A newly discovered gene mutation can cause syndromic obesity at a young age, accompanied by muscle weakness, cognitive problems & high mortality.

Childhood obesity is sometimes associated with severe neurological disorders and intellectual developmental delays of unknown origin. A new study, published in Diabetes, has elucidated a new form of severe obesity in children, linked to specific mutations in the P4HTM gene, and concurrently, uncovered a new mechanism contributing to disruptions in brain function that impact the regulation of appetite.

A novel genetic approach, led by Professor Philippe Froguel from the Department of Metabolism, Digestion and Reproduction, together with researchers from French Inserm in Lille and from Forman Christian College and Children Hospitals in Pakistan, has provided a significant breakthrough in understanding these severe forms of childhood obesity, known as 'syndromic' due to their association with other serious disorders.

"Our research underscores the short-term severity of this syndromic obesity type." Professor Philippe Froguel Chair in Genomic Medicine

The P4HTM gene has no relation to any known appetite-regulating genes to date. P4HTM contains the necessary instructions for producing a protein that plays a crucial role in maintaining the balance of oxygen in our body and protects against the effects of tissue oxygen deficiency (hypoxia). This protein is particularly abundant in our brain and plays a vital role in regulating our energy production (which requires oxygen) and thus our weight.

Mutations have been discovered in children from consanguineous families in Pakistan, as well as in children of Indian and Moroccan origin. These mutations lead to severe obesity that appears from a very young age, accompanied by muscle weakness, cognitive problems, and developmental delays. Unfortunately, in 43% of unrelated cases, these mutations have led to the deaths of children.

To discover this new obesity gene, the researchers used an original statistical approach to compare sequences of the entire human genome. The study involved nearly 400 children suffering from severe obesity, as well as 1,000 individuals from the general population of Pakistan and also 200,000 participants from the British UK Biobank cohort.

Managing severe childhood obesity

Speaking about the findings, Professor Froguel said: "Our research underscores the short-term severity of this syndromic obesity type. We, therefore, recommend checking for the presence of P4HTM gene mutations in young patients with severe obesity, especially those who also exhibit early muscle weakness and cognitive disorders. Early screening could enable appropriate and timely management of these patients."

Professor Froguel's team was the first to identify mutations in the MC4R gene responsible for childhood obesity in 1998. In 2023, a drug directly derived from this discovery, setmelanotide, which activates this hormonal receptor in the brain, is beginning to be used in certain forms of genetic obesity. 

This new study opens up new avenues for research into the functioning of our energy balance disruption, which results in severe obesity. Researchers hope that these discoveries will pave the way for improved diagnostic and treatment strategies to combat severe obesity in children.

Biallelic mutations in P4HTM cause syndromic obesity. Sadia Saeed, Lijiao Ning, Alaa Badreddine, Muhammad Usman Mirza, Mathilde Boissel, Roohia Khanam, Jaida Manzoor, Qasim M Janjua, Waqas I. Khan, Bénédicte Toussaint, Emmanuel Vaillant Souhila Amanzougarene, Mehdi Derhourhi, John F Trant, Anna-Maria Siegert, Brian Y. H. Lam, Giles S.H. Yeo, Layachi Chabraoui, Asmae Touzani, Abhishek Kulkarni, I. Sadaf Farooqi, Amélie Bonnefond, Muhammad Arslan, Philippe Froguel. Diabetes 2023; db221017. https://doi.org/10.2337/db22-1017