Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Leptin Receptor Deficiency

What is Leptin Receptor Deficiency?

• Leptin receptor deficiency is a condition that causes severe obesity beginning in the first few months of life. Affected individuals are of normal weight at birth, but they are constantly hungry and quickly gain weight.​
• The extreme hunger leads to chronic excessive eating (hyperphagia) and obesity.
• People with leptin receptor deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production of hormones that direct sexual development. Affected individuals experience delayed puberty or do not go through puberty, and they may be unable to conceive children (infertile).​
• Leptin receptor deficiency is a rare cause of obesity. Its prevalence is unknown.​
• Leptin is a hormone produced mainly by the white adipose tissue, with multiple actions in the endocrine and immune systems, including glucose homeostasis, reproduction, bone formation, tissue remodeling and inflammation.
• Leptin is a key regulator of energy homeostasis, by regulating energy intake and expenditure through its actions on the arcuate nucleus of the hypothalamus. Leptin levels are positively correlated with fat mass, being increased in obesity.​
• Leptin is a hormone that is produced by the body’s fat cells. The leptin hormone tells our brain when we have enough fat stored that we don’t need to eat, and that we can burn calories at a usual rate.​

How Do You Get It?

• The LEPR gene provides the body’s instructions for making a specific protein called the leptin receptor. This important receptor helps the body regulate weight.​
• When there is a change or variant in the LEPR gene, the leptin receptor cannot function correctly, and leptin cannot attach to the receptor. When the leptin does not attach to the receptor, your brain does not get the message that it is full. Without the correct signal, your body can start to think that it is starving.​
• In humans, leptin deficiency is observed in lipodystrophy syndromes, which present with low or absent leptin levels due to abnormal deposition and distribution of adipose tissue. In addition, congenital human leptin deficiency may also be caused by mutations in the leptin gene.
• Researchers from the U.S. National Library of Medicine have discovered at least 18 mutations in our genetic code that lead to leptin receptor deficiency. ​
• All 18 LEPR mutations prevent proper interaction between leptin and its receptor protein, hindering the body’s ability to feel full.​​

What Are The Symptoms?

• The main signs and symptoms of this condition include:
  • Insatiable hunger
  • Severe obesity that occurs early in life
  • Delayed or absent puberty
• 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 It Treated?

• Congenital leptin deficiency can be successfully treated with daily subcutaneous injections of recombinant human leptin, resulting in sustained positive effects on weight loss, reducing appetite, appropriate pubertal development and hyperinsulinemia.
• As a result, the prognosis for patients undergoing treatment appears to be excellent. ​
• However, misdiagnosed patients are at risk of developing the complications normally associated with severe obesity (in particular type 2 diabetes), with the prognosis being hampered further by an increased rate of mortality due to childhood infection.​

Where Can I Learn More???

• Check out our cornerstone on this disease here.