Description of the Syndrome

Prader–Willi syndrome (PWS) is a complex neurobehavioral/metabolic disorder which is due to the absence of or lack of expression of normally active paternally expressed genes from the chromosome 15q11-q13 region.  PWS can occur due to a de novo deletion in the paternally inherited chromosome region; because the individual inherited 2 copies of chromosome 15 from their maternal parent; or due to imprinting defects which lead to lack of expression of the genes in the region.  Clinical features of PWS include hypotonia and poor feeding in infancy which almost always requires some type of assisted feeding for a period of time.  Low resting energy expenditure is present throughout life.  Obesity typically begins around age 2 years if the diet is not restricted. Ultimately, the central neurological defect associated with the condition causes PWS patients to sense that they are starving and signals them to further conserve energy and to significantly increase their caloric intake.  This results in even lower resting energy expenditure, hyperphagia, morbid obesity, and a progression to diabetes. Mental retardation, growth hormone deficiency, behavioral problems and neuroendocrine abnormalities are also characteristic of PWS.

Morbidity and Mortality

The death rate among PWS patients has been estimated at 3% per year at all ages, about twice that of the general population.   Among older PWS patients, much of the mortality and morbidity is associated with morbid obesity and diabetes.  Both contribute to cardiovascular disease risk and to risk of congestive heart failure, each of which is a significant cause of mortality in adult PWS patients.  Among children common causes of death include hypothalamic dysregulation of respiration, particularly during infection related stress, which may be associated with central adrenal insufficiency.  Once hyperphagia presents, choking and poison ingestion become more common causes of death.

As hyperphagia presents, PWS patients become food obsessed, and are constantly food seeking.  Food is often locked up and otherwise tightly regulated.  This leads behavioral complications, making the patient difficult to manage, which impacts the caregiver and other family members.  Families including children with PWS show poorer perceived quality of life compared with families of children with other complex health conditions. They report difficulties in family functioning, communication problems, and higher numbers of conflicts. They experience significant behavioral distress, with higher than average levels of depression and feelings of isolation, anger and worry. The vast majority of the normal siblings of PWS children show moderate-to-severe symptoms of Post Traumatic Stress Disorder.

Unmet Medical Need

There is no current therapeutic that effectively controls hyperphagia. The greatest unmet medical need in PWS is to address hyperphagia, low energy expenditure, and the progression to obesity, morbid obesity and diabetes and their resulting cardiovascular complications.

Prevalence

Prader-Willi Syndrome (PWS) is the most common syndromic form of obesity and may affect between 350,000 and 400,000 individuals worldwide. Both sexes are affected equally and there is no strong evidence for increased risk in specific countries or gene pools.

The Prader-Willi Syndrome USA Organization estimate prevalence at 1 per 12,000 to 1 per 15,000.

The committee on genetics of the American Academy of Pediatrics states PWS affects both genders equally and occurs in people from all geographic regions; its estimated incidence is 1 in 15,000 to 1 in 25,000 live births.

Links

Additional information on Prader-Willi syndrome can be found at: