LEPR deficiency, like many rare disorders of obesity, begins at a very young age. Babies are normal weight at birth but show signs of constant and insatiable hunger followed by severe, early-onset rapid weight gain within their first few weeks of life. In early childhood, abnormal eating and food-seeking behaviors develop, such as fighting with other children over food, hoarding, and secretly hiding food. If food is denied, aggressive behavior is noted. Some people also develop type 2 diabetes by early adulthood.

How is LEPR deficiency inherited?
LEPR deficiency is inherited in an autosomal recessive manner. This means that someone with LEPR deficiency will have two copies of the genetic variant which cause the disorder. You can only inherit an autosomal recessive disorder if both of your parents are “carriers” for the disorder, meaning they both carry one copy with the genetic variant and one copy without it.

In very rare cases, someone who is a carrier for LEPR deficiency (meaning they have just one disease-causing variant) may develop some of the symptoms of the disorder.

Did you know hunger isn't just triggered by your stomach? It also involves your brain. There are specific parts of your brain that control hunger by sending signals to your body, telling it when to eat and when to stop.

In rare genetic disorders of obesity, genetic variants interrupt these messages and hunger gets stuck in the "on" position. There are many parts in the brain that communicate with each other to regulate hunger. One of these areas is called the melanocortin-4 receptor, or MC4R pathway. Think of it like a road carrying news and information to and from the brain. When this pathway works the way it should, the brain receives a message that it's time to stop eating. In rare genetic disorders of obesity, part of this pathway is broken, and the body and brain can't communicate to each other properly. The brain doesn't get the message when the stomach is full and believes that the body is starving, even though there is food in the stomach.

Am I eligible?
The program is designed for those affected by severe obesity who suspect there is more to their obesity than diet and lifestyle. Typically, this includes symptoms such as insatiable hunger, weight gain while on a restricted diet and exercise, and severe obesity early in life.

To qualify, you must be:
• 18 years or younger, with a body mass index (BMI) in the 97th percentile or more, or
• 19 years or older, with a BMI of 40 or more and a history of childhood obesity before age 10

Select family members of participants who were previously tested through the Uncovering Rare Obesity program may also be eligible for testing.

At least 18 LEPR gene mutations that cause leptin receptor deficiency have been identified; this disorder is associated with excessive hunger, massive weight gain, and reduced production of hormones that direct sexual development (hypogonadotropic hypogonadism). Some of the mutations result in less receptor protein getting to the cell surface where leptin binding takes place. The receptors that get to the cell surface may bind to leptin, but their signaling function is impaired. The resulting shortage of leptin signaling disrupts normal feelings of hunger and satiety, leading to extreme weight gain.

Because hypogonadotropic hypogonadism occurs in leptin receptor deficiency, researchers suggest leptin receptor signaling is also involved in regulating the body's response to hormones which control sexual development, and this response is affected by LEPR gene mutations. However, the mechanism of this effect is unknown.