ESPE Abstracts (2015) 84 FC8.4

Severe Early-Onset Obesity Caused By Bioinactive Leptin due to a N103K Mutation

Martin Wabitscha, Jan-Bernd Funckea, Julia von Schnurbeina, Friederike Denzera, Georgia Lahrb, Christian Denzera, Anja Mossa, Klaus-Michael Debatinb, Peter Gierschikc, Sadaf Farooqid, Barbara Moeppsc & Pamela Fischer-Posovszkya

aDivision of Pediatric Endocrinology and Diabetes, University Medical Center Ulm, Ulm, Germany; bDepartment of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany; cInstitute of Pharmacology and Toxicology, University Medical Center Ulm, Ulm, Germany; dWellcome Trust–MRC Institute of Metabolic Science, Addenbrooke’s Hospital, University of Cambridge, Cambridge, UK

Background: Early-onset severe obesity due to leptin deficiency typically results from a defect of leptin production or secretion due to mutations in the leptin gene. Recently we described a new form of leptin deficiency caused by bioinactivity of the hormone and associated with high circulating leptin levels (New England Journal of Medicine 2015 372 48–54).

Method: Serum leptin was measured by ELISA. The leptin gene was sequenced in patient DNA. The secretory behavior and the biological activity of the identified mutation was assessed using HEK293 cells.

Results: We describe two siblings, a 9-year-old girl and a 6-year-old boy with severe early-onset obesity (BMI Z-score 3.5 and 4.1) and hyperphagia, both homozygous for a c.309C>A transversion in the leptin gene leading to a N103K amino acid exchange in the protein und high circulating levels of leptin being normal for body fat mass (59.7 and 74.6 ng/ml). Secretion studies in a HEK293 cells overexpressing either WT or mutant leptin demonstrated that the N103K is indeed released into the cell culture media. However, while the WT leptin was able to induce phosphorylation of Stat3 in HEK293 cells overexpressing the leptin receptor, the N103K mutant was unable to do so. Likewise, the mutant mCherry-tagged leptin did neither bind to nor internalize the leptin receptor, while the WT hormone exerted these functions. This set of experiments clearly demonstrates that the N103K leptin is secreted, but not functional. Treatment with metreleptin (0.03 mg/kg LBM per day) led to rapid improvement of eating behaviour and weight loss in both patients.

Conclusion: We present here further cases with severe early-onset obesity due to bioinactive leptin, which are successfully treated with recombinant human leptin. We strongly recommend considering this new disease entity in hyperphagic and severely obese children. High immunoreactive levels of circulating leptin do not exclude functional leptin deficiency.