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Tracing the Effect of the MC4R Pathway

TEMPO: A landmark registry for rare genetic disorders

Rare genetic disorders of obesity are caused by a mutation or variant in an individual’s gene, which can be either syndromic or non-syndromic
The best-known examples of syndromic monogenic obesity include Prader–Willi, Bardet–Biedl, Alström, Carpenter, Rubenstein–Taybi and Cohen syndromes

Obesity, a critical public health problem, is a challenging disease because the etiology is complex even within the same individual. Consuming high-calorie, low-nutrient foods and beverages, not getting enough physical activity, sedentary activities such as watching television, poor sleep routines, and medication use are all identified risk factor for obesity. A child’s environment also strongly impacts risk of developing obesity, and this contribution begins early in life. Genetic influences are distinct considerations that may have greater bearing, especially in individuals with severe early-onset obesity.

The article was authored Dr 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

Rare genetic disorders of obesity are caused by a mutation or variant in an individual’s gene, which can be either syndromic or non-syndromic. The best-known examples of syndromic monogenic obesity include Prader–Willi, Bardet–Biedl, Alström, Carpenter, Rubenstein–Taybi and Cohen syndromes. Children with these syndromes typically have dysmorphic features and may have intellectual disability. Our understanding of genetic variants that predispose an individual to severe obesity are still evolving. For example, genetic variants have been identified along the melanocortin-4 receptor (MC4R) pathway located in the hypothalamus, whose responsibilities include regulating body weight and appetite. The prevalence of MC4R gene mutations is as high as 5% in children with severe early-onset obesity. Other genes that are currently associated with obesity are proopiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) and leptin receptor (LEPR). People living with these rare genetic disorders of obesity tend to have severe obesity that begins early in life, and sometimes as early as infancy.  

There are several new efforts underway to improve the understanding of severe obesity that results from specific genetic disorders. In one example, a researcher at Vanderbilt University Medical Center is currently leading an IRB-approved genetic screening study, “The Genetic Obesity ID (GO-ID) Genotyping Study.”* The goal of the study is to identify individuals who may have obesity resulting from either POMC or LEPR deficiency. These individuals often present with early-onset morbid obesity (EOMO), hyperphagia and poor satiety. To join the study, an individual needs to be at least two years old, have severe obesity, and have symptoms suggestive of excessive appetite and poor satiety most likely from an early age. As these disorders are ultra-rare, it is anticipated that a large number of volunteers will need to be screened in order to identify subjects with the genetic variants or mutations.

At Nationwide Children's Hospital, we serve as a coordinating center for a new non-interventional international patient registry, called “Tracing the Effect of the MC4R Pathway in Obesity (TEMPO).”* The TEMPO registry aims to identify and enroll approximately 1,000 participants with rare genetic forms of obesity that are potentially related to key genes, upstream or downstream, of the MC4R. In addition, the TEMPO registry will evaluate the burden of disease on participants, caregivers, healthcare providers and the healthcare system.

We designed the TEMPO registry to be a voluntary, prospective, open-ended, registry. Participants must possess at least one of a few specific genotypes. This includes people who are homozygous or compound heterozygous for POMC, PCSK1 or LEPR variants that have led to a physician-confirmed diagnosis of either POMC or LEPR deficiency obesity. It also includes people with extreme obesity who have high-confidence, high-impact variations in the same three genes, or in the MC4R gene or other upstream MC4R pathway genes and selected variants downstream in the MC4R pathway. People with recognized syndromic forms of obesity are excluded. Data sources include electronic surveys completed by participants, caregivers and healthcare providers. The surveys, which are being completed at study entry and then annually thereafter, allow us to collect demographics, results of genetic testing, medical and family history, disease characteristics, resource utilization, and eating habits and hunger episodes.

The TEMPO registry will help us evaluate the prevalence of rare genetic disorders of obesity, the quality of life for people who are impacted, and the burden on caregivers, healthcare providers, and the healthcare system. We often find that many patients feel like obesity is their own fault. Hopefully enrolling in a registry may help them build a sense of community and better evaluate feelings of guilt and self-blame around their excessive weight gain. Researchers need to learn more about how the environment and genetics intersect and impact weight gain. With the information garnered through the TEMPO registry, we can collectively address the stigma and the bias directed at individuals with obesity by helping people appreciate the etiological complexity behind excessive weight gain and severe obesity.

*The GO-ID study and the TEMPO registry are funded by Rhythm Pharmaceuticals

References

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