About Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a rare epigenetic disorder affecting approximately 0.003 to 0.01% of the world's population. In newborns, it is characterized by muscle weakness (hypotonia), underdeveloped sucking reflex, and retarded development and growth. Later in childhood, patients develop excessive appetite and subsequently hyperphagia.

What is Prader-Willi syndrome?

Prader-Willi syndrome (PWS) is an epigenetic disorder that occurs in one in approximately 15,000 babies born. PWS affects males and females equally and affects all races and ethnicities. PWS is considered the most common genetic cause of life-threatening childhood obesity.

PWS was first described by Swiss physicians Andrea Prader, Alexis Labhart and Heinrich Willi in 1956 based on the clinical characteristics of nine children they examined. Common features defined in the first report included small hands and feet, abnormal growth and body composition (short stature, very low lean body mass and early childhood obesity), hypotonia (weak muscles) at birth, insatiable hunger, extreme obesity and intellectual disability.

PWS is an epigenetic disorder that results in the silencing of the expression of a group of genes on chromosome 15 (15q11-q13). Each person has two sets of chromosomes, one set inherited from the father (paternal) and one set inherited from the mother (maternal). The combination of the two inherited variants usually results in the expression of both maternal and paternal genes and the transmission of genetic traits from both parents. Normally, a stretch of DNA in the region of chromosome 15 (15q11-q13) is active only on the paternal chromosome, while genes on the maternally inherited chromosome are silenced. People who suffer from PWS do not have active genes in the affected region (PWS locus) on the paternal chromosome. Thus, PWS patients lack expression of important genes, but potentially functional copies of these genes are still stored on the maternal chromosome, but are inactive due to DNA methylation.

In PWS, the epigenetic disorder causing the inactivity of the paternal region of chromosome 15 (15q11-q13) can occur in one of three ways:


It occurs in approximately 70% of cases. It is caused by the loss of part of chromosome 15 inherited from the father.

UPD (uniparental disomy):

Gene imprinting defect:
In a very small percentage of cases (1-3%), a gene imprinting defect occurs in the PWS region of chromosome 15, where genes inherited from the father are present but inactive in the critical region.

What are the symptoms of Prader-Willi syndrome?

The symptoms of Prader-Willi syndrome are probably caused by a dysfunction of a part of the brain called the hypothalamus. The hypothalamus is a small endocrine organ at the base of the brain that plays a key role in many bodily functions, including the regulation of hunger and satiety, body temperature, pain, sleep-wake balance, fluid balance, emotions and fertility. Although hypothalamic dysfunction is thought to lead to the symptoms of PWS, it is not yet clear how the genetic abnormality causes hypothalamic dysfunction.

Symptoms of PWS change over the course of life, and individuals with PWS go through several nutritional stages. But in general, there are two basic stages of symptoms associated with PWS:

Early life

Infants with PWS are hypotonic or “floppy”, with very low muscle tone. Weak crying and a weak sucking reflex are typical. Babies with PWS are usually unable to breastfeed and often require feeding with a probe. If feeding difficulties are not carefully monitored and treated, these babies may suffer from “failure to thrive”. As these children grow, strength and muscle tone usually improve. Motor milestones are reached but usually delayed. Toddlers usually enter a period when they can begin to gain weight easily, even before they have an increased interest in food.

Infancy and other periods

Uncontrollable appetite (hyperphagia) and easy weight gain characterize the later stages of PWS. These features most commonly appear between the ages of 3 and 8, but their onset and intensity vary. Individuals with PWS lack normal hunger and satiety signals. They are usually unable to control their food intake and, unless closely monitored, overeat. Food-seeking behavior is very common.

In addition, the metabolic rate of people with PWS is lower than that of healthy individuals. The combination of these problems leads to morbid obesity and its many complications.

In addition to obesity, a number of other symptoms may be associated with PWS. Individuals typically exhibit cognitive problems, with measured IQ ranging from low normal values to moderate intellectual disability. In addition, PWS is manifested mainly by the following symptoms:

  • Hyperphagia (insatiable hunger)
  • Hypotonia (weak muscle tone)
  • Hypogonadism (insufficient secretion of sex hormone, incomplete sexual development)
  • Hypothyroidism (underactive thyroid gland)
  • High levels of anxiety and cognitive rigidity
  • Growth hormone deficiency (short stature)
  • Delayed psychomotor development
  • Mental retardation
  • Respiratory problems
  • Sleep disturbances
  • Bone thinning
  • Decreased sensitivity to pain
  • Scoliosis
  • Poor body temperature regulation
  • Gastrointestinal problems - reduced mobility, gastroparesis
  • Self-injurious behaviour (skin scratching)
  • Increased risk of central adrenal insufficiency, seizures and hypoglycaemia
  • Mental illness

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

There may be some subtle differences in the characteristics of PWS based on genetic subtype: for example, persons with the deletion may have fair skin and fair hair compared to other family members and may be more prone to seizures; persons with PWS by UPD may be at greater risk for mental illness in young adulthood. Overall, however, there is considerable overlap between genetic subtypes. It is likely that the thousands of non-PWS genes that show normal interindividual variability also contribute significantly to the variability in PWS symptoms among persons with the disorder.

How is PWS diagnosed?

PWS is diagnosed using a blood test that looks for genetic abnormalities specific to PWS - this is called a methylation analysis. The FISH (fluorescence in-situ hybridisation) test identifies PWS based on the deletion, but does not diagnose other forms of PWS. The methylation test identifies all types of PWS and is the preferred test for diagnosis. If the methylation test is performed first, further testing may be needed to determine whether PWS is caused by paternal deletion, UPD or gene imprinting defects.

Is Prader-Willi syndrome hereditary?

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

Is there a cure for Prader-Willi syndrome?

There is currently no cure for Prader-Willi syndrome and most research to date has focused on treating specific symptoms. For many individuals affected by this disorder, eliminating some of the most difficult symptoms of the syndrome, such as voracious appetite and obesity, would represent a significant improvement in quality of life and the ability to live independently.

The Epigenteo Foundation supports research into the treatment of PWS with the aim of achieving lasting therapeutic results.