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Leptin Mutation Causes Early-Onset Extreme Obesity

A mutation in the gene encoding the appetite-controlling hormone leptin (LEP) found to cause extreme obesity in a young child, researchers report.

Martin Wabitsch et al describe insatiable appetite and early-onset extreme obesity in a 2-year old caused by a homozygous transversion in LEP.  The boy had a high serum level of leptin (42.6 ng/mL), researchers reported in the January 1 issue of the New England Journal of Medicine, but this leptin was inactive in signaling satiety to the central nervous system.

The mutation (c.298G→T) replaces an aspartic acid position 100 in LEP with a tyrosine (p.D100Y). Both parents, who were first cousins, were found to be heterozygous carriers of his mutation.

Wabitsch et al used studies in cell lines to show that the mutant protein was secreted but did not bind or activate the leptin receptor. Injection of leptin-deficient ob/ob mice with the mutant protein failed to reduce food intake or body weight.

ob/ob mice, which are homozygous for a mutation the leptin gene
ob/ob mice, which are homozygous for a mutation the leptin gene

The child was 2 years and 6 months old when first seen by doctors, and weighed 33.7 kg (>99th percentile). His body mass index was 38.6 kg/m2. When he was given an unlimited breakfast, he rapidly consumed 680 kcal. He also had recurrent ear and pulmonary infections and a history of severe pneumonia.

He was treated with subcutaneous metreleptin (Myalept), a drug approved by the US Food and Drug Administration in February 2014 for treatment of leptin deficiency in patients with congenital generalized or acquired generalized lipodystrophy. The boy’s excessive eating and weight then decreased rapidly, with concurrent metabolic and hormonal changes, the authors reported.

Medscape News wrote that the finding is important because current recommendations advise measurement of serum leptin concentrations in children who have rapid weight gain in the first months of life, to identify congenital leptin deficiency. But the child in the NEJM study instead had a high serum level of biologically inactive leptin.

As such, the authors wrote that circulating levels of the hormone that appear to be normal in relation to body mass index and fat mass do not rule out disease-causing mutations in LEP, and might obscure the correct diagnosis.

Wabitsch told HealthDay News that this condition is very rare, but that he already has identified a second and third case, which he will present in an upcoming article.

“I am sure there are many other patients who have this disease with biologically inactive leptin, and they are not detected because doctors test the leptin in their blood and find there is no deficiency,” he said.

Doctors have known about the role that leptin has in appetite regulation since the 1990s, Wabitsch said, but leptin injections were not effective in reducing appetite or weight. That’s because some people who have leptin-associated obesity have receptors that don’t receive the hormone’s signal properly, he explained. It doesn’t matter how much healthy leptin is circulating in their system—their nervous system can’t receive the message that the person is full.

Wabitsch says future research should focus on the “feedback circle” of appetite controlled by hormones like leptin and ghrelin, which increase appetite when the body needs fuel.

However, doctors faced with an obese child who can’t stop eating should consider the possibility that the child might have this leptin mutation, Wabitsch added.

Leptin expert, Elif A Oral (University of Michigan, Ann Arbor), told Medscape News that the finding could lead to development of assays or tests for assessing leptin responsiveness. Also, because the active form of leptin helped this patient, whose leptin signaling pathway was intact, leptin might be used to treat some cases of extreme obesity, even when circulating leptin is present.

Oral added that this article provided a good example of the importance of studying rare diseases, because they can provide new insights into human biology.

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Kristine Novak

Kristine Novak

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About The Author:

Dr. Kristine Novak

Dr. Kristine Novak

Dr. Kristine Novak is a science writer and editor based in San Francisco. She has extensive experience covering gastroenterology, hepatology, immunology, oncology, clinical, and biotechnology research discoveries.

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