In 2014, the global prevalence of severe obesity (body mass index [BMI] ≥35 kg/m2) was 2.3% in men and 5.0% in women.1 Although obesity is influenced by environmental factors, a subset of genetic factors may play a crucial role in rare genetic disorders of obesity.2 Individuals with these rare genetic disorders of obesity often present with excessive hunger, impaired satiety, preoccupation with food, and severe obesity in early childhood, findings that are traceable to impairments in circuitries within the hypothalamus.3-5
In these individuals, lifestyle modifications focusing on diet and exercise and pharmacologic interventions may be ineffective because they often do not target the underlying challenges of controlling hunger. To improve identification of individuals with rare genetic disorders of obesity and to better understand their burden, researchers have launched the Tracing the Effect of the MC4R Pathway in Obesity (TEMPO) Registry, a landmark international patient registry.6
The melanocortin-4 receptor (MC4R) pathway includes key proteins associated with obesity, such as leptin (LEP) and its receptor (LEPR), pro-opiomelanocortin (POMC), and proprotein convertase subtilisin/kexin type 1 (PCSK1).7 When LEP binds to LEPR on the surface of POMC neurons, neuropeptides such as alpha- and beta-melanocyte-stimulating hormone are released, acting on the MC4R to trigger satiety, energy expenditure, and weight loss.8 Deficiencies in the genes encoding these key proteins disrupt MC4R activation, which can impair signaling along the pathway.3
Although few cases have been published on obesity associated with impaired signaling along the MC4R pathway, authors of an epidemiologic analysis predicted that approximately 12,800 individuals in the United States may have biallelic mutations in LEPR, POMC, or PCSK1 that lead to protein deficiencies.9 The analysis included only 3 rare allele mutations (prevalence <0.1%); hence, this might be an underestimation of the true prevalence of rare genetic disorders of obesity.9 For physicians to recognize and treat an individual with these genetic variants, more information must be available on what clinical signs and symptoms to investigate.
Goals of the TEMPO Registry
The TEMPO registry garners information on the burden of rare genetic disorders of obesity on individuals, parents/caregivers, healthcare providers (HCPs), and the healthcare system.6 It is a voluntary, ongoing, open-ended registry that enrolls individuals with impaired MC4R pathway signaling caused by rare genetic variants resulting in early-onset severe obesity. HCPs may use this registry to learn more about the identification, diagnosis, and treatment of rare genetic disorders of obesity. With an anticipated participation of approximately 1000 individuals worldwide, the registry is expected to serve as a comprehensive data repository for researchers studying these rare disorders.
TEMPO Registry Process
Eligible individuals with genetic variants in selected genes in the MC4R pathway are referred to coordinating centers by their HCP or by genetic screening studies (eg, Genetic Obesity ID).6 Individuals with rare genetic disorders of obesity must meet the following BMI criteria for severe obesity to be included in this registry: BMI >40 kg/m2 for adults aged ≥18 years, and for children aged 2 to 17 years, BMI >1.4 times that of the age- and sex-adjusted 95th percentile value. Individuals diagnosed with syndromic forms of obesity such as Bardet-Biedl syndrome, Alström syndrome, or Prader-Willi syndrome will be excluded.
After enrollment, the participant, parent/caregiver, and HCP will complete online surveys that collect information about the participant’s diagnosis, medical history, lifestyle, and effect on the family. Surveys will be completed annually thereafter in an open-ended follow-up period. While enrolled in the registry, the participant’s HCP may recommend treatment options or make referrals to appropriate clinical trials.
Diagnosis and proper treatment of individuals with rare genetic disorders of obesity are crucial to help improve quality of life, reduce social stigma, and alleviate feelings of guilt or blame experienced by these individuals and their parents/caregivers.10 The TEMPO registry could potentially provide data for analyses that can help improve the care we provide for this vulnerable subgroup of patients.
Disclosures: Editorial assistance was provided under the direction of the authors by Rajni Parthasarathy, PhD, CMPP, and Sherri Damlo of MedThink SciCom with support from Rhythm Pharmaceuticals, Inc.
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