A mutation in a gene encoding leptin (LEP) would cause leptin to become biologically inactive and cause early-onset extreme obesity, according to a Brief Report published in the New England Journal of Medicine (NEJM). Dr. Martin Wabitsch and colleagues from the University of Ulm, Germany, reported a case of a 2-year-old boy who presented with early-onset extreme obesity. After sequencing the LEP genomic DNA using standard protocols, the researchers identified a new pure-hybrid reversal site (c.298G→T), which resulted in a change of aspartate to tyrosine at the 100th amino acid site (p.D100Y). This child has high circulating levels of mutant leptin, but this mutant leptin cannot bind or activate leptin receptors. Animal studies have shown that this mutant leptin protein does not reduce dietary intake and weight loss in leptin-deficient ob/ob mice. This child was treated with recombinant human leptin (metribuzin) and showed a rapid return to normal dietary habits and weight loss. Figure A, weight change curves before and after metribuzin treatment compared to normal children of the same age at different percentiles Figure B, children with leptin mutations The researchers write, “Based on our findings, although circulating levels of the hormone may appear normal relative to body mass index and total body fat in some obese patients, the presence of a pathogenic mutation in the gene encoding leptin cannot be ruled out , there is also the potential to prevent a correct diagnosis.”