Bioinactive leptin mutant identified in two more patients

NEW YORK - Investigators have identified two siblings with severe early onset obesity due to a mutation in the leptin gene that renders the hormone biologically inactive.

Dr. Martin Wabitsch of University Medical Center in Ulm, Germany, and colleagues identified the first known case of severe early onset obesity due to bioinactive leptin, in a two-year-old boy, reporting their findings in the New England Journal of Medicine in January 2015 (

In the new report, online July 14 in the Journal of Clinical Endicrinology & Metabolism, Dr. Wabitsch and his team describe two additional cases caused by a different mutation in the gene.

The first case of severe early onset obesity due to absence of leptin was reported in the 1990s, Dr. Wabitsch noted in a telephone interview with Reuters Health. The disease is extremely rare, he added, with only about 40 patients worldwide identified to date.

In the new report, the researchers describe a 9-year-old girl and a 6-year-old boy, born in Germany, who both exhibited extreme hyperphagia and rapid weight gain. Both children had high serum leptin levels. Sequencing of their leptin genes revealed that both had a base substitution causing them to secrete a mutant form of leptin, p.N103K. Lab studies confirmed that the mutant protein was inactive.

After treatment with subcutaneous leptin injections, both children showed rapid improvement. Previously, Dr. Wabitsch noted, the children had been focused only on searching for food, and had no interest in playing or being with other children. "This behavior changed and in addition they lose weight and their metabolic profile also gets healthy," he added.

"Children gaining weight in the first years in a very rapid and extreme way, children who are hyperhpagic, always food-seeking, they should be investigated for leptin deficiency, which will mean lack of leptin in the circulation or the presence of biologically inactive leptin," Dr. Wabitsch said. "Both diseases can be ruled out by sequencing the leptin gene."

This research was supported by individual grants and fellowships. The authors reported no disclosures.


J Clin Endocrinol Metab 2015.

References: Reuters Health
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