ESPE Abstracts (2019) 92 S1.3

Rare Genetic Forms of Obesity: Clinical Approaches and Current Treatments in 2019

Christine Poitou


INSERM, Nutriomics UMR_S U1166, University Pierre et Marie Curie, Institute of Cardiometabolism and Nutrition (ICAN) Assistance Publique-Hôpitaux de Paris, Nutrition Department, French Reference Centre for Prader-Willi Syndrome,, PARIS, France


Obesity—defined as excess fat mass which impacts on physical health—is a complex and multifactorial disease where numerous environmental factors (overeating and/or reduced physical activity) act in concert with genetic factors. Understanding molecular mechanisms of obesity has rapidly improved in recent years due to the development of faster, more specific genetic screening tools (1). Rare genetic obesities are distinguished from more-common polygenic obesities where multiple susceptibility genes with slight individual effects combine to modify weight. Cumulative genetic contributions can be amplified by 'obesogenic' lifestyles (overeating feeding, sedentary living, stress, etc).

Genetic obesities can present with different clinical symptoms depending on the genes involved; a) monogenic obesities with rare early-onset obesity combined with abnormal feeding behavior and endocrine disorders, and which are mainly due to autosomal recessive mutations in genes of—or associated with—the leptin/melanocortin pathway, which plays an essential role in the hypothalamic control of food intake; b) over 100 syndromic obesities corresponding to severe early-onset obesity with additional phenotypes (intellectual disability, dysmorphic features, and organ-specific developmental abnormalities), such as the most frequent Prader-Willi (PWS) and Bardet-Biedl (BBS) syndromes; and c) oligogenic obesity, such as melanocortin 4 receptor (MC4R)-linked obesity, characterized by a varying severity of obesity, partly dependent on environmental factors, and the absence of specific phenotype.

It is vitally important to diagnose genetic forms of obesity as specific management provided by specialized and multidisciplinary teams, is needed as soon as possible (from early childhood) (1). Early diagnosis and management of these rare obesity forms should enable improved prognosis into adulthood. Nevertheless, the transition between pediatric care and adult specialists remains a critical point in time, and is often associated with medical and social breakdowns (2). Current active research has identified several promising therapeutic molecules and target pathways for genetic obesities, which should change the prognosis for these rare severe forms of obesity (3-6).

References: 1. Huvenne H et al. Dubern B, Clément K, Poitou C. Obes Facts. 2016;9(3):158-73

2. Paepegaey AC et al. Endocr Connect. 2018 May;7(5):663-672

3. Allas S et al. PLoS One. 2018 Jan 10;13(1):e0190849.

4. Collet TH et al. Mol Metab 2017 Oct;6(10):1321-1329

5. Kühnen P et al. N Engl J Med. 2016 Jul 21;375(3):240-6.

6. Clement K, et al. Nature Medicine 2018.

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