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Rare genetic melanocortin 4 receptor (MC4R) pathway associated obesities can impose a significant burden on patients and their caregivers, especially due to associated hyperphagia. 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. 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. How to Diagnose Rare Genetic MC4R Pathway Associated Obesities Experts consensus guidelines, including a Pediatric Obesity Algorithm by Dr. 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. Lindsay Fourman Register here Rhythm Medical Affairs LinkedIn: 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.

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1 On the other hand, there are other rare types of obesities resulting from some rare but highly impactful genetic variants or deletions (i.e. Bardet- Biedl Syndrome, POMC deficiency, LEPR deficiency, Prader-Willi Syndrome), or even acquired hypothalamic damage (i.e. acquired hypothalamic obesity) ( Figure 1). Rare genetic variants or damage to the hypothalamus can lead to impairment of a critical pathway, the hypothalamic melanocortin-4 receptor (MC4R) pathway, otherwise known as the leptin-melanocortin pathway. This pathway is responsible for regulating hunger and energy expenditure and any impairment in the pathway leads to rare MC4R pathway diseases. 2-3 It is important to be aware of this unique subset of obesity associated with MC4R pathway diseases as MC4R pathway diseases are likely underdiagnosed and early identification of MC4R pathway diseases is essential for optimal disease management. 4-6 Figure 1: Rare Hypothalamic MC4R Pathway Diseases The MC4R signaling pathway regulates hunger, satiety, and energy expenditure, consequently affecting body weight. 7-8 Genetic variants that impair function of genes involved in the MC4R Pathway function, or physical damage to the hypothalamus leads to decreased alpha-MSH and impaired downstream activation of the MC4R pathway. 9 Figure 2: Impairment of the MC4R Signaling Pathway MC4R pathway diseases caused by rare genetic variants are classified as monogenic or syndromic in nature. 10 Monogenic obesity refers to obesity due to variants in single genes (e.g. POMC deficiency, LEPR deficiency, PCSK1 deficiency, SRC1 deficiency, SH2B1 deficiency, etc.) along the MC4R pathway. Syndromic obesity refers to obesity that is also due to genetic variants or deletions in the pathway but also associated with additional phenotypes such as organ-specific developmental abnormalities, such as visual impairment, renal anomalies, cognitive impairment, dysmorphic features, etc. 10-11 Rare Genetic Diseases of Obesity Provider Listing A patient's diagnostic journey can be complex and may take years.

Obesity is a complex, chronic disease that is a major risk factor for other cardiovascular, renal and metabolic conditions, including liver disease and cardiovascular disease. Sandy Sommer, Head of the Therapeutic Area for Cardiovascular, Renal and Metabolic at Boehringer Ingelheim, explains why it is vital that we view obesity and related metabolic conditions through the lens of connectivity.