A recent case report reveals that two children with rare genetic mutations experienced excessive and uncontrollable hunger due to interference with the hormone leptin.
This hormone is produced by white fat cells and interacts with brain regions responsible for appetite regulation. Unlike the hormone ghrelin, which fluctuates, leptin levels remain relatively stable and indicate the body's fat reserves. When fat stores decrease, leptin triggers a "starvation mode" response.
Rare Genetic Mutations Led to Insatiable Hunger in Two Children, Case Report Reveals
The Curious Case of the Insatiable Hunger of the Two Children
A recent case report, titled "Rare Antagonistic Leptin Variants and Severe, Early-Onset Obesity" published in The New England Journal of Medicine, highlights two unrelated children with rare genetic mutations that interfere with leptin, a hormone responsible for regulating appetite.
Prior to this report, researchers had identified 21 genetic variants that disrupt leptin production, release, or sensitivity, leading to excessive hunger known as hyperphagia.
According to Live Science, the case report describes a 14-year-old boy and a 2-year-old girl, both with different mutations affecting their leptin genes. Despite having elevated leptin levels and increased body fat percentages, the children were still unable to feel satiated.
Medical professionals ruled out other conditions associated with heightened appetite and weight gain in childhood, such as Prader-Willi and Bardet-Biedl syndromes, before focusing on the children's leptin genes.
In laboratory experiments using human cells, researchers found that the modified versions of leptin produced by the children's genes had limited signaling capabilities. While these variants could bind to the receptors in the brain, they failed to trigger significant signaling.
This meant that even though the children produced substantial amounts of modified leptin, the hormone was unable to communicate to their brains that sufficient energy was stored in their bodies, resulting in unrelenting hunger as their brains attempted to compensate for an imaginary energy deficit.
High-Dose Leptin Reverses the Children's Condition
The two children with rare genetic mutations affecting leptin have been successfully treated with increased doses of metreleptin, MedPage Today reports. The patients had abnormally high levels of circulating leptin and were experiencing insatiable hunger. The researchers ruled out conditions like Prader-Willi and Bardet-Biedl syndromes.
In vitro experiments revealed impaired binding between the modified leptin proteins produced by the children's genes and the leptin receptors. The initial treatment with metreleptin at the recommended dose had no effect, prompting the researchers to increase the doses.
The boy's dose was gradually increased and then tapered down, while the girl's dose was increased and tapered later. Both patients also engaged in exercise programs and fasting to enhance the impact of exogenous leptin.
After several days of treatment, both patients achieved significant weight loss, normalized food intake, and experienced satiety. The boy lost 27.8% of his weight by day 131 and 40.5% by day 264, with a drop in body mass index (BMI) from 54.3 to 26.9. The girl lost 36.5% of her weight by day 238, with a BMI decrease from 31.6 to 17.6 by day 1,260.
The study highlights the successful treatment of patients with antagonizing leptin variants, overcoming the receptor antagonism through increased metreleptin doses. This innovative approach demonstrates the potential for tailored therapies based on in vitro results, providing a novel advancement in human medicine.
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