Synopsis: Prader-Willi Syndrome (PWS) affects approximately one out of every twelve to fifteen thousand people from both sexes and all races.
Prader-Willi Syndrome (PWS) involves a disorder of chromosome 15. The disorder affects approximately one out of every twelve to fifteen thousand people from both sexes and all races.
Defining Prader-Willi Syndrome
The major characteristics of the disorder include hypotonia, hypogonadism, hyperphagia, cognitive impairment, and difficult behaviors. One of the major medical concerns associated with PWS is morbid obesity.
While the cause of PWS is complex, the disorder is the most common known genetic cause of life-threatening obesity in children. PWS commonly causes low muscle tone, incomplete sexual development, short stature when not treated with growth hormone, as well as a chronic sense of hunger which, coupled with a metabolism that utilizes far fewer calories than is common, may lead to excessive consumption of food and life-threatening obesity. The compulsion to consume food makes consistent supervision a necessity. The person's average I.Q. is around seventy, although people with I.Q.'s considered, 'normal,' nearly always have learning issues. People with PWS also experience motor and social deficits.
At birth, people with PWS usually have a low birth weight, weak muscles - also referred to as, 'hypotonia,' and experience difficulty sucking due to the presence of hypotonia, which can lead to a diagnosis of failure to thrive. Children with PWS move into a second stage of, 'thriving too well,' which typically has an onset between the ages of two and five years, although it may occur later. An extreme and unsatisfied drive to consume food, also referred to as, 'hyperphagia,' lasts throughout the person's lifetime. Children with PWS usually have very sweet and loving personalities, yet this phase is also characterized by increased appetite, weight control issues, motor delays, as well as some behavioral issues and unique medical issues.
Causes and Diagnosis of Prader-Willi Syndrome (PWS)
The cause of PWS is genetic, from a loss of genes that are usually contributed by the child's father, which remain unidentified at this time. What is known is that PWS occurs from three main genetic errors. Approximately seventy-percent of people with the disorder have a non-inherited deletion in the paternally-contributed chromosome 15. Around twenty-five percent have maternal uniparental disomy (UPD), or two maternal 15 and no paternal chromosome 15. Two-to-five percent of people with PWS have an error in the, 'imprinting,' process, which renders the paternal contribution non-functional.
Genetic testing is the preferred means of diagnosing PWS. DNA methylation analysis can confirm a diagnosis of the disorder. 'FISH,' and DNA techniques may identify the particular gene cause ad associated risk of recurrence. People who have received test results that are either negative or inconclusive should be re-tested. The risk of recurrence is significant only in rare cases with imprinting mutations, inversions, or trans-locations. Families that have PWS should receive genetic counseling.
Prader-Willi Syndrome - Concerns
There are a number of concerns associated with Prader-Willi Syndrome (PWS). These concerns are related to areas such as weight, behavior, developmental concerns, and additional concerns. What follows are descriptions of some of these concerns.
Appetite Disorder: The cause of a person with PWS' disordered appetite function is thought to be hypothalamic dysfunction. Obsession with food and compulsive eating commonly start before the person reaches age six. The urge to eat is both overwhelming and physiological, they experience difficulties with controlling this urge and require constant vigilance.
Weight Management Challenge: Adding to the stress of an excessive appetite is the fact that people with PWS use less calories that people without the disorder, commonly between 1,000 and 1,200 kcal per day for adults, because of low muscle mass and inactivity. Doctors often recommend a balanced and low-calorie diet that includes vitamin and calcium supplements for people with PWS, as well as regular weight checks and periodic diet reviews. Due to a tendency to binge, weight control depends on external food restriction and could require locking the kitchen and food storage areas. Daily exercise is also recommended for people with PWS.
Behavior Issues: While infants and young children with PWS are usually loving and happy, exhibiting few behavior problems, older children and adults with PWS may experience difficulties with behavior regulation. Older children and adults with PWS may manifest difficulties with transitions and unanticipated changes. The onset of behavioral symptoms commonly coincide with the onset of hyperphagia, although not all behaviors are food-related. Difficulties often peak while the person is in adolescence or early adulthood. Establishment of daily routines, structure, firm rules and limits - as well as, 'time-outs,' and positive rewards work best for management of behaviors.
Psychotropic medications such as serotonin reuptake inhibitors may be beneficial in treating obsessive-compulsive disorder symptoms, perseveration, and mood swings. While depression is common among adults with PWS, psychotic episodes are rare.
Motor Skills: Milestones in motor development are usually delayed in children with PWS by one to two years, although hypotonia improves. Children with PWS may continue to experience deficits in coordination, strength, balance, and motor planning. Physical and occupational therapies can assist in the promotion of skills development and proper functioning. Children with the disorder may require growth hormone treatment. Exercise and sports activities should be encouraged, with adaptations being made as needed.
Oral Motor and Speech: The presence of hypotonia can create problems with feeding in children with PWS, as well as delayed speech and poor oral-motor skills. Children with the disorder may require speech therapy and should be assessed in infancy. Picture communication and sign language may be used in order to reduce frustration and assist communication efforts. Products that enhance the production of saliva can help with articulation problems. Training in social skills may improve a child with PWS' pragmatic language use. Despite delays verbal abilities often become an area of strength for children with PWS.
Cognition: People with PWS have I.Q.'s that range between 40 and 105, with an average of 70. People with PWS who have, 'normal,' I.Q.'s may still experience learning disabilities. Problem areas can include short-term auditory memory, attention, and abstract thinking. Typical strengths among persons with PWS include long-term memory, receptive language, and reading abilities. Early infant stimulation is something that should be encouraged. The need for special education services and supports is something that should be assessed in preschool and beyond.
Growth: A diagnosis of failure to thrive while a child with PWS is in infancy may require tube feeding. Infants need to be monitored closely to ensure they receive an adequate amount of calories and gain weight appropriately. Growth hormone is usually deficient causing short stature, high body fat ratio, and lack of pubertal growth spurt - even in people with PWS who have an average weight. The need for growth hormone therapy is something that should be assessed in both children and adults with PWS.
Sexual Development: Sex hormone levels in people with PWS, both testosterone and estrogen, are commonly low. The presence of,'Cryptochidism,' in male infants might require surgery. Children of both genders have good responses to treatment for hormone deficiencies, although side effects have been reported. The appearance of pubic hair at an early age is common, although the onset of puberty is usually late and incomplete.
Other Common Concerns
People with PWS usually experience general good health. If their weight is controlled, their life expectancy may be average, and their health and functioning can be maximized. The constant need to restrict food and manage behavior can be stressful for family members. Family counseling may be needed. Both adolescents and adults with PWS can function well in supported living programs and group environments if the needed diet control and structures are provided. Employment through sheltered workshops and other forms of highly-structured and supervised settings is successful for many people with PWS.
Prader-Willi Syndrome Children do not Sleep as Well at Night and Have Daytime Sleepiness
UC Davis MIND Institute - Added on 26 June 2013
Researchers with the UC Davis MIND Institute and Agilent Laboratories have found that Prader-Willi syndrome - a genetic disorder best known for causing an insatiable appetite that can lead to morbid obesity - is associated with the loss of non-coding RNAs, resulting in the dysregulation of circadian and metabolic genes, accelerated energy expenditure and metabolic differences during sleep.
The research was led by Janine LaSalle, a professor in the UC Davis Department of Medical Microbiology and Immunology who is affiliated with the MIND Institute. It is published online in Human Molecular Genetics.
"Prader-Willi syndrome children do not sleep as well at night and have daytime sleepiness," LaSalle said. "Parents have to lock up their pantries because the kids are rummaging for food in the middle of the night, even breaking into their neighbors' houses to eat."
The study found that these behaviors are rooted in the loss of a long non-coding RNA that functions to balance energy expenditure in the brain during sleep. The finding could have a profound effect on how clinicians treat children with Prader-Willi, as well as point the way to new, innovative therapies, LaSalle said.
The leading cause of morbid obesity among children in the United States, Prader-Willi involves a complex, and sometimes contradictory, array of symptoms. Shortly after birth children with Prader-Willi experience failure to thrive. Yet after they begin to feed themselves, they have difficulty sleeping and insatiable appetites that lead to obesity if their diets are not carefully monitored.
The current study was conducted in a mouse model of Prader-Willi syndrome. It found that mice engineered with the loss of a long non-coding RNA showed altered energy use and metabolic differences during sleep.
Prader-Willi has been traced to a specific region on chromosome 15 (SNORD116), which produces RNAs that regulate gene expression, rather than coding for proteins. When functioning normally, SNORD116 produces small nucleolar (sno) RNAs and a long non-coding RNA (116HG), as well as a third non-coding RNA implicated in a related disorder, Angelman syndrome. The 116HG long non-coding RNA forms a cloud inside neuronal nuclei that associates with proteins and genes regulating diurnal metabolism in the brain, LaSalle said.
"We thought the cloud would be activating transcription, but in fact it was doing the opposite," she said. "Most of the genes were dampened by the cloud. This long non-coding RNA was acting as a decoy, pulling the active transcription factors away from genes and keeping them from being expressed."
As a result, losing snoRNAs and 116HG causes a chain reaction, eliminating the RNA cloud and allowing circadian and metabolic genes to get turned on during sleep periods, when they should be dampened down. This underlies a complex cycle in which the RNA cloud grew during sleep periods (daytime for nocturnal mice), turning down genes associated with energy use, and receded during waking periods, allowing these genes to be expressed. Mice without the 116HG gene lacked the benefit of this neuronal cloud, causing greater energy expenditure during sleep.
The researchers said that the work provides a clearer picture of why children with Prader-Willi syndrome can't sleep or feel satiated and may change therapeutic approaches. For example, many such children have been treated with growth hormone because of short stature, but this actually may boost other aspects of the disease.
"People had thought the kids weren't sleeping at night because of the sleep apnea caused by obesity," said LaSalle. "What this study shows is that the diurnal metabolism is central to the disorder, and that the obesity may be as a result of that. If you can work with that, you could improve therapies, for example figuring out the best times to administer medications."
The study's other study authors include Weston T. Powell, Rochelle L. Coulson, Florence K. Crary, Spencer S. Wong, Robert A. Ach and Dag H. Yasui, all of UC Davis, and Peter Tsang and N. Alice Yamada of Agilent Laboratories.
The work was funded by National Institutes of Health grants F31NS073164 and 1R01NS076263 and the Prader-Willi Foundation.
UPDATE: A new way of looking at Prader-Willi Syndrome -15 Nov 2012
An Australian study reveals that people with the rare genetic disorder known as Prader-Willi Syndrome may have an impaired autonomic nervous system. This discovery opens up a new way of looking at the insatiable appetite experienced by all sufferers, as well as their very high risk of cardiovascular disease.
The autonomic nervous system controls our inner organs, including our gut, heart, liver and blood vessels. It is a finely tuned, dynamic system, responding moment-by-moment to the body's needs.
Researchers from Sydney's Garvan Institute of Medical Research, including Drs Alexander Viardot and Lisa Sze, Professor Lesley Campbell and Louise Purtell, undertook meal studies, comparing 10 adults with Prader-Willi Syndrome with 11 healthy matched obese people and 9 healthy lean people.
Their findings, now published online in the international journal Clinical Endocrinology, showed that heart rate variability, an indicator of autonomic nervous system function, was not normal in people with Prader-Willi Syndrome.
In a healthy person, the time between one heartbeat and the next varies considerably during a meal because the autonomic nervous system is very actively regulating the body's response to food and blood flow.
In people with Prader-Willi Syndrome, the study found, heartbeats were far too regular after a meal. This allowed the researchers to infer autonomic nervous system impairment.
"This is the first study to show that the response of the autonomic nervous system to food intake is abnormal in Prader-Willi Syndrome," said endocrinologist Dr Alex Viardot, one of the principal investigators.
"A range of abnormalities we see in Prader-Willi patients could be linked to it - including how the body secretes appetite suppressing gut hormones, and also controls appetite through the central nervous system."
"We believe the finding introduces a fresh perspective on the pathophysiology of this disease, potentially leading to alternative treatments in the future."
Study leader Professor Lesley Campbell agreed, emphasizing the fact that the researchers matched obese people very closely with Prader-Willi patients in order to establish exactly what is intrinsic to Prader-Willi. "As a result of that close matching, we believe we are seeing the actual defect induced by the syndrome," she said.
"The autonomic nervous system is very hard to assess - and previous Prader-Willi studies have tended to look at the grosser autonomic nervous functions, such as pupil function, which has its limitations."
"To measure a very finely regulated thing like heart rate is a sensitive and reproducible way of measuring autonomic nervous function. This is the benefit of our study - it's a reliable test."
UPDATE: The Hebrew University of Jerusalem May 12 2014
Major breakthrough in understanding Prader-Willi Syndrome, a parental imprinting disorder
Scientists at the Hebrew University of Jerusalem have reported a major breakthrough in understanding the molecular basis for Prader-Willi syndrome (PWS), perhaps the most studied among the class of diseases that involves defects in parental imprinting.
The work, described in the latest online edition of the prestigious journal Nature Genetics, was led by Prof. Nissim Benvenisty, the Herbert Cohn Professor of Cancer Research and director of the Stem Cell Unit at the Alexander Silberman Institute of Life Sciences at the Hebrew University; and his PhD student Yonatan Stelzer. Also assisting in the research were graduate student Ido Sagi and Dr. Ofra Yanuka and Dr. Rachel Eiges.
Parental imprinting is a mode of inheritance that results in a small subset of genes to be expressed exclusively from either the mother or father. Prader-Willi syndrome is perhaps the best characterized disease of this sort. It is a multi-system disorder characterized by learning disabilities, excessive weight gain and defective sexual development, and is known to result from aberrations in paternal genes in what is known as the Prader-Willi genomic region of chromosome 15.
"What characterizes this chromosomal region is that paternal genes are active, while the maternal genes are inactive. And while most people would have one normal working and one silenced set of these genes, people with Prader-Willi syndrome have only a defective set (the paternal one) and a silenced (maternal) set," explains Stelzer.
In order to achieve a greater understanding of this process, the Hebrew University investigators created a model for the Prader-Willi syndrome by reprogramming skin cells from PWS patients into embryonic-like cells. Utilizing this system, the investigators have shown that the genes expressed from the father are actually affecting and silencing the genes that are expressed from the mother. These findings have significance in the way that we view parental imprinting and in particular the molecular basis of Prader-Willi syndrome, the scientists say.
Future research should allow further characterization of the contribution of this novel genetic region to the origin of this disease, and perhaps pave the way for identification of possible treatment and characterization of PWS patients. Furthermore, the identification of functional, genomic cross-talk in regions containing parental imprinted genes may significantly change our overall understanding of the evolution of this phenomenon in placental mammals, say the researchers.
The research study, "The non-coding RNA IPW regulates the imprinted DLK1-DIO3 locus in an induced pluripotent stem cell model of Prader-Willi syndrome," was partially funded by the Israel Science Foundation-Morasha Foundation and by the Israel Ministry of Science and Technology Infrastructure.