Prader-Willi Syndrome

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.  Hypotonia and low muscle mass is present throughout life.  The accumulation of excess body fat 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.  PWS patients at this stage are food obsessed and constantly food seeking. They will wake up at night to eat, steal food, bargain for food, steal money to buy food, eat frozen food, pet food, or spoilt food, or consume non-food items. Mental retardation, growth hormone deficiency, behavioral problems, including aggressive behaviors 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, more than twice that of the general population.   Among older PWS patients, much of the mortality and morbidity is associated with complications of 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. Other behavioral complications occur in parallel even if they are not caused by hyperphagia. 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 Post Traumatic Stress reactions.

Unmet Medical Need

There is no currently approved therapeutic that effectively controls hyperphagia. The greatest unmet medical need in PWS, as determined by parents and caregivers of PWS patients is to address hyperphagia and problematic food related behaviors. These same parents and caregivers viewed reducing temper outburst severity and frequency as very important.

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 in 12,000 to 1 in 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. Finally, the International Prader-Willi Syndrome Organization states that between 1 in 12,000 and 1 in 22,000 people is born with Prader-Willi syndrome.

Links

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

PRADER-WILLI SYNDROME – Soleno