Rare Genetic MC4R Pathway Associated Obesities

Sponsored Content: This blog post was sponsored and submitted by Rhythm Pharmaceuticals, Inc.

Rare genetic melanocortin 4 receptor (MC4R) pathway associated obesities can impose a significant burden on patients and their caregivers, especially due to associated hyperphagia.¹

“Emotionally, [I felt] upset and frustrated because I knew I wasn’t supposed to be eating that much” – Adult Patient with BBS

“‘She couldn’t do as well in school because she was thinking about what was in her lunchbox or what she was going to get at lunch or when she could eat it or how soon to lunch. It was very obsessive the amount of thoughts about the timing of food.’’ — Parent of patient with BBS

Rare Genetic MC4R Pathway Associated Obesities are not as Rare

MC4R pathway-associated obesities associated with rare genetic variants are not as rare as you may believe. From a 2022 analysis of 11,671 patients who were genetically tested with a 79-genes and 1 chromosome genetic test panel that is reflective of nearly all of the most frequently tested genes associated with obesity found that 73.5% of individuals had at least 1 pathogenic variant, likely pathogenic variant or variant of uncertain significance.² The eligibility criteria for genetic testing were either ≥ 19 years of age with a with a BMI of 40 kg/m² or higher, or a BMI at or above the 97th percentile for children aged ≤ 18 years, or an immediate family member of selected, previously tested patients, or individuals showing clinical symptoms of Bardet-Biedl syndrome (BBS). A June 2024 analysis of the same genetic testing program of 43,013 individuals (32% of whom were adults and 68% were children), found pathogenic/likely pathogenic variants identified in all age groups, including adult patients.²

To learn more about how to identify rare genetic diseases of obesity, please visit https://uncoveringrareobesity.com/.

When to Suspect Rare Genetic MC4R Pathway Associated Obesities

While rare MC4R pathway diseases present with a variety of clinical characteristics depending on the gene involvement (i.e. possible red/orange hair in a Caucasian patient with POMC deficiency), there are two key clinical features common to many rare genetic MC4R pathway diseases: early-onset severe obesity and hyperphagia.^3,4 While general obesity can occur at any age, the age of onset for monogenic & syndromic obesity is as early as a few months of age but often appears in early childhood.⁴ In the literature, early-onset severe obesity is usually defined as a BMI ≥95th percentile with an age <5 years.⁴ The other cardinal clinical feature is hyperphagia, which is defined as a chronic pathological, insatiable hunger with impaired satiety differentiated by other types of overeating by its severity and persistence.⁵ Unlike other types of hunger such as cravings or food noise, hyperphagia is marked with a persistent pre-occupation with food, prolonged time to satiation and shortened duration of satiety, a prolonged feeling of hunger and specific abnormal behaviors which manifest differently in children and adults (e.g. may manifest as emotional effects for adults and tantrums for food in children).^1,5 Other abnormal food-seeking behaviors include but are not limited to waking up at night for food, sneaking or hiding food and experiencing distress if food is unavailable.

How to Diagnose Rare Genetic MC4R Pathway Associated Obesities

Experts consensus guidelines, including a Pediatric Obesity Algorithm by Dr. Cuda et al. 2022, recommend genetic testing in patients that present with the following: the two cardinal symptoms (hyperphagia & severe obesity before the age of 5), a family history of notable weight differences between members, and other clinical characteristics of rare MC4R pathway diseases (i.e., neurological abnormalities, growth abnormalities, endocrine abnormalities).^3,4,7 Monogenic obesities such as those associated with genetic variants in POMC, PCSK1, LEPR or other genes can be diagnosed with genetic testing.^4,8

On the other hand, for syndromic obesities such as BBS, genetic testing is not required, and the diagnosis can be made based on clinical symptoms.⁹ Besides the two cardinal symptoms, the most common symptoms are rod-cone dystrophy, polydactyly, hypogonadism, renal abnormalities and cognitive impairment.¹⁰ Genetic testing can be used to aid in diagnosis, however, the scientific understanding of genetics underlying BBS is constantly evolving. As of today, there are 29 different genes known to be associated with BBS. That, along with technological limitations, makes relying solely on genetic testing difficult.

LEPR: Leptin receptor; PCSK1: Proprotein convertase subtilisin/kexin type 1; POMC: Pro-opiomelanocortin

Rhythm Upcoming Webinars

U.S. healthcare professionals are invited to join Rhythm’s upcoming disease education webinars focused on Acquired Hypothalamic Obesity (HO), an acquired form of MC4R pathway-related obesity. Each session will offer clinical insights and a unique perspective on this complex condition.

• Session 1: Wednesday, September 10 at 7:15pm ET
  Presented by Dr. Ashley Shoemaker, and Lainey, a patient living with acquired HO Register here
• Session 2: Thursday, October 16 @ 12pm ET
  Presented by Dr. Lindsay Fourman Register here

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If you are a US-based healthcare professional who is interested in learning more about rare neuro-endocrine MC4R pathway diseases, please follow us on our LinkedIn Medical Affairs page.