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Research View

EXPECTED SIGNIFICANCE OF RECENT RESEARCH SPONSORED BY PWSA (USA)

March 2010

Reported By: Janalee Heinemann, MSW Director of Research & Medical Affairs

The following are fourteen grants sponsored by PWSA (USA) plus our Medical Database project and their expected significance. 

We want to thank all who have donated or hosted fundraisers to make this important research possible.  We are improving the quality and length of our children’s lives TODAY!  It is not just a dream for tomorrow. 

Impact of Dietary Content upon Gastrointestinal Motility in Individuals with Prader-Willi Syndrome (PWS)
Klish & Scheimann 

Meals that contain large amounts of carbohydrates and can quickly raise blood sugar levels are known to increase appetite. On the other hand, meals that contain large amounts of fats are known to slow down how quickly the stomach empties into the intestine. This slows the breakdown of carbohydrates and absorption of sugars and keeps blood sugar levels relatively lower. In PWS, this delayed gastric empting may relate to gastroparesis, in which the stomach stretches with food that accumulates because of ineffective stomach contractions (when severe, this can lead to stomach rupture).

Dr. Klish’s team, headed by Dr. Ann O. Scheimann, is studying how quickly meals with varying fat and carbohydrate content exit the stomachs of people with PWS, the gut hormone responses to meal content and the relationship of the type of meal to how full that person feels after eating. In addition, blood tests before and after each meal will help check the relationship of ghrelin and other gastrointestinal peptides to stomach emptying. This grant will further our understanding of the signals that make a person with PWS feel hungry or full and may alert parents and medical providers to a dietary component to gastroparesis, and potentially, to gastric perforation.

What we know to date: They have started with the first patient as a pilot for the study.  The child had delayed gastric emptying noted at one hour on a high fat diet.  Of interest, the food appeared to collect in the fundus area of the stomach- which is the area in patients with eating disorders who develop gastric dilation which is felt to be vulnerable.  There are several patients tentatively scheduled for study visits over the summer.  They plan to present the results on gastric emptying studies and glucose/insulin curves at the 2009 PWSA (USA) national conference. 

Click here to see the abstract

Effect of Rimonabant, a new anti-obesity medication, on appetite, feeding behavior, body weight, and composition of Patients with PWS
 Motaghedi & Angulo

Rimonabant (Accomplia) works by blocking the CB-1 receptors that manages food intake. The receptors are in the brain, but also throughout the body, particularly in fat cells. Among other things, they account for the abrupt increase in appetite experienced by people who smoke marijuana.   Many of our PWS researchers think this drug has the best chance of impacting the appetite with PWS. 

Doctors claim that this system of receptors is disrupted by chronic overeating. The drug re-establishes the balance in the system, repressing appetite.

Acomplia's (Rimonibant) unique approach attacks the receptor in the brain that makes people hungry when they smoke marijuana. This protein receptor is referred to as the cannabinoid receptor found on the surface of brain cells.

Researchers in Europe have demonstrated positive effects in obese patients. This medication has not yet been approved for use in the United States, however, is undergoing FDA investigation.  The researchers have permission to use it for this study and are examining the use of this medication with individuals with PWS to determine its effects on weight loss, Ghrelin and Leptin levels.  The study is also examining Rimonabant’s effect on appetite and feeding behavior in individuals with PWS.

Development of a Microsphere Suspension Assay for the High Throughput Screening of Prader-Willi Subjects
Newkirk & Butler

Expected Significance

The researchers have designed a novel test for the detection of genomic copy number changes called quantitative microsphere hybridization (QMH).   Current PWS testing has limitations in identifying some of the genetic subtypes.  This research has two major aims. 

Aim 1) Development of a high-resolution, high-throughput, low-cost test for screening PWS subjects to distinguish different types of deletions including IC (imprinting center) defects. The QMH could become a cost-effective, rapid screening method for PWS. No such assay currently exists for identification of IC mutations in subjects with PWS. 

 Aim 2) Development of a panel of unique sequence probes for use in FISH analysis for typical type I, type II and IC deletions, which currently cannot be distinguished or in some cases even detected using current commercial probes.

Genetic Underpinnings of Restricted Repetitive Behavior 
Kim, Driscoll, Lewis, Cook, Storch & Badner

Expected Significance

Their goal is to identify genetic factors contributing to restricted repetitive behaviors (RRB), such as stereotypic movements, self-injurious behaviors, obsessions, compulsions, insistence on sameness, among individuals with PWS, focusing on the Prader-Willi syndrome critical region (15q11-q13).  

RRB is also a diagnostic feature of Autism Spectrum Disorders (ASDs).  Increased rates of ASDs have been reported among individuals with PWS.  Findings from this research project will lead to new treatment for RRB in individuals with Prader-Willi syndrome.  This study will generate data that may also help to understand underlying genetic mechanisms for ASD whose prevalence rate is significantly high in PWS.  In addition, this project will also provide an opportunity to test the hypothesis of gene-gene interactions.

A Pilot Study of Psychotropic Medications in PWS
Dykens & Roof

Although there have been significant advances in - and application of -- psychotropic medication with PWS, reactions to these medications are dramatically variable.  Dr. Elisabeth Dykens, Elizabeth Roof and colleagues have been working to shed new light on why there is such variability in the respond to psychotropic medications. 

What we know to date:  An article in our last newsletter explained some of the causes they found for the variability in response to the medications and gave tips on usage.  Most of the participants were taking an SSRI and another agent.  They explained the relationship between dosage and drug metabolism.  Their study also identifies the CYP450 enzyme status in those with PWS.  With this study, we should be able to identify more accurately what drugs work better - and as important -- in what dosage for PWS.  They are submitting their work for publication and assisting us with a Medical Alert for psychiatrists.

Sex Hormones/Sexuality
Gross-Tsur & Hirsch (Israel)

The researchers are doing a study on gonadal function (testes in males and ovaries in females) in PWS and sexual behavior.

What we know to date:  They had a larger than expected response and their study population now represents a true cross-section of all known with PWS in Israel (total+92) so they expanded their study.  They write, “It is already clear to us that our PWS population represents a wide spectrum of reproductive hormone function ranging from near gonadotropin deficiency, to cases of precocious pubertal development.  The interviews with our adolescent and adult participants show without a doubt that sexuality is a very important issue that must be dealt with in counseling and caring for PWS individuals.” 

The Expression and Regulation of Necdin in the Mouse Central Nervous System: Relation to Hyperphagia
Reyes

One of the proteins made by chromosome 15 genes that are disrupted in PWS is called necdin. Necdin is found in the brain (particularly in the hypothalamus) and is needed for normal development and interconnection of brain cells. Because hypothalamic dysfunction may change the secretion of neurotransmitters that affect appetite and because small hypothalamii and increased appetite are hallmarks of PWS, researchers suspect a necdin deficiency may cause the insatiable hunger associated with PWS. Dr. Reyes and her team are examining how necdin is expressed in brain cells and if expression relates to appetite. In mice, she is examining how to identify brain cells that express necdin, if necdin levels are different in varying models of over-eating, eating schedules, and chemically stimulated hunger, and if artificially deleting the necdin gene leads to hungrier mice.

What we know to date:  They hypothesized that a necdin deletion in alphs-MSH neurons may contribute to hyperphagia (loss of a neuropeptide that inhibits food intake) observed in Prader-Willi patients. Initial experiments were successful in identifying a population of neurons within the hypothalamus that coexpress alpha-MSH and necdin. However, the majority of alpha-MSH positive neurons do NOT express necdin, and the majority of necdin+ neurons do not contain alpha-MSH.  This may suggest that other neuropeptides may be of greater importance in mediating the hyperphagia observed in Prader-Willi patients.  Another possibility is that the observed hyperphagia is not driven by a loss of function of the anorexigenic  neural populations, but rather an aberrant expression or function of an orexigenic  population, for example NPY.  Experiments are currently underway to colocalize necdin and NPY. Given the observed expression pattern of necdin (dense expression in the basal medial arcuate), we anticipate the colocalization will indeed be observed. What remains unknown is how the loss of necdin within these neurons affects their development and function.                 

Functional Magnetic Resonance Imaging of Reduced Satiety in Prader-Willi Syndrome and Obesity
 Miller, Driscoll & Goldstone

The pathways within the brain that control food intake are regulated by many factors, including input from other parts of the brain and hormonal signals from the gut. These pathways can be studied using functional Magnetic Resonance Imaging (fMRI). Previous brain imaging studies have shown that there is an increased reward response to viewing pictures of food in individuals with Prader-Willi syndrome (PWS) which may result in abnormalities of appetite control.

Expected Significance

This study seeks to identify which abnormalities in the appetite regulating hormonal-brain pathways lead to excessive food intake in PWS, and to see if any of those abnormalities can be changed with an increased meal size. The researchers expect to find key differences in the hormonal-brain pathways in response to different meal sizes which will increase our understanding of the factors involved in the sensations of hunger and fullness in individuals with PWS. These findings can then serve as the basis for future studies in PWS which will investigate treatments targeted to the specific brain pathway and hormonal abnormalities found in this study.

Autistic Symptomatology in PWS: Examining Behavioral and Neurobiological Similarities between PWS and Autism Spectrum Disorders
 Dimitropoulos

Expected Significance

The grant will further characterize and examine the types of autistic behaviors in individuals with PWS and also in individuals without PWS but diagnosed with autism to find similarities and differences. It is thought that individuals with  PWS exhibit behaviors characteristic of autism and these investigators want to address this issue by further defining the types of autistic behavior in PWS and compare with autistic behaviors recorded in those individuals without PWS but diagnosed with autism spectrum disorders. This study could impact on treatment of children in the future with both PWS and autism.

Expression of Four Genes Between Chromosome 15 Breakpoints BPI and BP2 in Subjects with Prader-Willi Syndrome and Impact on Cognitive and Behavior Measures
 Bittel, Zarcone & Butler

Second year approved – abstract on progress report on first year follows:

The researchers are focusing on the 70% of those with PWS who have a paternal chromosome 15q11-q13 deletion deletion.  They can further classify them as either a large typical Type I (TI) deletion involving breakpoints BP1 and BP3 or a smaller typical Type II (TII) deletion involving breakpoints BP2 and BP3.   New findings have also shown unique deletions distally beyond BP3.

The researchers are working to quantify the expression of four genes, and correlate the differences between Type I and Type II previously reported. This project allows the investigators to expand their pilot data and analysis.

Expected Significance

Preliminary analyses of their new data tend to support their hypothesis that changes in expression of these genes, result in alterations in behavior and cognition. They will study both the size and type of deletion.  The enhanced gene expression patterns will then be correlated with behavior and clinical outcomes (and deletion size) in individuals with PWS, and compared with maternal disomy and comparison subjects.  This will help to explain why there are such variances in behavior, food seeking and cognition. 

Impact of Prader-Willi Syndrome on the Parent-Sibling Relationship and Caregiving Availability for Unaffected Sibling(s)
 Mazaheri, Rae-Seebach, Wendy Packman, Field

Expected Significance

The purpose of this study is to learn about the impact that Prader-Willi Syndrome (PWS) has on the parent-sibling relationship, as well as on the quality and availability of caregiving for unaffected sibling(s).  They are investigating both the parent(s) and the unaffected sibling(s) perceptions of these issues as they relate to their psychological health and emotional well being.  Information learned through this study will help identify needs of parents and siblings of children with PWS.  It will also lead to effective interventions aimed at improving communication and building stronger relationships between family members, as well as assisting health practitioners in providing comprehensive care for these families.

Causes of Death in Prader-Willi Syndrome
Stevenson & PWSA (USA) Study of Deaths Committee

PWSA (USA) has demographic information on 232 individuals with PWS who have died.  When we began this study in Dec 2005, there were 147 deaths known to us.  Requests for information through family-completed questionnaires were sent and we have received 68 completed questionnaires. Autopsy reports have been received on 32 individuals.  This study could help delineate causes of death and early demise in patients with PWS in order to provide clinicians with guidance in patient management to decrease morbidity and mortality.

The following are a few of the statistics from this study:

· The average age of death was 32, median age was 33 – up from 27 in Dec 2005

· The oldest was 64, the youngest was an infant

· Only 55% died in the hospital

· 75% of parents thought it was a sudden death

· 82% said it was an unexpected death (Did parents understand how morbid obesity is still the #1 cause of death in PWS?)

· 92% were not on growth hormone at the time of death and 79% had never been on growth hormone

· The average weight was 227 lbs and average height was 4’9”

· The heaviest weight was 600 lbs 

·  Choking deaths – 11 deaths – average age in general population 1-4 yrs of age.  Average age with PWS was 24 yrs.

Stomach necrosis and rupture deaths – example of the synchronicity between our medical crisis work and our study of deaths.  1) We have published alerts, sent special mailings about the risk of overeating binges – especially with a person with PWS who is slim.  We have also published this risk factor in a journal.   2) We now have new information on possible thinning of the lining of the stomach via a recent medical crisis that may explain a piece of the puzzle of why some are more at risk. 

PWSA (USA) Medical Database

 Thanks to the cooperation of parents, in our medical database, we have over 1,650 children and adults with PWS this has led us to a better understanding of many PWS issues. The following is just a small sample. 

The 2nd survey is now available.  You can call the PWSA (USA) office for a copy or (preferably) go on line to www.pwsausa.org/population. It is important that if you have not filled out the first survey, you complete that one first. 

Growth hormone therapy (GHT):   738 children with PWS between the ages of 6 to 18 yrs old = 493 have had GHT; 245 have not. 

· Not on GHT = 81% with obesity problems

· On GHT = 55% with obesity problem

· Not on GHT, = 8% have diabetes

· On GHT = less than 1%

· Not on GHT, 49% had sleep apnea

·  On GHT = 39% (many more children probably get tested for sleep apnea if on GHT than those not on GHT)

Scoliosis:  All ages with scoliosis was 33%

· 0-5 yrs old = 15%

· 6-18 yrs old = 35%

·  18-34 yrs old = 47%

Average age for scoliosis surgery in USA is 12.4 yrs – virtually same as a France study of 12.3 years.  A presentation at conference on scoliosis in PWS and our statistics was given by Harold van Bosse, M.D. who is a new member of our Clinical Advisory Board.  This information will be available in the member’s only section of the web site and in the Gathered View newsletter. 

A few more significant facts:

· The percentage of parents who received assisted reproduction with PWS is higher than the general population.

· More obesity with Deletion

· More autistic characteristics in UPD

· Morbid obesity drops dramatically in the 35 and older age range.  My thoughts on the three reasons are:

· Those that are dramatically obese die before that age from obesity related complications.

· Many of our young adults with PWS go into supportive living placement thus due to the 24-hour-a-day supervision, are more able to loose weight.

·  According to Dr. Driscoll’s study, there appears to be a decrease in appetite as the person with PWS ages.

PWSA (USA) medical and death statistics have been used in several publications including:

Obesity study in France -- French adults with PWS have significantly higher rates of obesity than adults in the UK and the USA, but growth in French children with PWS is similar to the USA and Germany. Clinical management has a greater impact on obesity outcome in PWS than cultural factors.   Note that most adult with PWS in France still live at home. 

Growth Hormone & Mortality in PWS by Phillip Lee, MD -- He was able to show by statistics that there is no greater mortality threat in PWS due to growth hormone

Gastrointestinal Complications Associated with Death in Prader-Willi Syndrome David A. Stevenson, Janalee Heinemann, Moris Angulo, Merlin G. Butler, Jim Loker, Norma Rupe, Patrick Kendell, Carolyn Loker, Carol Clericuzio, Ann Scheimann—In the Journal of Pediatric Gastroenterology and Nutrition , this article alerts the physician to consider an emergent evaluation for gastric rupture and necrosis in individuals with PWS who present with vomiting and abdominal pain.

WHAT WE ARE DOING FOR RESEARCH BEYOND GRANT SPONSORSHIP

Protect the Future -- PWSA (USA) is financially sponsoring two PWS research fellow trainees for the Rare Disease Clinical Research Network (RDCRN).  We believe we need to help train the next generation of PWS researchers. 

  • Co-chair of the Coalition for Patients Advocacy Group (CPAG) thus I have frequent contact with the Office of Rare Diseases (ORD) and the National Institute of Health (NIH).  There are over 7,000 rare diseases.  Meetings and conference calls I attend give visibility and focus to OUR rare disease.
  • Wrote an article for NORD -- commending the FDA’s Orphan Drug Act for approving the indication for growth hormone therapy (GHT) with PWS, with a goal of broadening the approval.
  • Assist with the recruitment of subjects for ALL appropriate grants, not just PWSA (USA) grants.

    • Host Medical Awareness booths -- besides giving medical packets to hundreds of physicians at each event, we have special packets for researchers and meet with both researchers and physicians to answer questions.
  • Support new researchers in the field of PWS in a variety of ways – sponsored some to attend the Conference on Clinical Research for Rare Diseases;  most of the renown  researchers on our two advisory boards mentor new researchers;  respond almost daily to their question and requests.

     

    edited: 02/09/2012

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