Purpose: Bi-allelic pathogenic leptin gene variants cause severe early onset obesity usually associated with low or undetectable circulating leptin levels. Recently, variants have been described resulting in secreted mutant forms of the hormone leptin with either biologically inactive or antagonistic properties.
Methods: We conducted a systematic literature research supplemented by unpublished data from patients at our center as well as new in vitro analyses to provide a systematic classification of congenital leptin deficiency based on the molecular and functional characteristics of the underlying leptin variants and investigated the correlation of disease subtype with severity of the clinical phenotype.
Results: A total of 28 distinct homozygous leptin variants were identified in 148 patients. The identified variants can be divided into three different subtypes of congenital leptin deficiency: classical hormone deficiency (21 variants in 128 patients), biologically inactive hormone (3 variants in 12 patients) and antagonistic hormone (3 variants in 7 patients). Only 1 variant (n=1 patient) remained unclassified. Patients with biological inactive leptin have a higher percentage of 95th BMI percentile (%BMIp95) compared to patients with classical hormone deficiency. While patients with both classical hormone deficiency and biological inactive hormone can be treated with the same starting dose of metreleptin, patients with antagonistic hormone need a variant-tailored treatment approach to overcome the antagonistic properties of the variant leptin.
Main conclusions: Categorization of leptin variants based on molecular and functional characteristics helps to determine the most adequate approach to treatment of patients with congenital leptin deficiency.
Keywords: antagonistic hormone; biologically inactive hormone; disease classification; early-onset obesity; leptin; monogenic obesity.
© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.