Years published: 2023
NORD gratefully acknowledges Prof. Dr. Martin Wabitsch, Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany for assistance in the preparation of this report.
Congenital leptin deficiency (CLD) is a rare, inherited condition that affects how the body processes energy, responds to food and stores fat. Infants with CLD are constantly hungry and quickly gain weight and become obese. Children with CLD have extreme hunger (hyperphagia), low energy and abnormal behaviors related to food. People affected with CLD produce little or no sex hormones (hypogonadotropic hypogonadism) resulting in late or absent puberty and infertility. CLD is caused by changes (pathogenic variants or mutations) in the LEP gene, which is responsible for making a protein called leptin. Leptin is important for regulating appetite and growth of body fat. This condition is inherited in an autosomal recessive pattern. Diagnosis is based on a clinical examination, symptoms and the results of genetic testing. Diet, behavior modification, exercise programs and bariatric surgery have been used to help manage the symptoms of CLD. Treatment is available for this condition using a drug called metreleptin, a recombinant form of human leptin, which reverses the symptoms of CLD. With treatment, people with CLD develop a normal appetite, lose weight and fat and regain normal sex hormone levels.
CLD is rare, making it difficult to predict exactly how it will affect someone who is newly diagnosed. It is one of several conditions that include early-onset obesity, and these conditions can be difficult to distinguish from each other without a careful physical examination and genetic testing.
Most babies with CLD have a normal weight at birth. The earliest symptoms of CLD are constant hunger and excessive eating leading to rapid weight gain and obesity before one year of age. People with CLD always feel hungry even after eating a full meal and often have abnormal behaviors related to food. Many have low levels of sex hormones (hypogonadotropic hypogonadism) causing delayed or absent puberty and infertility. Other symptoms include low energy levels, low blood pressure and insulin resistance, which can lead to type 2 diabetes. Children with CLD are often prone to infections, due to an immune system that doesn’t work correctly. Excessive weight gain can lead to other symptoms such as abnormal bone growth, liver disease and difficultly walking.
CLD is caused by pathogenic variants (mutations) in the LEP gene. The LEP gene is responsible for making the protein, leptin. Leptin is made by fat cells and helps regulate energy storage in the body by balancing how much fat is made and how much is burned for energy. Without leptin, the body doesn’t recognize when the body has enough energy and it’s time to stop eating.
CLD is inherited in families in a recessive pattern. Recessive genetic disorders occur when an individual inherits a non-working gene from each parent. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy. The chance for a child to receive working genes from both parents is 25%. The risk is the same for males and females.
Congenital leptin deficiency is a very rare disorder. It has been estimated that 1 in 4.4 million people may have this condition. Many come from parts of the world where it is customary for relatives to marry.
Congenital leptin deficiency is diagnosed based on a clinical examination, symptoms and the results of laboratory and genetic testing. Because there are several inherited conditions that include excessive hunger and early-onset obesity, genetic testing may be done to help make a specific diagnosis. This testing often involves using a gene panel, allowing the lab to look for genetic variants in several different genes at the same time. Genetic testing is usually done with a blood or saliva sample. It is helpful to speak to a genetics professional before having genetic testing to learn more about the risk, benefits and limitations.
Congenital leptin deficiency is treatable with leptin replacement using recombinant human leptin, also known as metreleptin. Treatment results in a decreased appetite and significant weight and fat loss. In addition, leptin replacement leads to normal sexual development, decreased insulin levels and restores the immune system.
People with congenital leptin deficiency may be treated by a variety of different medical specialists, including gastroenterologists, nutritionists and endocrinologists. A psychologist or other mental health professional can help people cope with the symptoms of this condition.
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