The MC4 pathway is a key cell signaling pathway in humans that regulates energy expenditure, homeostasis, and appetite. MC4’s critical role in weight regulation was validated with the discovery that a mutation of the MC4 receptor gene results in early-onset and severe obesity, as do other genetic defects in the MC4 pathway.

Prader-Willi syndrome and POMC-null obesity are rare genetic disorders of obesity associated with defects in the MC4 signaling pathway.

Prader Willi Syndrome (PWS)

PWS is a rare genetic disorder that causes life-threatening obesity, with a prevalence ranging from approximately one in 8,000 to one in 25,000 patients in the United States. PWS patients exhibit intellectual disability and delayed growth. A hallmark of the disease is severe hyperphagia, which leads to severe obesity and other complications.

For PWS patients, obesity is the greatest health threat, and these patients often die at a young age from obesity-related complications. Hyperphagia has a significant negative impact on the patients’ quality of life as well as causes obesity and a range of associated co-morbidities. Normal satiety, or the feeling of fullness after eating, does not exist in a person with PWS. The physiological drive to eat is so powerful and overwhelming that most PWS patients will go to great lengths to eat large quantities of food, even if it is spoiled, indigestible, or unpalatable to others.

Hyperphagia impairs the PWS patients’ ability to live independently, requiring costly and constant supervision to prevent overeating. Without supervision, PWS patients are likely to die prematurely as a result of choking, stomach rupture, or tissue necrosis, or from complications caused by morbid obesity, such as right heart failure and respiratory failure. While a small number of PWS patients are cared for in costly group homes, the majority of PWS patients are cared for in their homes, and their families undertake substantial effort to create physical barriers to eating. These efforts result in extremely stressful environments as caregivers often place locks and alarms on cabinets and refrigerators that contain food to impede PWS patients’ efforts to obtain food at all times. The typical annual cost of treating a PWS patient is approximately $100,000, excluding the often significant costs of drug therapies related to other medical and psychological conditions, and the costs of any lost time from work experienced by their families due to responsibilities related to the care of a PWS patient.

Currently, there is no approved treatment for PWS, and most research to date has targeted the treatment of specific symptoms. For many individuals affected by the disorder, the elimination of some of the most difficult aspects of the syndrome, such as hyperphagia and obesity, would represent a significant improvement in quality of life and provide the potential opportunity for patients to live independently.

POMC-Null Genetic Obesity

First described as “POMC deficiency syndrome,” patients with POMC-null obesity lack the pro-opiomelanocortin (POMC) gene, which results in early-onset, severe obesity and extreme hunger. This genetic disorder may also be associated with hormonal deficiencies, such as hypoadrenalism, and red hair and fair skin are common. POMC-null obesity is a very rare genetic disorder, and there are no approved treatments for the obesity and hyperphagia associated with this condition.