Monogenic leptin deficiency in early childhood obesity

Abstract

Summary Background Early childhood obesity is a public health problem worldwide. It affects different aspects of physical and mental child's health. Identifying the etiologies, especially treatable and preventable causes, can direct health professionals toward proper management. Analysis of serum leptin levels and leptin gene mutations is a rapid and easy step toward the diagnosis of congenital leptin deficiency that is considered an important cause in early childhood obesity. Objectives The aim of this study was to diagnose monogenic leptin deficiency in Egyptian children presenting with early onset obesity (EOO). Methods The current cross‐sectional study included 80 children who developed obesity during the first year of life with BMI > 2 SD (for age and sex). The studied population was subjected to history taking, auxological assessment, serum leptin assay, and leptin gene sequencing. Results Ten cases had leptin deficiency (12.5%), while 18 cases showed elevated leptin levels (22.5%). Leptin gene variants in the coding region were identified in 30% of the leptin‐deficient group: two novel homozygous disease‐causing variants (c.104 T > G and c.34 delC) and another previously reported homozygous pathogenic variant (c.313C > T). Conclusion Leptin deficiency is considered a significant cause of monogenic obesity in Egyptian children with early‐onset obesity as the diagnosis of these patients would be a perfect target for recombinant leptin therapy.

When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin

“…The most recent cross-sectional study conducted by ElSaeed et al. (2020) ( 22 ) revealed a new frameshift mutation p.Leu12fs, caused by a single cytosine nucleotide deletion at position 34 in exon 2. This new variant was identified in a 10-year-old girl, with normal birthweight.…”

“…This pathogenic variant was also identified in a 3-year-old Egyptian female, who presented with the classical features of leptin deficiency, with a normal birthweight of 3 kg, but expressive weight gain leading to obesity after 5 months. Her BMI was 29.4 kg/m², and she exhibited high blood pressure, hyperphagia, aggressive behavior when demanding food, and very low leptin level (0.1 ng/dl) ( 22 ).…”

Genetic polymorphisms associated with obesity in the Arab world: a systematic review

“…3), and according to the clinical phenotype, they are considered as "common variants"; as they were found to be associated with obesity in other non-Arab countries, including China, Croatia, and Brazil (Table S3). LEP variants (c.313 C > T, rs1349419, rs2167270, (TTTC) n polymorphism) have been associated with obesity in other non-Arab ethnic countries, including Pakistan, Mexico, Malaysia, and India [36,[64][65][66] (Table S3).…”

“…Given the complex nature of obesity and the fact that it does not follow a typical Mendelian transmission pattern, it is believed that several susceptibility genes with low or moderate effects play a role in predisposition to the disease [31,32]. There is firm evidence that genes influencing energy homeostasis and thermogenesis, adipogenesis, leptin-insulin signaling transduction, and hormonal signaling peptides play a role in the development of obesity [33][34][35][36][37]. Several potential obesity candidate genes and variants have been documented, including LEP and LEPR, which have been mainly implicated in monogenic obesity, as well as FTO, APOE, PPARG, and PPARA which have been mainly implicated in polygenic/common obesity [31,32].…”

Temporal Leptin to Determine Cardiovascular and Metabolic Fate throughout the Life

“…Alteration in serum leptin concentration (e.g., leptin deficiency or elevated leptin level) is one of the strongest single contributors causing childhood early onset obesity [ 70 ]. Children with mutations in genes encoding leptin or leptin receptors develop childhood monogenic obesity with higher BMI than age-matched, obese children without leptin deficiency [ 71 ].…”