RF24 | PSUN127 Congenital Leptin Deficiency: Metabolic, Reproductive, and Psychological Impacts of Therapy

Background Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Monogenic obesity disorders, including CLD, have been reported to be prevalent among children with severe obesity in a consanguineous Pakistani population. Targeted therapy is available in the form of recombinant human leptin (metreleptin). We previously reported baseline characteristics of the first cases of CLD identified in the United States, sisters of Pakistani origin with a family history of consanguinity. This report provides follow-up after 18 months of metreleptin therapy in an observational research protocol. Clinical Case Two sisters ages 18 yrs (A; BMI 45.2 kg/m2) and 20 yrs (B; 45.0 kg/m2) were referred for evaluation of obesity. Both had hyperphagia and excessive weight gain by age 3 months. They had been treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years and was treated with metformin and liraglutide with suboptimal glycemic control (HbA1C 9.3%). At the time of their initial evaluation, serum leptin levels were undetectable. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. Treatment was initiated with metreleptin 5 mg daily SC in Sister A and 3.75 mg SC daily, increasing to 5 mg daily at Week 8 in Sister B. Both remained on therapy throughout the 18 month observational trial without serious adverse effects or clinical evidence of neutralizing antibodies. At study end, both had substantial weight loss (Sister A: 45.3 kg or 32.8% of initial weight, Sister B: 39.1 kg or 33.1% of initial weight). Clinically significant improvements in related parameters were observed, including percent body fat (Sister A: -13%, Sister B: -18%), HOMA2-IR (A: -83%, B: -80%), ALT (A: -90%, B: -91%), triglycerides (A: -47%, B: -26%), hsCRP (A: -80%, B: -84%), FGF-21 (A: -81%, B: -67%), and adiponectin (A: +42%, B: +37%). In both sisters, hepatic steatosis improved and bone mineral density increased (A: +0.7 SD, B: +0.6 SD). At study end, Sister A's HbA1C was 5.4% off medication. Spontaneous regular menses resumed after 3 months of therapy in Sister A and four months in Sister B. Improvements were observed in mood, self-esteem, physical function, energy, quality of life, dietary disinhibition, and perceived hunger, measured by validated questionnaires. Conclusion Metrelepin produced significant improvements in weight, metabolic profiles, hepatic steatosis, reproductive function, mood and quality of life in our patients. Given the efficacy of metreleptin therapy, screening for CLD should be undertaken for any patient presenting with hyperphagia and early onset of obesity. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Sunday, June 12, 2022 1:24 p.m. - 1:29 p.m.