von Schnurbein Julia, Zorn Stefanie, Nunziata Adriana, Brandt Stephanie, Moepps Barbara, Funcke Jan-Bernd, Hussain Khalid, Farooqi I Sadaf, Fischer-Posovszky Pamela, Wabitsch Martin
Division of Paediatric Endocrinology and Diabetes, Department of Paediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, 89075, Germany.
Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, Ulm, 89075, Germany.
J Clin Endocrinol Metab. 2024 Sep 16;109(10):2602-2616. doi: 10.1210/clinem/dgae149.
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.
We conducted a systematic literature research supplemented by unpublished data from patients at our center as well as new in vitro analyses to provide a systematic classification of congenital leptin deficiency based on the molecular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.
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.
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.
双等位基因致病性瘦素基因变异导致严重的早发性肥胖，通常与循环瘦素水平低或检测不到有关。最近，已描述了一些变异，其导致分泌具有生物学无活性或拮抗特性的突变形式的瘦素激素。
我们进行了系统的文献研究，并辅以来自我们中心患者的未发表数据以及新的体外分析，以基于潜在瘦素变异的分子和功能特征对先天性瘦素缺乏进行系统分类，并研究疾病亚型与临床表型严重程度的相关性。
在148例患者中鉴定出总共28种不同的纯合瘦素变异。所鉴定的变异可分为先天性瘦素缺乏的3种不同亚型：经典激素缺乏（128例患者中的21种变异）、生物学无活性激素（12例患者中的3种变异）和拮抗激素（7例患者中的3种变异）。仅1种变异（n = 1例患者）仍未分类。与经典激素缺乏患者相比，具有生物学无活性瘦素的患者第95百分位体重指数百分比更高。虽然经典激素缺乏和生物学无活性激素的患者都可以用相同的起始剂量的美曲普明治疗，但拮抗激素患者需要一种根据变异量身定制的治疗方法来克服变异瘦素的拮抗特性。
基于分子和功能特征对瘦素变异进行分类有助于确定治疗先天性瘦素缺乏患者的最适当方法。
