Wabitsch Martin, Pridzun Lutz, Ranke Michael, von Schnurbein Julia, Moss Anja, Brandt Stephanie, Kohlsdorf Katja, Moepps Barbara, Schaab Michael, Funcke Jan-Bernd, Gierschik Peter, Fischer-Posovszky Pamela, Flehmig Bertram, Kratzsch Jürgen
Division of Pediatric Endocrinology and DiabetesDepartment of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
Mediagnost GmbHReutlingen, Germany.
Eur J Endocrinol. 2017 Mar;176(3):315-322. doi: 10.1530/EJE-16-0821. Epub 2016 Dec 22.
Functional leptin deficiency is characterized by high levels of circulating immunoreactive leptin (irLep), but a reduced bioactivity of the hormone due to defective receptor binding. As a result of the fact that affected patients can be successfully treated with metreleptin, it was aimed to develop and validate a diagnostic tool to detect functional leptin deficiency.
An immunoassay capable of recognizing the functionally relevant receptor-binding complex with leptin was developed (bioLep). The analytical quality of bioLep was validated and compared to a conventional assay for immune-reactive leptin (irLep). Its clinical relevance was evaluated in a cohort of lean and obese children and adults as well as in children diagnosed with functional leptin deficiency and their parents.
In the clinical cohort, a bioLep/irLep ratio of 1.07 (range: 0.80-1.41) was observed. Serum of patients with non-functional leptin due to homozygous amino acid exchanges (D100Y or N103K) revealed high irLep but non-detectable bioLep levels. Upon treatment of these patients with metreleptin, irLep levels decreased, whereas levels of bioLep increased continuously. In patient relatives with heterozygous amino acid exchanges, a bioLep/irLep ratio of 0.52 (range: 0.48-0.55) being distinct from normal was observed.
The new bioLep assay is able to diagnose impaired leptin bioactivity in severely obese patients with a homozygous gene defect and in heterozygous carriers of such mutations. The assay serves as a diagnostic tool to monitor leptin bioactivity during treatment of these patients.
功能性瘦素缺乏的特征是循环免疫反应性瘦素（irLep）水平升高，但由于受体结合缺陷，该激素的生物活性降低。鉴于受影响的患者可以用米替福辛成功治疗，旨在开发并验证一种检测功能性瘦素缺乏的诊断工具。
开发了一种能够识别与瘦素功能相关的受体结合复合物的免疫测定法（bioLep）。对bioLep的分析质量进行了验证，并与传统的免疫反应性瘦素（irLep）测定法进行了比较。在一组瘦和肥胖的儿童及成人以及被诊断为功能性瘦素缺乏的儿童及其父母中评估了其临床相关性。
在临床队列中，观察到bioLep/irLep比值为1.07（范围：0.80 - 1.41）。由于纯合氨基酸交换（D100Y或N103K）导致非功能性瘦素的患者血清显示出高irLep水平，但未检测到bioLep水平。用米替福辛治疗这些患者后，irLep水平下降，而bioLep水平持续上升。在具有杂合氨基酸交换的患者亲属中，观察到bioLep/irLep比值为0.52（范围：0.48 - 0.55），与正常情况不同。
结论新的bioLep测定法能够诊断严重肥胖且具有纯合基因缺陷的患者以及此类突变的杂合携带者中的瘦素生物活性受损。该测定法可作为监测这些患者治疗期间瘦素生物活性的诊断工具。
