Prader–Willi syndrome: cycloid psychosis in a genetic subtype?

Prader–Willi syndrome (PWS) is a genetically determined disorder associated with the loss of the paternal contribution to the proximal part of the long arm of chromosome 15. Its pathophysiology is dominated by hypothalamic dysfunctions. The psychopathological phenotype comprises affective and psychotic symptoms as well as an increase of pre-existent obsessive-compulsive behaviors. The present study comprises 19 PWS patients who were referred for neuropsychiatric evaluation because of psychotic deterioration. Patients were assessed by using the elements of semistructured symptom checklists. In the majority a genetic analysis was performed to detect the underlying chromosomal defect. In 16 of the 19 patients a diagnosis of cycloid psychosis could be established. The other three showed a bipolar affective disorder. Of the psychotic patients, 11 were diagnosed as UPD and one as del 15q11–13. The remaining four patients were diagnosed clinically. For various reasons the genetic etiology could not be established. In PWS patients with a psychotic disorder (cycloid psychosis) a disproportional number of UPD is found.

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The phenomenology and diagnosis of psychiatric illness in people with Prader–Willi syndrome

Psychological Medicine ◽

10.1017/s0033291707002504 ◽

2008 ◽

Vol 38 (10) ◽

pp. 1505-1514 ◽

Cited By ~ 80

Author(s):

S. Soni ◽

J. Whittington ◽

A. J. Holland ◽

T. Webb ◽

E. N. Maina ◽

...

Keyword(s):

Family History ◽

Affective Disorder ◽

Psychiatric Illness ◽

Uniparental Disomy ◽

Psychotic Symptoms ◽

Chromosome 15 ◽

Prader Willi Syndrome ◽

Psychotic Illness ◽

Genetic Subtype ◽

History Of

BackgroundPsychotic illness is strongly associated with the maternal uniparental disomy (mUPD) genetic subtype of Prader–Willi syndrome (PWS), but not the deletion subtype (delPWS). This study investigates the clinical features of psychiatric illness associated with PWS. We consider possible genetic and other mechanisms that may be responsible for the development of psychotic illness, predominantly in those with mUPD.MethodThe study sample comprised 119 individuals with genetically confirmed PWS, of whom 46 had a history of psychiatric illness. A detailed clinical and family psychiatric history was obtained from these 46 using the PAS-ADD, OPCRIT, Family History and Life Events Questionnaires.ResultsIndividuals with mUPD had a higher rate of psychiatric illness than those with delPWS (22/34 v. 24/85, p<0.001). The profile of psychiatric illness in both genetic subtypes resembled an atypical affective disorder with or without psychotic symptoms. Those with delPWS were more likely to have developed a non-psychotic depressive illness (p=0.005) and those with mUPD a bipolar disorder with psychotic symptoms (p=0.00005). Individuals with delPWS and psychotic illness had an increased family history of affective disorder. This was confined exclusively to their mothers.ConclusionsPsychiatric illness in PWS is predominately affective with atypical features. The prevalence and possibly the severity of illness are greater in those with mUPD. We present a ‘two-hit’ hypothesis, involving imprinted genes on chromosome 15, for the development of affective psychosis in people with PWS, regardless of genetic subtype.

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Thoughts on the behavioural phenotypes in Prader-Willi syndrome and velo-cardio-facial syndrome: a novel approach

Acta Neuropsychiatrica ◽

10.1111/j.1601-5215.2007.00202.x ◽

2007 ◽

Vol 19 (4) ◽

pp. 244-250 ◽

Cited By ~ 8

Author(s):

Willem Verhoeven ◽

Jos Egger ◽

Siegfried Tuinier

Keyword(s):

Psychotic Disorders ◽

Bipolar Affective Disorder ◽

Probabilistic Approach ◽

Deletion Syndrome ◽

Psychotic Symptoms ◽

Prader Willi Syndrome ◽

Behavioural Phenotype ◽

Genetic Syndrome ◽

Increased Risk ◽

Velo Cardio Facial Syndrome

Background:In both Prader-Willi syndrome (PWS) and 22q11 deletion syndrome [velo-cardio-facial syndrome (VCFS)], an increased risk for psychotic disorders is reported, which are as a rule not included in the behavioural phenotype of these two syndromes. For the description of a behavioural phenotype, the complete spectrum of physical, developmental, neuropsychological and psychiatric aspects is generally not taken into account. Moreover, psychiatric signs and symptoms often do not meet the criteria for a categorical diagnosis.Objective:In this study, a further specification of psychotic symptoms in PWS and VCFS is shown as well as a proposal for a new model to ascertain predictors, including behavioural, for a genetic syndrome.Methods:Over the past years, 27 patients with PWS and 19 with VCFS were referred for neuropsychiatric evaluation because of psychotic symptoms. In all the patients, a standardised psychiatric examination was performed; seven of the patients with VCFS were evaluated by means of an extensive neuropsychological battery.Results:In both patient groups, a rather specific psychopathological profile seemed to be present, which in the case of patients with PWS showed some resemblance with bipolar affective disorder. In patients with VCFS, no formal psychiatric diagnosis could be established. Because the psychopathological profiles were rather aspecific, they are not sufficient to predict membership of a certain syndrome.Conclusions:A quantitative probabilistic approach toward the description of a (behavioural) phenotype is suggested. For such a procedure, large data sets and international collaboration are required.

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Cyfip1 haploinsufficiency increases compulsive-like behavior and modulates palatable food intake: Implications for Prader-Willi Syndrome

10.1101/264846 ◽

2018 ◽

Cited By ~ 2

Author(s):

Richard K Babbs ◽

Qiu T Ruan ◽

Julia C Kelliher ◽

Jacob A Beierle ◽

Melanie M Chen ◽

...

Keyword(s):

Fragile X ◽

Neurodevelopmental Disorder ◽

Type I ◽

Prader Willi Syndrome ◽

Palatable Food ◽

Obsessive Compulsive ◽

Interacting Protein ◽

Heritable Trait ◽

Compulsive Behaviors ◽

Parent Of Origin

Binge eating (BE) is a heritable trait associated with eating disorders and involves rapid consumption of large quantities of food. We identified cytoplasmic FMRP-interacting protein 2 (Cyfip2) as a major genetic factor underlying BE and concomitant compulsive-like behaviors in mice. CYFIP2 is a gene homolog of CYFIP1 - one of four paternally-deleted genes in patients with the more severe Type I Prader-Willi Syndrome (PWS). PWS is a neurodevelopmental disorder where 70% of cases involve paternal deletion of 15q11-q13. PWS symptoms include hyperphagia, obesity (if untreated), cognitive deficits, and obsessive-compulsive behaviors. We tested whether Cyfip1 haploinsufficiency (+/-) would enhance premorbid compulsive-like behavior and palatable food (PF) intake in a parent-of-origin-selective manner. We tested Cyfip1+/- mice on a C57BL/6N (N) background that were homozygous for the BE-associated missense mutation in Cyfip2 (S968F) as well as mice that we backcrossed to homozygosity for the C57BL/6J (J) allele at Cyfip2 (Cyfip2J/J). Cyfip1+/- mice showed increased compulsive-like behavior on both backgrounds, increased PF consumption on the Cyfip2N/N background in a paternally-enhanced manner, and decreased PF consumption in male Cyfip1+/- mice on the Cyfip2J/J background in a maternally selective manner. In the hypothalamus, there was a maternally-enhanced reduction of Cyfip1 transcription, but a paternally-enhanced reduction in CYFIP1 protein. In the nucleus accumbens, there was a maternally-enhanced reduction in CYFIP1 protein. Together, increased compulsive-like behavior, parent-of-origin-, and genetic background-dependent effects of Cyfip1 haploinsufficiency on PF consumption implicate CYFIP1 in behaviors in neurodevelopmental disorders involving reduced expression of CYFIP1, including PWS, Fragile X Syndrome, and 15q11.2 Microdeletion Syndrome.

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Behavioral features in Prader-Willi syndrome (PWS): consensus paper from the International PWS Clinical Trial Consortium

Journal of Neurodevelopmental Disorders ◽

10.1186/s11689-021-09373-2 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Lauren Schwartz ◽

Assumpta Caixàs ◽

Anastasia Dimitropoulos ◽

Elisabeth Dykens ◽

Jessica Duis ◽

...

Keyword(s):

Clinical Trials ◽

Genetic Disorder ◽

Assessment Tools ◽

Limiting Factor ◽

Prader Willi Syndrome ◽

Obsessive Compulsive ◽

Behavioral Challenges ◽

Behavioral Features ◽

Compulsive Behaviors ◽

Temper Outbursts

AbstractPrader-Willi syndrome (PWS) is a rare neurodevelopmental genetic disorder associated with a characteristic behavioral phenotype that includes severe hyperphagia and a variety of other behavioral challenges such as temper outbursts and anxiety. These behaviors have a significant and dramatic impact on the daily functioning and quality of life for the person with PWS and their families. To date, effective therapies addressing these behavioral challenges have proven elusive, but several potential treatments are on the horizon. However, a limiting factor for treatment studies in PWS is the lack of consensus in the field regarding how to best define and measure the complex and interrelated behavioral features of this syndrome. The International PWS Clinical Trials Consortium (PWS-CTC, www.pwsctc.org) includes expert PWS scientists, clinicians, and patient advocacy organization representatives focused on facilitating clinical trials in this rare disease. To address the above gap in the field, members of the PWS-CTC “Behavior Outcomes Working Group” sought to develop a unified understanding of the key behavioral features in PWS and build a consensus regarding their definition and description. The primary focus of this paper is to present consensus definitions and descriptions of key phenotypic PWS behaviors including hyperphagia, temper outbursts, anxiety, obsessive–compulsive behaviors, rigidity, and social cognition deficits. Patient vignettes are provided to illustrate the interrelatedness and impact of these behaviors. We also review some available assessment tools as well as new instruments in development which may be useful in measuring these behavioral features in PWS.

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Segmental maternal heterodisomy of the proximal part of chromosome 15 in an infant with Prader–Willi syndrome

European Journal of Human Genetics ◽

10.1038/sj.ejhg.5201168 ◽

2004 ◽

Vol 12 (5) ◽

pp. 411-414 ◽

Cited By ~ 9

Author(s):

Sergey Nazarenko ◽

Elena Sazhenova ◽

Alessandra Baumer ◽

Albert Schinzel

Keyword(s):

Proximal Part ◽

Chromosome 15 ◽

Prader Willi Syndrome

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Pathophysiology and treatment of secondary obsessive-compulsive behaviors and tics

Seminars in Clinical Neuropsychiatry ◽

10.1053/scnp.2000.16529 ◽

2000 ◽

Vol 5 (4) ◽

pp. 250-258

Author(s):

Robinder Kaur Bhangoo

Keyword(s):

Obsessive Compulsive ◽

Compulsive Behaviors

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A Case Of Prader-Willi Syndrome With Behavioural Disturbances: A Successful Multidisciplinary Management Approach

Journal of Clinical and Health Sciences ◽

10.24191/jchs.v5i1.9825 ◽

2020 ◽

Vol 5 (1) ◽

pp. 83

Author(s):

Nor Jannah Nasution Raduan ◽

Mohd Razali Salleh ◽

Norharlina Bahar ◽

Mohd Faiz Md Tahir ◽

Najwa Hanim Md Rosli

Keyword(s):

Neurodevelopmental Disorder ◽

Pressure Control ◽

Family Therapist ◽

Sleep Apnoea ◽

Obstructive Sleep Apnoea Syndrome ◽

Management Approach ◽

Adolescent Psychiatrist ◽

Prader Willi Syndrome ◽

Obstructive Sleep ◽

Genetically Determined

Prader-Willi Syndrome (PWS) is a genetically determined neurodevelopmental disorder occurring in 1 in 15,000 births. PWS is a rare case in Malaysia and a successful approach to its management has not been well reported here. We present a case of a 13-year-old boy with Prader-Willi Syndrome with prominent behavioural disturbances characterised by temper tantrums, compulsive food intake, stubbornness, stealing and impulsivity further complicated by underlying morbid obesity, poorly controlled type 2 diabetes mellitus, hypertension, dyslipidaemia, obstructive sleep apnoea syndrome and intellectual disability. Multidisciplinary approach involving child and adolescent psychiatrist, occupational therapist, counsellor, family therapist, endocrinologist and dietician has shown to improve the patient’s weight, glucose and blood pressure control and most importantly the behavioural disturbances.

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Prospective Prenatal Diagnosis of Prader–Willi Syndrome due to Maternal Disomy for Chromosome 15 following Trisomic Zygote Rescue

Prenatal Diagnosis ◽

10.1002/(sici)1097-0223(199708)17:8<780::aid-pd133>3.0.co;2-z ◽

1997 ◽

Vol 17 (8) ◽

pp. 780-783 ◽

Cited By ~ 18

Author(s):

Eileen Roberts ◽

K. Stevenson ◽

T. Cole ◽

D. H. A. Redford ◽

E. V. Davison

Keyword(s):

Prenatal Diagnosis ◽

Chromosome 15 ◽

Prader Willi Syndrome

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Translational approach to study flexibility as an endophenotype of obsessive compulsive disorders

European Psychiatry ◽

10.1016/j.eurpsy.2014.09.331 ◽

2014 ◽

Vol 29 (S3) ◽

pp. 546-546

Author(s):

N. Benzina ◽

S.L. Mondragon ◽

N. Ouarti ◽

L. Mallet ◽

E. Burguiere

Keyword(s):

Reversal Learning ◽

Behavioral Flexibility ◽

Repetitive Behaviors ◽

Reward Contingency ◽

Neural Basis ◽

Obsessive Compulsive ◽

Compulsive Behaviors ◽

Translational Approach ◽

Obsessive Compulsive Disorders ◽

Compulsive Disorders

Behavioral flexibility is the ability of a subject to change its behavior according to contextual cues. In humans, Obsessive Compulsive Disorders (OCD) is characterized by repetitive behavior, performed through rigid rituals. This phenomenological observation has led to explore the idea that OCD patients may have diminished behavioral flexibility. To address this question we developed innovative translational approaches across multiple species, including human patients suffering from obsessive-compulsive disorders, and rodent genetic models of OCD to provide original data in the perspective of enlightening the neurocognitive bases of compulsive behaviors. Behavioral flexibility may be challenged in experimental tasks such as reversal learning paradigms. In these tasks, the subject has to respond to either of two different visual stimuli but only one stimulus is positively rewarded while the other is not. After this first association has been learned, reward contingency are inverted, so that the previously neutral stimulus is now rewarded, while the previously rewarded stimulus is not. Performance in reversal learning is indexed by the number of perseverative errors committed when participants maintain their response towards previously reinforced stimulus in spite of negative reward. Unsurprisingly, this behavioral task has been adapted to mice using various response modalities (T-maze, lever press, nose-poke). Using animal models of compulsive behaviors give much more possibilities to study the deficient functions and their underlying neural basis that could lead to pathological repetitive behaviors. Here we present new behavioral set-ups that we developed in parallel in human (i.e. healthy subjects and OCD patients) and mice (i.e. controls and SAPAP3-KO mice) to study the role of the behavioral flexibility as a possible endophenotype of OCD. We observed that the subjects suffering of compulsive behaviors showed perseverative maladaptive behaviors in these tasks. By comparing the results of a similar task-design in humans and mouse models we will discuss the pertinence of such translational approach to further study the neurocognitive basis of compulsive behaviors.

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