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Monogenic obesity is a rare form of obesity caused by a disease-causing change in a single gene. These genes often play essential roles in the biological pathways that regulate appetite, hunger, fullness, and energy balance.
Unlike common obesity, which usually develops through the combined influence of many genetic variants and environmental factors, monogenic obesity can result from a specific genetic change with a substantial effect on the body’s ability to regulate food intake.
How does monogenic obesity develop?
One important pathway involves the communication between fat cells and the brain. Fat cells produce a hormone called leptin, which provides information about the body’s energy stores. Leptin acts on receptors in the brain, helping regulate appetite and energy balance.
Signals involving leptin and other molecules ultimately influence the melanocortin pathway, which includes the melanocortin-4 receptor encoded by MC4R. This pathway helps regulate hunger and satiety.
When a disease-causing genetic variant disrupts one of these pathways, the brain may not respond appropriately to signals that normally reduce hunger or help a person feel full. This can lead to persistent hunger, increased food intake, and severe weight gain from a young age.
Which genes cause monogenic obesity?
Several genes are associated with recognised forms of monogenic obesity:
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MC4R: Disease-causing variants can interfere with appetite regulation and are among the more frequently identified causes of monogenic obesity.
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LEP: Certain variants can cause leptin deficiency, resulting in severe early-onset obesity and intense hunger.
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LEPR: Variants may prevent the body from responding appropriately to leptin signals.
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POMC: Some variants can cause obesity alongside other hormonal problems, including adrenal insufficiency and, in certain cases, altered pigmentation.
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PCSK1: Variants may affect the processing of hormones and cause obesity with other endocrine or gastrointestinal manifestations.
The exact clinical features depend on the gene, the specific variant, and how it affects the protein’s function.
What symptoms may suggest monogenic obesity?
Possible warning signs include:
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Severe obesity beginning in infancy or early childhood.
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Persistent, intense hunger or a strong drive to eat.
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Excessive weight gain despite attempts to manage food intake.
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A family history of severe early-onset obesity.
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Hormonal abnormalities, developmental differences, or unusual physical features.
Not every child with these features has monogenic obesity. A thorough clinical assessment is necessary to evaluate other possible causes.
How is monogenic obesity diagnosed?
A healthcare professional reviews the person’s growth history, age at onset, appetite, medical history, family pedigree, and any associated clinical features. If a genetic cause is suspected, testing may include an obesity-related gene panel or broader genetic testing.
Results may identify a pathogenic or likely pathogenic variant, a variant of uncertain significance, or no explanatory variant. A variant of uncertain significance does not establish a diagnosis on its own.
Can monogenic obesity be treated?
Management depends on the underlying genetic condition and the individual’s clinical needs. Care may include nutritional guidance, specialist obesity management, monitoring for complications, and genetic counselling. Certain treatments are available for specific molecular diagnoses and may be considered by specialists when appropriate.
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