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Five Hyperphagia Grants Sponsored in 2011 by PWSA (USA) 

Transcranial Direct Current Stimulation (tDCS)

Dr. Merlin G. Butler and Dr. Albert Poje at the University of Kansas School of Medicine, Kansas City, Kansas; Dr. Filipe Fregni at Harvard University, Boston, Massachusetts 

This is a procedure whereby a weak electric direct current is transmitted into the brain via external electrodes without any known side effects.  Previous data have shown that tDCS to the prefrontal cortex of the brain can change food craving in healthy subjects and preliminary data in 5 adults with PWS have shown encouraging results.  This study is designed to test if tDCS is effective in PWS.  If this pilot study is successful, it could lead to further, larger studies which if successful could lead to a therapeutic technique to reduce hyperphagia in PWS. 

They will perform tDCS on 12 adults with PWS, 12 obese controls, and 12 non-obese controls.

tDCS has been shown to impact craving via the pre-frontal cortex, an area of known difference in PWS as shown by fMRI. Also, tDCS has been shown to moderate hunger/appetite in normal subjects, so it is possible that tDCS could have a beneficial clinical effect on hyperphagia in PWS for extended intervals after tDCS. This study is designed to test that possibility and understand if tDCS is effective in PWS.   

This above grant was funded by PWSA (USA) thanks to a partnership with the Capraro Family Foundation, a 401(3) and also designated funding in honor of Nicholas Joncas. 

Leptin Resistance in Mouse Models of Hyperphagia

Rachel Wevrick, Ph.D., Department of Medical Genetics, University of  Alberta, Canada 

The hypothesis that leptin receptor (LepR) signaling defects can cause congenital leptin  resistance in PWS hypothalamic neurons, preceding obesity and contributing to hyperphagia and obesity will be tested in PWS and similar genetic disorders such as Bardet-Biedl syndrome (BBS). The insensitivity to multiple hormones signaling energy needs (e.g., ghrelin) and broader phenotypes of PWS further suggests that more complex processes are affected in PWS.  Defective intracellular signaling pathways may overlap with the leptin response pathways in the brain. 

The aim is to examine leptin sensitivity in murine models of PWS and related disorders, including mice carrying targeted inactivation of the Snord116/MBII-85, necdin, and Magel2 PWS candidate genes, the Smith-Magenis gene Rai1, and BBS genes. The long-term goal is to determine whether defective LepR signaling is responsible for hyperphagia in PWS and related genetic disorders, and possibly contributes to hyperphagia in the general population. 

The knowledge that individuals with PWS are congenitally leptin resistant would draw attention to this disorder as a model for other forms of leptin resistance, and would provide a sound and logical explanation for the severe post-weaning hyperphagia that is so characteristic of PWS.  

Brain-Derived Neurotrophic Factor in PWS & MC4R Function-Altering Mutations

Joan C. Han, M.D., Senior Clinical Fellow, Unit on Growth and Obesity

Jack A. Yanovski, M.D., Ph.D., Head, Unit on Growth and Obesity Program in Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH 

Brain-derived neurotrophic factor (BDNF) is a protein that is important in nervous system development and function. BDNF is well-expressed in the hypothalamus, a key region in the brain for energy homeostasis, and appears to function downstream of the leptin-melanocortin signaling pathway to control appetite. In both animals and humans, diminished BDNF function is associated with hyperphagia and obesity. They are studying BDNF in two hyperphagic disorders: Prader-Willi syndrome and MC4R function-altering mutations. They hypothesize that patients with PWS may have increased BDNF during infancy, followed by a decline in BDNF that precedes the onset of hyperphagia and persists after the onset of obesity. They also hypothesize that patients with MC4R mutations will have decreased BDNF, the severity of which will be associated with the degree of MC4R functional loss caused by the specific mutation(s) in each individual. To test these hypotheses, they are conducting 2 cross-sectional studies comparing serum BDNF concentrations in: 1) 75 subjects with PWS (25 infants, 25 non-obese children, and 25 obese children) and 75 healthy control subjects matched for age, sex, race, and BMI; 2) 50 subjects with MC4R mutations and 50 healthy control subjects matched for age, sex, race, and BMI. If alterations in BDNF are found to be associated with PWS and/or MC4R mutations, these investigations could lead to future studies of BDNF receptor agonists as mechanism-specific pharmacologic therapy for hyperphagia and obesity in PWS and MC4R mutations, or BDNF receptor antagonists for failure-to-thrive in neonatal PWS. 


1) Patients with PWS will have increased BDNF during infancy, followed by a decline in BDNF that will precede the onset of hyperphagia and persist after the onset of obesity.

2) Patients with MC4R mutations will have decreased BDNF, the severity of which will be associated with the degree of MC4R functional loss caused by the specific mutation(s) in each individual. 

Abnormal Proteins Drive the Hyperphagia in PWS

Barbara Y. Whitman, Ph.D., Susan E. Myers, M.D. Jeffrey Teckman, M.D. ,Yie-Hwa Chang, Ph.D. 

Hypothesis: While both genetic and brain imaging studies offer some interesting

possibilities in terms of research and pathophysiologic pathways, the  results of these studies are only the first step; explanatory results from either of these methodologies depend on further elucidation of the protein metabolic abnormalities. A number of genes involved in protein processing are located in the PWS region. They assert that the mechanism of hyperphagia in PWS involves signaling via serum proteins and/or peptides that are unique in type or magnitude compared to obese non-PWS patients or normal controls. Thus they are investigating this hypothesis using state of the art proteonomic analysis comparing rigorously defined PWS patients, obese non-PWS patients and normal controls. 

Probing Genes for Hyperphagia in Rare Obesity-related Syndromes

Merlin G. Butler, M.D., Ph.D., Professor, Psychiatry and Pediatrics, Kansas University Medical Center in collaboration with Dan J. Driscoll, Ph.D., Professor, Pediatrics and Genetics, Departments of Pediatrics, Molecular Genetics and Microbiology, University of Florida, College of Medicine, Jan Marshall, B.A., Senior Professional Assistant at the Jackson Laboratory and the Genetics Coordinator of Alström Syndrome, Randi J. Hagerman, M.D., Medical Director, University of California-Davis, M.I.N.D. Institute and Professor of Pediatrics, Endowed Chair in Fragile X Syndrome Research 

The study of rare genetic obesity-related disorders with hyperphagia including Prader-Willi syndrome (PWS), Alström syndrome (ALMS) and fragile X syndrome (FXS) allows a window of opportunity to not only provide potential insights into genetic, biochemical and developmental pathways by probing the genes for hyperphagia and obesity impacting on each rare disorder, but also applicable to the growing problem of obesity in the general population.  Defining the genetic cause of obesity syndromes should enrich our understanding of obesogenic pathways in common or exogenous obesity, a major public health problem resulting in increased morbidity and mortality with severe economic burdens on healthcare systems, loss in worker productivity and decreased quality of life for affected individuals 

They propose that the three rare disorders (PWS, ALMS, and FXS) will individually be associated with unique structural and functional genetic patterns identifiable with the latest microarray technology and bioinformatics tools. Integration of structural and functional genetic profiles for PWS, ALMS, and FXS along with their clinical, hyperphagia and obesity measures, when compared with obese and non-obese comparison subjects, will enable the discovery and characterization of a more precise molecular signature for each rare syndrome useful for diagnosis and causation.  Identifying gene targets or molecular pathways common to the obese phenotype seen in individuals with rare obesity-related disorders and those non-syndromic subjects with exogenous obesity will have the potential to stimulate new directions for study using pharmaceutical interventions tailored for each syndrome with hyperphagia and obesity in general.



edited: 02/09/2012

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