Background: Proteins encoded by LEP, LEPR and MC4R genes are principally involved in driving the leptin-melanocortin pathway. Mutations in these genes induce a rare and severe form of monogenic obesity but the long-term evolution of these afflictions is unknown. Here, we carried out a clinical investigation on 132 children with LEP, LEPR and MC4R deficiency from Pakistan to evaluate progression of the disease and its impact on co-morbidities and mortality.
Methods: Severely obese children (BMI SDS .3.5) from 454 families were clinically examined and screened for mutations in three genes using Sanger and WES. Serum hormones, leptin, insulin, cortisol, TSH, and DNA damage marker, 8-OHdG, were determined using ELISA.
Results: We identified 132 probands and 13 family members with homozygous loss-of-function variants in LEP (n=83), LEPR (n=31) or MC4R (n=18). In majority of leptin and LEPR deficient children, obesity and hyperphagia manifested at an early infancy (<1-2 year) compared to MC4R deficiency (4-6 year). Our data demonstrate no remarkable remission of longitudinal growth in LEP or LEPR deficient subjects compared to controls. However, a discernible increase in growth was evident in MC4R deficient subjects during 10-15 years of life. Insulin levels were significantly higher in the mutant groups as compared to control that increased progressively with advancing age. Hyperinsulinemia was more pronounced in LEPR deficiency at the age of 10-15 years. Serum leptin concentrations tended to be higher in LEPR deficiency compared to subjects with MC4R mutations in the first 5 years of life but not at a more advanced age. Cortisol levels that were higher in leptin deficiency during early childhood compared to other groups, declined with age. Mean TSH concentrations were normal in the three mutant groups. DNA damage as evidenced by serum 8-OHdG was more pronounced in LEP deficient children than those in other two groups and was minimal in MC4R deficiency. Mortality due to severe respiratory, gastric problems or pneumonia was reported to be higher in LEP deficient (26%) compared with LEPR deficient children (9%). No deaths were reported in MC4R deficiency.
Conclusions: This large study revealed a distinctly higher incidence of morbidity and mortality at an earlier age in leptin and leptin receptor deficiency compared with MC4R deficient subjects. Remarkably, longitudinal growth was normal in LEP and LEPR deficient but noticeably increased in MC4R deficient subjects. A predisposition to diabetes increased with age in the mutant groups and oxidative stress was maximal in leptin deficiency.
15 Sep 2022 - 17 Sep 2022