ESPEYB20 9. Obesity and Weight Regulation Genetic Obesity and Genetic Risk Score (3 abstracts)
9.8. A National Multicenter Study of Leptin (LEP) and Leptin Receptor (LEPR) deficiency and systematic review
Besci Ö , Fırat SN , Özen S , Çetinkaya S , Akın L , Kör Y , Pekkolay Z , Özalkak S , Özsu E , Erdeve SS , Poyrazoglu S , Berberglu M , Aydin M , Omma T , Akinici B , Demir K & Oral EA
Division of Metabolism, Endocrinology and Diabetes, Caswell 2 Diabetes Institute, Ann Arbor, MI 48105, USA. eliforal@med.umich.edu J Clin Endocrinol Metab. 2023 Feb 24;dgad099. doi: 10.1210/clinem/dgad099. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/36825860/.
Brief summary: This paper describes 18 patients with bi-allelic leptin deficiency (LEP, n=11) or leptin receptor deficiency (LEPR, n=7), including 10 new cases and two novel variants. In addition, in a review of the literature (until July 2022), the authors identified n=75 patients living with LEP deficiency and n=90 with LEPR deficiency (n=152 included for comparison between groups).
This report is one of the most comprehensive compilations of available data on these two rare forms of monogenic obesity. Interestingly, they authors found that patients with LEP deficiency were diagnosed at a younger age, had a higher median BMI SD score at diagnosis, and were more likely to have hyperinsulinemia.
Unfortunately, this highly interesting article has some limitations. The authors failed to identify or include all publications on patients with LEP/LEPR deficiency. For example, the largest publication on patients with LEP/LEPR deficiency (1) (n=52 LEP, n=17 LEPR) is not included, even though the authors had identified the article. In this respective publication, clinical data is grouped according to variants, thus data for 45 patients cannot be used for detailed analysis, however data for single patients is provided for n=24 patients. Another limitation is they did not consider the fact that BMI SD scores correct for increasingly skewed distributions with age, with the result that BMI SD scores tend to have higher values in younger patients. Thus, if patients with LEP deficiency are diagnosed at a younger age, their BMI SDS scores may be artifactually higher than older children with LEPR mutations. On the other hand, if LEP deficiency does indeed lead to higher BMI SD scores, it might explain why these patients are diagnosed at an earlier age. Here the 69 additional patients from Saeed et al. (1) might have been helpful (BMI SDS values are provided for all). Saeed et al. reported much higher BMI SD score values without any difference between the groups (1).
Concerning co-morbidities, reported case series might be incomplete and not well defined. The finding of a higher risk of hyperinsulinemia in patients living with LEP deficiency compared to patients with LEPR deficiency is nevertheless very interesting. Leptin is known to influence glucose metabolism (2) and while some of its effects are modulated via the LEPR (2) these findings strengthen the idea that leptin might have a direct influence independent of that receptor.
In summary, while the data collection is not complete, the authors provide interesting insights into the typical phenotypes and differences between these two rare conditions. Future research is needed, including more such patients, to confirm the here found associations.
References: 1. Saeed S, Arslan M, Manzoor J, et al. Genetic Causes of Severe Childhood Obesity: A Remarkably High Prevalence in an Inbred Population of Pakistan. Diabetes. Jul 2020;69(7):1424–1438. doi: 10.2337/db19-1238. 2. da Silva AA, do Carmo JM, Hall JE. CNS Regulation of Glucose Homeostasis: Role of the Leptin-Melanocortin System. Curr Diab Rep. May 26 2020;20(7):29. doi: 10.1007/s11892-020-01311-1.
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ESPE Yearbook of Paediatric Endocrinology
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