Congenital Leptin Deficiency

Disease Overview

Summary

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) 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.

Introduction

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.

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Synonyms

• obesity due to congenital leptin deficiency
• LEPD
• leptin deficiency or dysfunction
• obesity, morbid due to congenital leptin deficiency
• CLD
• leptin deficiency

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Signs & Symptoms

Most infants with CLD are born at a normal weight. Symptoms typically begin in infancy and include:

• Severe, constant hunger (hyperphagia) leading to rapid weight gain and early-onset obesity
• Low energy levels and lethargy
• Low sex hormone levels (hypogonadotropic hypogonadism) often resulting in delayed or absent puberty and infertility
• Insulin resistance that increases the risk of type 2 diabetes
• Frequent infections due to impaired immune function
• Other complications of obesity including liver disease, difficulty walking and abnormal bone growth

Low blood pressure and behavioral issues around food may also occur. Despite severe obesity, children with CLD do not develop osteoporosis.

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Causes

CLD is caused by changes (pathogenic variants) in the LEP gene. This gene is responsible for making a protein called leptin, a hormone crucial for regulating body weight. Leptin is secreted by fat cells in proportion to their size, so more fat means more leptin. This increase in leptin signals the brain that energy stores are sufficient.

Leptin binds to the leptin receptor, a protein located on the surface of cells in various tissues, especially in the hypothalamus, a brain region that regulates hunger, thirst, sleep, mood, body temperature and hormone release. When leptin binds its receptor in the hypothalamus, it triggers signaling pathways that reduce hunger and promote the feeling of fullness (satiety).

In congenital leptin deficiency, variants in the LEP gene lead to a complete absence of leptin. Without leptin, the brain does not receive the signal that the body has enough energy, resulting in persistent hunger and rapid weight gain. Additionally, because leptin signaling plays a role in the regulation of reproductive hormones, its absence also contributes to hypogonadotropic hypogonadism, leading to delayed or absent puberty and infertility. The exact mechanisms linking leptin and reproductive hormone control remain unclear.

CLD is inherited in a recessive pattern. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, 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 gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.

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Affected populations

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 blood relatives to marry.

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Disorders with Similar Symptoms

CLD is one of several rare inherited conditions that include early-onset extreme obesity with few or no other signs or symptoms. These conditions are due to variants in one of the genes that normally work together to help regulate hunger and growth of body fat. These conditions may be difficult to diagnose based solely on clinical examination and sometimes genetic testing is the only way to tell the difference between them.

Some of these conditions include:

PCSK1 deficiency also begins with early childhood obesity and intense hunger. However, it starts with severe diarrhea, digestive issues and poor growth in infancy and involves several hormone problems. It also includes excessive thirst and frequent urination which are not seen in CLD. Treatment is with setmelanotide, not metreleptin

POMC deficiency is a condition in which the main symptoms include constant hunger and excessive feeding, known as hyperphagia with rapid weight gain. Hyperphagia leads to obesity by one year of age, and without treatment, affected people remain obese throughout life. Other symptoms include low levels of a hormone called adrenocorticotropic hormone (ACTH) and adrenal insufficiency which can be fatal if not treated early. In addition, people can have pale skin and hair. Treatment is with a drug called setmelanotide.

Leptin receptor deficiency (LEPR deficiency) is a condition in which Individuals have almost the same symptoms as people with congenital leptin deficiency such as extreme hunger, early obesity and delayed puberty. They also have the same inheritance pattern (autosomal recessive) and early age of onset. This condition is caused by variants in the LEPR gene. People have normal or high levels of leptin, but their bodies can’t use it properly. This condition is treated with setmelanotide (not metreleptin, which does not work when the receptor is faulty).

Obesity due to melanocortin 4 receptor (MC4R) gene variants is a condition in which affected people have severe hunger and develop obesity during childhood. Weight and length are normal at birth. People with MC4R deficiency are often taller than average, which is one of the distinguishing features of this condition. People with two MC4R gene variants develop an extreme form of obesity comparable to people with leptin or leptin receptor deficiency.

There are other inherited conditions that include obesity in childhood as one of several features. People with these conditions have other signs and symptoms along with excess weight. These conditions include:

Bardet-Biedl syndrome (BBS)

Alström syndrome

Beckwith-Wiedemann syndrome

Prader-Willi syndrome

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Diagnosis

Congenital leptin deficiency is diagnosed based on clinical examinations, 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.

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Standard Therapies

CLD is treatable with recombinant human leptin (metreleptin) which has shown strong benefits:

• Dramatic reduction in appetite
• Sustained weight and fat mass loss
• Normalization of puberty and sex hormone levels
• Improved immune function (e.g., increase in CD4+ T cells)
• Improved insulin sensitivity, glucose metabolism and lipid profiles
• Restoration of neural responses related to satiety and food reward in the brain

Metreleptin does not significantly affect energy expenditure, cortisol levels, or bone mineral density.

Researchers have found 28 different LEP gene variants in people with CLD. These variants have been grouped into three main types based on how they affect the body. Knowing which type of LEP variant a person has can help determine the most effective treatment and improve long-term health.

• Classical deficiency is the most common type where leptin is not made at all
• Inactive hormone where the body does make leptin, but it doesn’t work properly and can’t send the right signals to the brain; associated with more severe obesity than classical deficiency
• Blocking hormone where there is a form of leptin that gets in the way and blocks the normal leptin signals

Most people with the classical or inactive type of leptin respond well to metreleptin. However, people with the blocking type may need a special treatment plan tailored to their specific gene variant.

People with congenital leptin deficiency usually need to be seen by many specialists such as endocrinologists, nutritionists, immunologists and mental health professionals. These specialists should work together as a team in a coordinated manner for the best management.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES

von Schnurbein J, Zorn S, Nunziata A, et al. Classification of Congenital Leptin Deficiency. J Clin Endocrinol Metab. 2024;109(10):2602-2616. doi:10.1210/clinem/dgae149

Salum KCR, Rolando JM, Zembrzuski VM, Carneiro JRI, Mello CB, Maya-Monteiro CM, Bozza PT, Kohlrausch FB, da Fonseca ACP. When leptin Is not there: A review of what nonsyndromic monogenic obesity cases tell us and the benefits of exogenous leptin. Front Endocrinol (Lausanne). 2021 Aug 24;12:722441.

Yeo GSH, Chao DHM, Siegert AM, Koerperich ZM, Ericson MD, Simonds SE, Larson CM, Luquet S, Clarke I, Sharma S, Clément K, Cowley MA, Haskell-Luevano C, Van Der Ploeg L, Adan RAH. The melanocortin pathway and energy homeostasis: From discovery to obesity therapy. Mol Metab. 2021 Jun; 48:101206.

Clément K, Mosbah H, Poitou C. Rare genetic forms of obesity: From gene to therapy. Physiol Behav. 2020 Dec 1;227:113134. Epub 2020 Aug 14.

Yupanqui-Lozno H, Bastarrachea RA, Yupanqui-Velazco ME, Alvarez-Jaramillo M, Medina-Méndez E, Giraldo-Peña AP, et al. Congenital leptin deficiency and leptin gene missense mutation found in two Colombian sisters with severe obesity. Genes. 2019; 10(5):342.

Wasim M, Awan FR, Najam SS, Khan AR, Khan HN. Role of leptin deficiency, inefficiency, and leptin receptors in obesity. Biochem Genet. 2016 Oct;54(5):565-72. doi: 10.1007/s10528-016-9751-z. Epub 2016 Jun 16.

Paz-Filho G, Mastronardi CA, Licinio J. Leptin treatment: facts and expectations. Metabolism. 2015 Jan;64(1):146-56.

Farooqi S, O’Rahilly S. 20 years of leptin: Human disorders of leptin action. J of Endocrinology 2014; 223:1, T63-70,  DOI: https://doi.org/10.1530/JOE-14-0480

Farooqi IS, Keogh JM, Yeo GS et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med, 2003; 348: 1085–1095.

INTERNET

LEPD Deficiency. Online Mendelian Inheritance in Man (OMIM) MIM 614962, Last updated: 07/14/2023. https://omim.org/entry/614962 Accessed May 14, 2025.

Congenital Leptin Deficiency. MedlinePlus. Updated Dec 1, 2013 Available from: https://medlineplus.gov/genetics/condition/congenital-leptin-deficiency/#:~:text=Description&text=Congenital%20leptin%20deficiency%20is%20a,hungry%20and%20quickly%20gain%20weight. Accessed May 14, 2025.

Obesity due to congenital leptin deficiency. Orphanet. Last updated May 2007. Available from: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=66628 Accessed May 14, 2025.

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