Two kids didn't know how to stop eating due to a rare genetic mutation

The two kids, a 14-year-old boy and a two-year-old girl, had hyperphagia, severe obesity and high circulating levels of leptin.
Sejal Sharma
Representational image
Representational image

Vasil Dimitrov/iStock 

Foods with high fat, oil, and sugar content taste good but often cause overeating, obesity, and significant health conditions. But what stimulates the brain to cause overeating?

Doctors have identified never-seen-before genetic mutations in two unrelated children, which drove them to overeat in large amounts. The two kids, a 14-year-old boy, and a two-year-old girl, had hyperphagia (extreme unsatisfied drive to consume food), severe obesity, and high circulating levels of leptin (a hormone that tells the body when it’s full).

Serving as the signal for energy sufficiency in the brain, a critically low level of leptin triggers behavioral, metabolic, and endocrine responses. The hormone directs the central nervous system to adjust the body’s food intake and energy expenditure.

Both children carried different leptin-disrupting genetic mutations. Both patients had high levels of circulating leptin, a finding consistent with their high-fat mass. After checking each kid’s leptin gene, the team identified two leptin variants in their bodies.

So, what usually happens with increased leptin is that the body goes into starvation mode, thereby promoting reduced food intake and increased energy expenditure to counteract the current energy surplus. But even though the children made high levels of leptin, the hormone could not signal to the brain that their bodies had enough stored energy. This meant that their hunger couldn’t be satiated for these kids.

The doctors initiated metreleptin (a synthetic form of leptin) treatment at a dose usually recommended to treat these kids immediately. But the treatment had no effect, meaning a higher dosage of metreleptin had to be initiated. 

In addition, both patients also had to follow a diet and participate in vigorous fasting and an exercise program to lower leptin production. In time, their food intake was normalized, their hunger satiated, and they lost weight.

As had been anticipated by the doctors, both patients developed antibodies against metreleptin. Antileptin antibodies are thought to delay the clearance and thus increase the half-life of leptin in circulation, said the study.

The researchers, part of the study, said, “Our work exemplifies how thorough in vitro characterizations can make decisive contributions to overall therapeutic success.”

The study was published in the journal The New England Journal of Medicine.

Study abstract:

Hormone absence or inactivity is common in congenital disease, but hormone antagonism remains controversial. Here, we characterize two novel homozygous leptin variants that yielded antagonistic proteins in two unrelated children with intense hyperphagia, severe obesity, and high circulating levels of leptin. Both variants bind to the leptin receptor but trigger marginal, if any, signaling. In the presence of nonvariant leptin, the variants act as competitive antagonists. Thus, treatment with recombinant leptin was initiated at high doses, which were gradually lowered. Both patients eventually attained near-normal weight. Antidrug antibodies developed in the patients, although they had no apparent effect on efficacy. No severe adverse events were observed. (Funded by the German Research Foundation and others.)

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