Última actualización:
3/3/2026
Años publicados: 2026
NORD gratefully acknowledges Kate Richardson, MS, CGC, Assistant Professor, McGovern Medical School, Department of Pediatrics, Division of Medical Genetics, Sara Picket, Genetic Counseling student, David F. Rodriguez-Buritica, MD, Associate Professor, Medical Genetics Division, UTHealth, Houston and Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, for their assistance in the preparation of this report.
Summary
MC4R deficiency is a genetic disorder that causes severe, early-onset obesity. Additional symptoms may include increased appetite and decreased satisfaction after eating. Additional health conditions caused by excess weight are common if untreated.
MC4R deficiency is caused by genetic changes (pathogenic variants) in the MC4R gene. Variants in MC4R can cause the melanocortin 4 receptor to not send messages of fullness or satisfaction after eating, so a person continues to feel hunger. Most people with MC4R deficiency inherited the MC4R variant from a parent. Symptoms of MC4R deficiency vary greatly, even amongst family members with the same genetic change.
People with MC4R deficiency are less likely to lose weight by traditional means such as diet and exercise. Injectable weight loss drugs may be prescribed to aid in weight loss which can help reduce the chances of weight-related health conditions. Identifying a genetic cause for obesity can increase access to prescription weight-loss medications and reduce social stigma.
Introduction
MC4R deficiency was first recognized in the late 1990s to early 2000s as genetic changes were detected amongst those with severe obesity. Further genetic testing studies done in the obese population identified that about 5% of those with severe obesity have a genetic change in the MC4R gene1. There is still more to learn about this condition and the interaction of genetics and diet/lifestyle.
People with MC4R deficiency may have the following signs and symptoms:
MC4R deficiency is caused by disease-causing changes (pathogenic variants) in the MC4R gene. Genes are the body’s instruction manual for creating proteins that play critical roles in the body. The MC4R gene variant provides instructions for making the melanocortin 4 receptor, which is part of the leptin–melanocortin pathway, a system that regulates appetite and energy balance.
Leptin is a hormone produced by fat tissue. It signals to the brain that the body has sufficient energy stores. The melanocortin 4 receptor helps transmit these signals within the brain. When MC4R function is reduced or absent, normal appetite regulation is disrupted, and hunger signals may remain elevated. 2
Every person has two copies of the MC4R gene, one inherited from each parent. In many cases, having one pathogenic variant in one copy of the MC4R gene is enough to cause symptoms. This pattern is known as autosomal dominant inheritance. Most individuals with MC4R deficiency inherit the variant from an affected parent, although the severity of symptoms can vary widely, even among family members who carry the same variant. When a parent has a pathogenic MC4R variant, each child has a 50% chance of inheriting it with every pregnancy. This risk is the same for males and females. In some cases, a person may inherit two pathogenic variants, one from each parent. Individuals who have variants in the two copies of the MC4R gene typically develop symptoms at an earlier age and often have more severe obesity. 3
MC4R deficiency is the most common known single-gene cause of obesity. However, estimates of how common it is can vary depending on how researchers define a “disease-causing” variant and which group of people is being studied.
In the general population, clearly disease-causing MC4R gene variants are estimated to occur in about 1 in 2,000 to 1 in 5,000 people. Some studies have reported higher numbers when using laboratory tests to identify variants that reduce receptor function. For example, one UK birth study found loss-of-function MC4R gene variants in about 1 in 337 individuals (0.30%). However, this higher number includes variants that do not always lead to obesity. This is called incomplete penetrance, meaning that not everyone who carries the variant will develop the condition. Larger population studies, including research from the UK Biobank, suggest that only some MC4R gene variants consistently and strongly increase the risk of obesity. 4
Among people with severe obesity beginning in early childhood, about 2–6% are found to carry a pathogenic MC4R gene variant. This makes MC4R deficiency the most common identifiable single-gene cause of obesity in this group. Because genetic testing is not routinely done for most people with obesity, many people with MC4R deficiency may remain undiagnosed.1
A diagnosis of MC4R deficiency is based on genetic testing identifying a pathogenic variant in the MC4R gene. This disorder cannot be diagnosed based on symptoms alone. MC4R deficiency should be considered for anyone with severe obesity (Body Mass Index (BMI) greater than the 95% percentile for age) under the age of five.
While no medications are specifically FDA-approved for MC4R deficiency, several treatments have demonstrated to be useful. People with MC4R deficiency are less likely to lose weight by traditional means such as diet and exercise. Weight loss surgeries (bariatric surgery) can be effective, but regaining weight after surgery is common for people with MC4R deficiency.
Medications approved for obesity have also been studied in individuals with MC4R deficiency. These include GLP-1 receptor agonists, such as liraglutide (Saxenda, Victoza) and semaglutide (Wegovy, Ozempic), as well as tirzepatide (Zepbound, Mounjaro), which activates both the GLP-1 and GIP pathways.5
GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) are natural hormones released from the intestine after eating. They help regulate blood sugar levels, slow the emptying of food from the stomach, and signal to the brain that the body is full. Medications that mimic these hormones can reduce appetite and increase feelings of fullness. Importantly, these treatments act through mechanisms that do not rely directly on the MC4R receptor. 5
Clinical studies suggest that individuals with MC4R deficiency can achieve meaningful weight loss with these medications, similar to people without MC4R gene variants. In trials, liraglutide was associated with an average weight loss of approximately 6% in people with MC4R gene variants, comparable to results seen in those without such variants. Tirzepatide has been associated with greater weight reduction, with studies reporting average weight loss of about 18% in people with MC4R deficiency. As with all treatments, individual responses vary. 5
Setmelanotide (brand name Imcivree) is a medication that directly activates the MC4R receptor. It is approved by the U.S. Food and Drug Administration (FDA) for certain rare genetic forms of obesity, including POMC deficiency, PCSK1 deficiency, LEPR deficiency, and Bardet–Biedl syndrome. Because setmelanotide works by stimulating the MC4R receptor, individuals whose MC4R gene variants result in a completely nonfunctional receptor would not be expected to benefit. However, people with variants that preserve partial receptor activity may respond. Early studies have shown weight loss in some MC4R gene variant carriers, but its role in treating MC4R deficiency specifically remains under investigation.6
If severe and irreversible kidney, heart, or other organ damage has already occurred due to obesity-related complications, additional medical interventions may be required.
Information on current clinical trials is posted on the Internet at https://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: http://www.centerwatch.com/
For information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
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