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Purpose Biallelic 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 Methods We conducted a systematic literature research supplemented by unpublished data from patients at our center as well as new in vitro analyses to provide a systematic classification of congenital leptin deficiency based on the molecular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 3 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 body mass index percentile 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 Conclusion 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. [ABSTRACT FROM AUTHOR]

Several case series of extreme early-onset obesity due to mutations in the human leptin receptor (LEPR) gene have been reported. In this review we summarize published functional and phenotypic data on mutations in the human LEPR gene causing severe early-onset obesity. Additionally, we included data on six new cases from our obesity center. Literature research was performed using PubMed and OMIM. Functional relevance of mutations was estimated based on reported functional analysis, mutation size, and location, as well as phenotypic characteristics of affected patients. We identified 57 cases with 38 distinct LEPR mutations. We found severe early-onset obesity, hyperphagia, and hypogonadotropic hypogonadism as cardinal features of a complete loss of LEPR function. Other features, for example, metabolic disorders and recurring infections, were variable in manifestation. Obesity degree or other manifestations did not aggregate by genotype. Few patients underwent bariatric surgery with variable success. Most mutations occurred in the fibronectin III and cytokine receptor homology II domains, whereas none was found in cytoplasmic domain. In silico data were available for 25 mutations and in vitro data were available for four mutations, revealing residual activity in one case. By assessing provided information on the clinical phenotype, functional analysis, and character of the 38 mutations, we assume residual LEPR activity for five additional mutations. Functional in vitro analysis is necessary to confirm this assumption. [ABSTRACT FROM AUTHOR]