Two children suffered from severe hyperphagia and obesity. After identifying the “culprit,” scientists helped them return to normal.
Two children in the UK experienced intense hunger, leading them to overeat. Recently, scientists discovered that both children had rare gene mutations that hinder leptin production—a crucial hormone that signals fullness to the body.
After being produced by white fat cells, leptin binds to the brainstem and hypothalamus, which are areas of the brain responsible for regulating appetite.
Scientists discover rare gene mutations causing hyperphagia – (Image credit: REUTERS).
While the “hunger hormone” ghrelin fluctuates, rising during fasting and decreasing after eating, leptin levels remain relatively stable and are related to the total amount of body fat. Thus, leptin informs the body about the energy reserves in fat and shifts the body into a “starvation mode” when energy reserves drop too low.
Previously, no cases had been reported worldwide of individuals with gene mutations that obstruct leptin production or secretion or prevent its effective action in the brain.
In the New England Journal of Medicine, scientists reported their new findings: they identified 21 genetic variants that disrupt leptin production or sensitivity, leading to excessive hunger, a condition known as hyperphagia.
The authors described two children who were not related: a 14-year-old boy and a 2-year-old girl, each carrying slightly different leptin-disrupting gene mutations.
Both children exhibited high levels of leptin in their blood, along with a high body fat percentage.
Doctors examined the leptin gene (LEP) of each child. They found that each child carried a unique version or variant of the LEP gene. The boy’s variant was designated P64S, while the girl’s was G59S.
Through experiments with human cells in a laboratory setting, the research team assessed how well the children’s leptin connected to the receptors it typically binds to in the brain.
Both leptin variants showed they could bind to the receptors; however, in the presence of normal leptin, the mutated variants blocked the receptors, preventing normal leptin from binding.
Thus, while the children produced a large amount of mutated leptin, this hormone could not signal to the brain that their bodies had excess energy reserves.
To treat the children, doctors provided metreleptin, a synthetic form of leptin.
Initially, both children required “higher than normal doses” to counteract the effects of their leptin variants in the brain.
Both children developed antibodies against metreleptin, which the doctors anticipated. There were no serious side effects. Combined with exercise, “both patients ultimately returned to a near-normal weight.”
