main Outcomes and Measures: Body composition (Dual Energy X-ray Absorptiometry) and metabolic parameters were compared in PWS adults (mean age, 25.5 ± 8.9 y) with deletion (n = 47) or uniparental disomy (UPD) (n = 26), taking into account GH treatment in childhood and/or adolescence. In subgroups, adipocyte size, fasting total ghrelin levels, and resting energy expenditure were measured, and hyperphagia was assessed by the Dykens Hyperphagia Questionnaire. Body composition (Dual Energy X-ray Absorptiometry) and metabolic parameters were compared in PWS adults (mean age, 25.5 ± 8.9 y) with deletion (n = 47) or uniparental disomy (UPD) (n = 26), taking into account GH treatment in childhood and/or adolescence. In subgroups, adipocyte size, fasting total ghrelin levels, and resting energy expenditure were measured, and hyperphagia was assessed by the Dykens Hyperphagia Questionnaire. In the whole sample, the deletion group had a higher BMI compared with UPD (40.9 ± 11.5 vs 34.6 ± 9.6 kg/m 2 , P = .02), but there was no difference between groups in percent body fat, metabolic profile, adipocyte size, resting energy expenditure, hyperphagia score, or ghrelin levels. In subjects previously treated with GH, BMI was not different between UPD and deletion groups (33.0 ± 9.7 vs 33.5 ± 11.1 kg/m 2 ). In addition, previous GH treatment was associated with decreased percent body fat and adipocyte volume only in the deletion group. A deletion genotype in adults with PWS is associated with increased BMI. GH treatment in childhood and/or adolescence limits this deleterious phenotypic

Deletion of the Snord116/SNORD116 Alters Sleep in Mice and Patients with Prader-Willi Syndrome.

PubMed

Lassi, Glenda; Priano, Lorenzo; Maggi, Silvia; Garcia-Garcia, Celina; Balzani, Edoardo; El-Assawy, Nadia; Pagani, Marco; Tinarelli, Federico; Giardino, Daniela; Mauro, Alessandro; Peters, Jo; Gozzi, Alessandro; Grugni, Graziano; Tucci, Valter

2016-03-01

Sleep-wake disturbances are often reported in Prader-Willi syndrome (PWS), a rare neurodevelopmental syndrome that is associated with paternally-expressed genomic imprinting defects within the human chromosome region 15q11-13. One of the candidate genes, prevalently expressed in the brain, is the small nucleolar ribonucleic acid-116 (SNORD116). Here we conducted a translational study into the sleep abnormalities of PWS, testing the hypothesis that SNORD116 is responsible for sleep defects that characterize the syndrome. We studied sleep in mutant mice that carry a deletion of Snord116 at the orthologous locus (mouse chromosome 7) of the human PWS critical region (PWScr). In particular, we assessed EEG and temperature profiles, across 24-h, in PWScr (m+/p-) heterozygous mutants compared to wild-type littermates. High-resolution magnetic resonance imaging (MRI) was performed to explore morphoanatomical differences according to the genotype. Moreover, we complemented the mouse work by presenting two patients with a diagnosis of PWS and characterized by atypical small deletions of SNORD116. We compared the individual EEG parameters of patients with healthy subjects and with a cohort of obese subjects. By studying the mouse mutant line PWScr(m+/p-), we observed specific rapid eye movement (REM) sleep alterations including abnormal electroencephalograph (EEG) theta waves. Remarkably, we observed identical sleep/EEG defects in the two PWS cases. We report brain morphological abnormalities that are associated with the EEG alterations. In particular, mouse mutants have a bilateral reduction of the gray matter volume in the ventral hippocampus and in the septum areas, which are pivotal structures for maintaining theta rhythms throughout the brain. In PWScr(m+/p-) mice we also observed increased body temperature that is coherent with REM sleep alterations in mice and human patients. Our study indicates that paternally expressed Snord116 is involved in the 24-h regulation of

Relationship between the IQ of people with Prader-Willi syndrome and that of their siblings: evidence for imprinted gene effects.

PubMed

Whittington, J; Holland, A; Webb, T

2009-05-01

Genetic disorders occasionally provide the means to uncover potential mechanisms linking gene expression and physical or cognitive characteristics or behaviour. Prader-Willi syndrome (PWS) is one such genetic disorder in which differences between the two main genetic subtypes have been documented (e.g. higher verbal IQ in one vs. higher performance IQ in the other; slower than normal reaction time in one vs. normal in the other). In a population study of PWS, the IQ distribution of people with PWS was approximately normal. This raises the question of whether this distribution arose from a systematic effect of PWS on IQ (hypothesis 1) or whether it was the fortuitous result of random effects (hypothesis 2). The correlation between PWS and sibling IQ was determined in order to discriminate between the two hypotheses. In the first case we would expect the correlation to be similar to that found in the general population (0.5); in the second case it would be zero. It was found that the overall PWS-sibling IQ correlation was 0.3 but that the two main genetic subtypes of PWS differed in their familial IQ relationships. As expected, the IQs of normal siblings correlated 0.5, and this was also the case with one genetic subtype of PWS (uniparental disomy) and their siblings, while the other subtype IQ correlated -0.07 with sibling IQ. This is a potentially powerful result that gives another clue to the role of genes on chromosome 15 in the determination of IQ. It is another systematic difference between the genetic subtypes of PWS, which needs an explanation in terms of the very small genetic differences between them.

Molecular and clinical characterization of two patients with Prader-Willi syndrome and atypical deletions of proximal chromosome 15q.

PubMed

Calounova, Gabriela; Hedvicakova, Petra; Silhanova, Eva; Kreckova, Gabriela; Sedlacek, Zdenek

2008-08-01

Prader-Willi syndrome (PWS) is caused by the disturbed expression of genes from the imprinted region of 15q11-q13, but the specific contributions of individual genes remain unknown. Most paternal PWS deletions are bracketed by recurrent breakpoints BP1 or BP2 and BP3. Atypical deletions are very rare. In the present work, we describe the molecular analysis of two patients with atypical deletions using microsatellite analysis, methylation-specific MLPA, and microarray CGH. A deletion of about 2 Mb in Patient 1 started at BP2 and ended in the middle of the typically deleted region within the UBE3A gene. The deletion in Patient 2 started 1.3 Mb distal from BP2 within the C15ORF2 gene, extended over 9.5 Mb, and ended within the AVEN gene in proximal 15q14. In Patient 1 both deletion breakpoints involved repetitive regions, which precluded cloning of the junction and pointed to non-allelic homologous recombination as a possible mechanism of this rearrangement. The breakpoints in Patient 2 were sequenced, and their structure suggested non-homologous end joining as the most likely cause of this deletion. The phenotype of both patients did not depart significantly from the typical clinical picture of PWS, although some symptoms in Patient 2 were also reminiscent of the phenotype of individuals with the recently described 15q13.3 microdeletion syndrome. Our findings support previous observations of relatively mild phenotypic effects resulting from deletions that extend distally from the PWS region and observations of the modest effects of different types of genetic defects on the spectrum and severity of symptoms in PWS. Copyright 2008 Wiley-Liss, Inc.

A new case of interstitial 6q16.2 deletion in a patient with Prader-Willi-like phenotype and investigation of SIM1 gene deletion in 87 patients with syndromic obesity.

PubMed

Varela, Monica C; Simões-Sato, Alex Y; Kim, Chong A; Bertola, Débora R; De Castro, Claudia I E; Koiffmann, Celia P

2006-01-01

The association of obesity, phenotypic abnormalities and mental retardation characterizes syndromic obesity. Its most common form is the Prader-Willi syndrome (PWS-- neonatal hypotonia, poor sucking, delayed psychomotor development, hyperphagia, severe obesity, short stature, small hands and feet, hypogonadism, mild to moderate mental retardation and behavioral disorders). A PWS-like phenotype has been described in patients with chromosome abnormalities involving the chromosome region 6q16.2 that includes the SIM1 gene. Herein we report cytogenetic and gene studies including a screening for the SIM1 gene deletion, performed on 87 patients with PWS-like phenotype, and describe the fifth case of syndromic obesity with an interstitial deletion of the chromosome segment 6q16-q21 and suggest that mutational analysis and further studies of the parental origin of chromosome alterations of 6q16.2 in patients with and without PWS-like phenotype are needed to evaluate possible imprinting effects of SIM1 gene and establish the contribution that alterations in this gene makes to the etiology of syndromic and non-syndromic obesity.