Doctors identify never-before-seen genetic mutations that led to 2 children's insatiable hunger

Two children who experienced intense, insatiable hunger that drove them to overeat have rare, never-before-seen genetic mutations that interfere with leptin, a key hormone that helps tell the body when it is full, a new case report says.

After white fat cells make leptin, it plugs into the brainstem and hypothalamus, brain regions that help control appetite. While the "hunger hormone" ghrelin constantly fluctuates, rising with fasts and falling after food intake, leptin levels remain relatively steady and are related to the body's total amount of white fat. Thus, leptin tells the body how much energy it has stored in fat and shifts the body into "starvation mode" when those stores fall too low. 

Rarely, people can carry genetic mutations that interfere with the production or secretion of leptin, or effectively block its effects in the brain. Prior to the new case report, published Wednesday (June 14) in The New England Journal of Medicine, scientists had found 21 genetic variants that messed with leptin production, release or sensitivity, resulting in insatiable hunger, known as hyperphagia.

In the new case report, the authors describe two unrelated children, a 14-year-old boy and a 2-year-old girl, who carried slightly different leptin-disrupting genetic mutations.

Related: Why does hunger sometimes cause nausea? 

Both children had high levels of leptin in their blood, which coincided with their high body fat percentages. After ruling out the Prader–Willi and Bardet–Biedl syndromes — two other rare genetic conditions that can lead to high appetite and weight gain in childhood — doctors checked each child's leptin gene, called LEP. They found that each child carried a distinct version, or variant, of the LEP gene; they named the boy's P64S and the girl's G59S. These genes coded for slightly modified versions of leptin.

Through studies with human cells in lab dishes, the team tested how well the children's leptin bound to the receptor it would normally plug into in the brain. Both versions of leptin bound to the receptor, but they triggered "marginal, if any, signaling." In the presence of normal leptin, the variant versions blocked the receptor and didn't allow normal leptin to plug in.

So while the children made high quantities of modified leptin, the hormone couldn't signal to the brain that their bodies contained ample amounts of stored energy. Without this signal, the kids' appetites couldn't be sated — their brains were attempting to compensate for an energy deficit that didn't exist.  

To treat the children, the doctors provided metreleptin, a synthetic form of leptin. At first, both kids required "higher-than-usual doses" of the treatment to overcome the effects of their leptin variants in the brain. Both children also participated in fasting and exercise programs, to help reduce their white fat and therefore their leptin production. This "eventually evoked a therapeutic response, with a normalization of food intake and satiety and weight loss," the authors wrote in the case report.

Both children developed antibodies against the metreleptin, which their doctors expected, but this didn't appear to affect the drug's effectiveness. There were no serious side effects and "both patients eventually attained near-normal weight."