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What is Prader-Willi Syndrome

About Prader Willi SyndromePrader-Willi Syndrome (PWS) is a genetic disorder that occurs in approximately one out of every 15,000 births. PWS affects males and females with equal frequency and affects all races and ethnicities. PWS is recognized as a common genetic cause of childhood obesity.

Prader Willi Syndrome was first described by Swiss doctors Andrea Prader, Alexis Labhart and Heinrich Willi in 1956 based on the clinical characteristics of nine children they had examined.  The common characteristics defined in the initial report included small hands and feet, abnormal growth and body composition (small stature, very low lean body mass and early onset childhood obesity), hypotonia at birth, insatiable hunger, extreme obesity and intellectual disability.

In recent years, the syndrome has been genetically characterized as an abnormality of chromosome 15, and definitive diagnosis is now based on genetic testing.

Contents

  1. What are the symptoms of Prader-Willi Syndrome(PWS)?
    1. Stage 1
    2. Stage 2
  2. What causes Prader-Willi syndrome?
    1. PWS by Deletion
    2. PWS by UniParental Disomy (UPD)
    3. PWS by Imprinting Mutation
  3. Are there differences in the severity of PWS based on the genetic subtype?
  4. How is PWS diagnosed?
  5. Is there a cure for Prader-Willi syndrome?
  6. Is Prader-Willi syndrome hereditary?
  7. How do these genetic defects cause the symptoms seen in Prader-Willi syndrome?
  8. I don’t understand a lot about genetics. Where can I learn more?

What are the symptoms of Prader-Willi Syndrome?

The symptoms of Prader-Willi syndrome are believed to be caused by dysfunction of a portion of the brain called the hypothalamus. The hypothalamus is a small endocrine organ at the base of the brain that plays a crucial role in many bodily functions, including hunger and satiety, temperature and pain regulation, fluid balance, puberty, emotions, and fertility. Although hypothalamic dysfunction is believed to lead to the symptoms of PWS, it is unclear how the genetic abnormality causes hypothalamic dysfunction.

There are two generally recognized stages of the symptoms associated with PWS:

Stage 1

In the first stage, infants with PWS are hypotonic or “floppy”, with very low muscle tone. Weak cry and a poor suck reflex are typical. Babies with PWS usually are unable to breastfeed and frequently require tube feeding. These infants may suffer from “failure to thrive” if feeding difficulties are not carefully monitored and treated. As these children grow older, strength and muscle tone generally improve. Motor milestones are achieved, but are usually delayed.

Stage 2

An unregulated appetite characterizes the second stage of PWS. This stage most commonly begins between ages 2 and 6 years old. Individuals with PWS lack normal hunger and satiety cues. They usually are not able to control their food intake and will overeat if not closely monitored. Food seeking behaviors are very common. In addition, the metabolic rate of persons with PWS is lower than normal. Left untreated, the combination of these problems will lead to morbid obesity and its many complications.

In addition to obesity, a variety of other symptoms can be associated with Prader-Willi syndrome. Individuals usually exhibit cognitive challenges with measured IQs ranging from low normal to moderate mental retardation. Those with normal IQs usually exhibit learning disabilities. Other issues may include speech apraxia/dyspraxia, short stature, small hands and feet, scoliosis, sleep disturbances with excessive daytime sleepiness, undescended testicles in males, high pain threshold, and infertility.  Behavioral difficulties may include obsessive-compulsive symptoms, skin picking, and difficulty controlling emotions. PWS is a spectrum disorder and symptoms vary in severity and occurrence among individuals.

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What causes Prader-Willi syndrome?

PWS is caused by a lack of active genetic material in a particular region of chromosome 15 (15q11-q13). Normally, individuals inherit one copy of chromosome 15 from their mother and one from their father. The genes in the PWS region are normally only active on the chromosome that came from a person’s father. In PWS, the genetic defect causing inactivity of chromosome 15 can occur in one of three ways:

PWS by Deletion

Most often, part of the chromosome 15 that was inherited from the person’s father is missing, or deleted, in this critical region. This small deletion occurs in approximately 70% of cases and usually is not detectable with routine genetic analysis such as amniocentesis.

PWS by UniParental Disomy (UPD)

Another 30% or so of cases occur when an individual inherits two chromosome 15’s from their mother, and none from the father. This scenario is termed uniparental disomy (UPD).

PWS by Imprinting Mutation

Finally, in a very small percentage of cases, a small genetic mutation in the Prader-Willi region causes the genetic material in that area to be inactive.

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Are there differences in the severity of PWS based on the genetic subtype?

At this time, there is no consistent evidence that the severity of PWS is related to genetic subtype.

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How is PWS diagnosed?

PWS is diagnosed with a blood test that looks for the genetic abnormalities that are specific to PWS. A FISH (flourescent in-situ hybridization) test identifies PWS by deletion but does not diagnose other forms of PWS. A methylation test will identify all types of PWS and is the preferred test for diagnosis. In cases where an imprinting mutation is suspected, blood will also be drawn from the parents.

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Is there a cure for Prader-Willi syndrome?

Currently there is no cure for Prader-Willi syndrome, and most research to date has been targeted toward specific treatments. For many individuals affected by the disorder, the elimination of some of the most difficult aspects of the syndrome, such as the insatiable appetite and obesity, would represent a significant improvement in quality of life and the ability to live independently. The Foundation for Prader-Willi Research is interested in advancing research toward understanding and treating specific aspects of the syndrome, with the goal of an eventual cure for PWS.

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Is Prader-Willi syndrome hereditary?

Deletion and UPD are random occurrences and generally are not associated with an increased risk of reoccurrence in future pregnancies. In the case of an imprinting mutation, Prader-Willi syndrome can recur within a family.

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How do these genetic defects cause the symptoms seen in Prader-Willi syndrome?

At this time, the mechanism by which the lack of functional genetic material on chromosome 15 leads to the symptoms associated with PWS is not understood.  Scientists are actively studying the normal role of the genetic sequences in the PWS region, and how their loss affects the hypothalamus and other systems in the body.

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I don’t understand a lot about genetics. Where can I learn more?

There is a host of information on the Internet about Prader-Willi syndrome. One of the best places to start in developing a better understanding of the syndrome is to investigate the genetics.

The Genetics Home Reference is a US National Library of Medicine sponsored site with a vast array of information to help understand genetics and genetic conditions. In addition, they have a home reference guide specifically for Prader-Willi syndrome.

Gene Reviews, targeted at health professionals, contains detailed descriptions of diagnosis and management of Prader-Willi syndrome.

One of the largest sources of information regarding research can be found on PubMed . This is an up-to-date, searchable database of more than 16 million research abstracts, with links to articles in the medical literature. Current research on PWS can be found by searching with the relevant terms of (prader willi, PWS, growth hormone, etc.)

PubMed is updated frequently, and the abstracts are not always understandable by the lay person.  FPWR monitors PWS research activity  closely, and some of the most relevant studies are summarized in FPWR’s Research Blog . If you want to stay in close touch with the latest research, you might find it better to subscribe to an RSS feed of the Research Blog postings.

There are also some government efforts toward research on rare diseases. The Office of Rare Diseases at the National Institute of Health has established a research consortium , headed by Dr. Alan Percy, to study Angelman, Rett, and Prader-Willi syndromes. The consortium is looking for help by signing up for their contact registry and agreeing to participate in relevant studies of PWS.

The National Human Genome Research Institute at the National Institutes of Health (NIH) has excellent resources on genetics and can help educate those who are interested on the unique aspects of PWS research. One of the unique features of the site is a talking genetics glossary. In addition, the Department of Energy co-sponsors the Human Genome Project, and they have a general resource for genetics education regarding the human genome.

Finally, Cold Spring Harbor Labs has an excellent resource called DNA from the Beginning for learning about genetics.

Note that over the years, PWS has been known as Prader-Willi, Prader-Labhart-Willi or Prader-Willi-Fanconi syndrome, with Prader-Willi syndrome being most commonly used today. Prader-Willi syndrome is also sometimes misspelled as “Prada Willi” syndrome, “Prader Labhart Willy”, “Prader Willy” syndrome or “Prader Willie” syndrome.

Are you concerned about your floppy, quite or sleep baby?  Click the following link

http://www.fpwr.ca/floppy-quite-or-sleepy-baby-does-my-child-have-prader-willi-syndrome/

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