Rare Disease Report

New Genetic Cause Uncovered for Early-Onset Extreme Obesity

JANUARY 20, 2015
Christin Melton, ELS,CMPP

A 2 ½ year old boy was brought to the Division of Pediatric Endocrinology and Diabetes at the University of Ulm in Germany to determine the cause of his rapid weight gain.1 When Martin Wabitsch, MD, PhD,  Pamela Fischer-Posovszky, PhD, and their colleagues saw the 34-kg (75-lb) toddler, they immediately suspected early-onset extreme obesity due to a deficiency in the leptin hormone. In an interview with Rare Disease Report, Wabitsch explained that “leptin is secreted from the fat cells and communicates information about the amount of energy stored to the hypothalamus, where appetite and satiety are regulated.” Like other children with early-onset extreme obesity, the boy frequently sought out food; in a supervised breakfast, he gobbled up 680 kcal of food—approximately half the recommended daily caloric intake for a moderately active 2-year-old.2

Martin Wabitsch, MD, PhDPrevious cases of congenital leptin deficiency were attributable to mutations in the LEP gene that resulted in low or nonexistent leptin levels. This patient’s test results, however, showed high circulating levels of leptin (42.g ng/mL).1 Genotyping revealed a novel transversion mutation (D100Y), but this mutation did not appear to interfere with expression or secretion of leptin. Through in vitro testing, the investigators determined that the mutated D100Y leptin failed to bind to the leptin receptor and was therefore nonfunctional. Further testing in vivo showed mice injected with non-mutated leptin reduced their food intake and lost weight, whereas mice injected with mutated D100Y leptin continued to eat normally regardless of the amount of leptin administered. This confirmed the hypothesis that D100Y leptin was inactive.

“Inactive leptin in the case of our patient is secreted in increasingly high amounts due to the fact that the infant grows fatter and fatter. However, the inactive leptin does not active the leptin receptor and the hypothalamus does not get the information about the huge amounts of adipose tissue—it just gets information that there is a lack of leptin. As a consequence, appetite and food intake are stimulated,” Wabitsch said.

The next step was to determine whether treatment with the leptin supplement metreleptin could reverse the child’s food-seeking behavior. First, they used cell cultures to establish that D100Y leptin did not compete with metreleptin in activating the leptin receptor, which confirmed their hypothesis that D100Y leptin was incapable of receptor binding. Next, they started the boy on daily injections of .03 mg/kg metreleptin—a dose similar to what is given to children with leptin deficiency. Almost immediately, he began to eat less. Over the 18-week treatment period, his weight dropped from a high of 43 kg (95 lb) to 35 kg (77 lb) and his body mass index declined from 44.6 kg/m2 to 34.2 kg/m2. Laboratory testing showed beneficial changes in his levels of leptin, insulin, triglycerides, aspartate aminotransferase, alanine aminotransferase, and other metabolic and hormonal markers. Wabitsch said the boy must take metreleptin for the rest of his life. However, because metreleptin is merely a substitute for a natural human hormone, he does not expect any harm to come from long-term use.

Pamela Fischer-Posovszky, PhDWabitsch said although early onset extreme obesity caused by D100Y leptin is rare, “We have already detected 2 more patients here in Germany and suspect several other cases worldwide.” He recommended that a child who has extreme weight gain during the first year of life despite adequate levels of leptin for biologically inactive leptin be tested for biologically inactive leptin. “This can be done by sequencing the leptin gene—samples can be sent to our laboratory to do this.” He also said his center was willing to treat any children identified as having this rare mutation.

Although the study’s findings have few direct implications for adults with lifelong obesity, most of whom have normal leptin levels, Wabitsch said, “This disease shows us once more that body weight is regulated by hormones, and an individual person has only a limited possibility to control body weight by his or her own willpower.” On this basis, Wabitsch expressed his belief  that “obesity prevention will not work very well on the level of self-responsibility but will be more successful when life conditions are changed by the responsible persons in the government and places where people work.”


1. Wabitsch M, Funcke JB, Lennerz B, et al. Biologically inactive leptin and early-onset extreme obesity. N Engl J Med. 2015;372:48-54.
2. US Department of Agriculture and US Department of Health and Human Services. Dietary Guidelines for Americans, 2010. 7th Ed. Washington, DC: US Government Printing Office. http://www.health.gov/dietaryguidelines/dga2010/DietaryGuidelines2010.pdf. Published December 2010. Accessed January 20, 2015.

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