Monogenic & Syndromic Obesity
It is a major medical problem beginning from childhood and seems to have an epidemic size as the World Health Organization (WHO) has estimated the number of children < 5 years old who are obese or overweight to be ~39 million.
Children are considered overweight when their BMI is between the 85th and 95th percentile for their age and gender, obese with a BMI ≥ 95th percentile, and extremely obese with a BMI ≥ 120% of the 95th percentile.
What is Monogenic Obesity?
Monogenic obesity follows a Mendelian pattern of inheritance and patients are usually characterized by severe obesity due to mutations in a specific gene. Mutations in genes implicated in the leptin–melanocortin pathway have been mostly associated with monogenic obesity.
Types of Monogenic Obesity
- Congenital Leptin Deficiency
- Congenital Leptin Receptor Deficiency
- POMC Deficiency
- PCSK1 Deficiency
- MC4R Deficiency
Leptin-Melanocortin Pathway
In this pathway, leptin—an adipose tissue hormone—binds to the hypothalamic leptin receptor, stimulating the production of proopiomelanocortin (POMC). Proprotein convertase subtilisin/kexin type 1 (PCSK1) cleaves POMC into melanocortin ligands, such as α- and β melanocyte–stimulating hormone, expediting binding and activation of the melanocortin-4 receptor (MC4R), thus reducing food intake and increasing energy consumption. BDNF (Brain derived neurotrophic factor) also has a regulatory role in this pathway.
Key Findings in Pakistani Children
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.
Remarkably high morbidity and mortality has been observed in children with LEP or LEPR deficiency. High incidence of pulmonary and GI infections is the main cause of deaths. Oxidative stress levels are notably higher in LEP than in LEPR or MC4R deficiency.
Current or novel medications against monogenic forms of obesity, though available in many developed countries, are unfortunately lacking in Pakistan—a country with the world's highest recorded prevalence of LEP-signaling deficiency.
Treatment Options
- Leptin deficiency: hormone replacement therapy with recombinant leptin
- LEPR deficiency: Setmelanotide (MC4R agonist)
- POMC deficiency: Setmelanotide (MC4R agonist)
- PCSK1 deficiency: Setmelanotide (MC4R agonist)
- MC4R deficiency: Semaglutide (GLP-1 RA), Tirzepatide (GLP-1/GIP RA)
Syndromic Obesity
Syndromic obesity refers to obesity that is associated with intellectual disability, dysmorphic features, or abnormalities affecting different organs and systems, with low frequency, high variability, and a Mendelian pattern of inheritance.
Important Syndromic Obesity Types
- Prader–Willi Syndrome (PWS)
- Bardet–Biedl Syndrome (BBS)
- Pseudohypoparathyroidism (PHP) Type 1a
- Alström Syndrome (ALMS)
- 16p11.2 Deletion Syndrome
- WAGR Syndrome
- Smith–Magenis Syndrome (SMS)
- Cohen Syndrome (CS)
- MYT1L-Variants Syndrome
- Börjeson–Forssman–Lehmann Syndrome (BFLS)
- Down Syndrome (DS)
- Kallmann Syndrome (KS)
- Carpenter Syndrome (CRPT1)
Research Findings: High Morbidity and Mortality
Key Conclusions
Comparative data from this retrospective cross-sectional study indicate a distinctly higher level of morbidity in children with LEP or LEPR deficiency compared with those with homozygous loss-of-function mutations in the MC4R gene.
Current or novel medications against monogenic forms of obesity, though available in many developed countries, are unfortunately lacking in Pakistan—a country with the world's highest recorded prevalence of LEP-signaling deficiency.
The treatments include hormone replacement therapy with recombinant leptin for subjects with LEP deficiency, the MC4R agonist setmelanotide for LEPR deficiency, and glucagon like peptide-1 receptor agonists for subjects with MC4R deficiency.
The fact that a sizable population of children are failing to achieve normal educational development and are becoming seriously ill and dying prematurely as the result of a deficiency in hormonal signaling for which relatively simple peptide treatments are readily available highlights serious flaws in the global system through which drugs are developed and made available to those who most need them.
