Registry Hopes to Shed Light on Rare Disorders of Genetic Obesity

November 13, 2018

For anyone living in the land of the Big Gulp, stuffed crust pizza, and the Cinnabon Caramel Pecanbon, it may be hard to imagine that obesity could be a sign of a rare disease.

In fact, there are a number of rare diseases in which obesity is a telltale manifestation of a genetic disorder. At the same time, developing an understanding of the underlying genetic mechanisms at play in these conditions may lead to a much better understanding of obesity in the broader population that could lead to new approaches to treating people who are overweight.

As with other conditions, such as cancer, a more nuanced understanding of obesity is emerging today. Rather than looking at obesity as a homogenous condition, scientists are coming to understand that it comes in many varieties. As this new understanding emerges, it may help doctors explain why some people do well with lifestyle changes, certain medications, or bariatric surgery, and others do not.

“We absolutely recognize that diet, activity, and all the environmental risk factors are very important, but we are coming to recognize that there are variants that play a role in weight regulation or appetite regulation that can interact with the environment in which we live in and make it more likely for us to present with obesity,” said Ihuoma Eneli, director of the Center for Healthy Weight and Nutrition at Nationwide Children’s Hospital and Professor of Pediatrics at The Ohio State University. “When we look at these rare disorders of genetic obesity, most of them present with early-onset, severe obesity. I’m not talking about the slightly chubby child, but the child you see at five or younger with severe obesity.”

Eneli is principal investigator of the TEMPO registry, which Rhythm Pharmaceuticals launched at the end of September. TEMPO is an acronym for “Tracing the Effect of the MC4R Pathway in Obesity.” The MC4R pathway, or melanocortin 4 receptor, is implicated in a number of rare disorders characterized by obesity. Dysfunction of the pathway, which regulates hunger, can be caused by mutations to one of several genes.

Rhythm is developing treatments for rare genetic disorders of obesity and its lead experimental therapy, an MC4R agonist, is in clinical development for a variety of these conditions. This includes POMC deficiency obesity, LEPR deficiency obesity, Bardet-Biedl syndrome, Alström syndrome, POMC heterozygous deficiency obesity, and POMC epigenetic disorders. Rhythm is developing a second experimental therapy for Prader-Willi syndrome.

Treating these conditions can be challenging, Eneli said. Patients can face a range of psycho-social issues in addition to their physical maladies. They have a difficult time from early childhood. They are often stigmatized and face bullying. The issues around food can also consume a lot of their emotional energy and be a regular source of friction between them and their caregivers.

“The general population still thinks obesity is a disorder of will power,” she said. “Because that’s the perception, it tends to drive a lot of the bias and stigma in our society today.”

Eneli hopes the registry will help provide new insights into genetic forms of obesity and help offer some understanding on the range of response to the current interventions available.

The TEMPO registry is open to patients two years of age and older who present with severe obesity early in childhood and may experience insatiable hunger, also known as hyperphagia. The registry will capture data entered by the patient, as well as healthcare providers and caregivers using online survey tools. Survey tools include questions on patient and caregiver demographics, physical activity, food and hunger episodes, quality of life, and caregiver perspective of burden of disease on the family. A full description of the eligibility requirements for the registry can be found on the website.

Though the registry is being used to identify patients who have rare genetic forms of early onset severe obesity that’s due to a genetic variation along the melanocortin 4 receptor pathway, it is expected to provide new insights into these genetic conditions and help improve the diagnosis of patients to provide for earlier interventions in the course of a disease.

“We hope to learn more about the course of the disorder over time, and the burden of the disease on the person who has the defect, their caregiver, and their healthcare provider,” said Eneli. “Our hope is that eventually healthcare providers will be able to use this to identify patients early in the course of their illness as well as improve their outcomes.”

November 13, 2018
Photo: The Infant Hercules
This file comes from Wellcome Images, a website operated by Wellcome Trust, a global charitable foundation based in the United Kingdom Wellcome blog post

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