Abstract
We discovered two adult sisters in Colombia, lineally consanguineous, with severe obesity and undetectable serum leptin levels despite markedly elevated body fat. Their clinical profile included childhood-onset extreme weight gain, intense hunger, hyperphagia, hypogonadotropic hypogonadism, and family history of obesity. Direct sequencing of the LEP gene revealed a novel homozygous missense mutation in exon 3 (c.350G>T [p.C117F]). The presence of this mutation, undetectable leptin, and severe obesity confirmed a diagnosis of monogenic leptin deficiency. Here we describe the clinical outcomes of a 12-month treatment with recombinant human leptin (metreleptin). Metabolic and endocrine assessments were conducted before and after therapy. Metreleptin therapy significantly reduced BMI: from 59 to 38 kg/m(2) (OBX1, age 27) and 60 to 48 kg/m(2) (OBX2, age 24). Total body fat mass decreased, serum lipids normalized, and insulin sensitivity improved. Hypogonadotropic hypogonadism reversed, and menstruation resumed. Thus, metreleptin reversed the major metabolic and endocrine abnormalities associated with leptin deficiency in these sisters. Limitations include the small sample size, absence of a control group, and lack of anti-metreleptin antibody measurements. Nevertheless, our findings support that leptin replacement with metreleptin is currently the only effective hormonal treatment for this monogenic form of human obesity.