Severe Early-onset Obesity Research Articles

POSB378 Health State Utilities Associated with Hyperphagia

Patients with rare genetic diseases of obesity, including monogenic or syndromic, often present with early-onset severe obesity and hyperphagia, characterized by an extreme, persistent, unsatisfied drive to consume food. Persistent hyperphagia-associated behaviors can lead to marked negative impact on the lives of patients. While utility values associated with general obesity are available in published literature, no published studies have estimated utilities associated with hyperphagia and any impact on patient’s quality of life beyond obesity.

The Spectrum of Genetic Variants Associated with the Development of Monogenic Obesity in Qatar

Introduction: Monogenic obesity (MO) is a rare genetic disease characterized by severe early-onset obesity in affected individuals. Previous genetic studies revealed 8 definitive genes for monogenic non-syndromic obesity; many were discovered in consanguineous populations. Here, we examined MO in the Qatari population, whose population is largely consanguineous (54%) and characterized by extensive obesity (45%). Methods: Whole genome sequencing data of Qatar Biobank samples from 250 subjects with obesity and 250 subjects with normal weight, obtained in association with the Qatar Genome Programme, were searched for genetic variants in the genes known to be associated with MO (i.e., LEP, LEPR, POMC, PCSK1, MC3R, MC4R, MRAP2, and ADCY3). The impact of the variants identified was investigated utilizing in silico tools for prediction in combination with protein visualization by PyMOL. Results: We identified potential MO variants in more than 5% of the cases in our cohort. We revealed 11 rare variants in 6 of the genes targeted, including two disease-causing variants in MC4R and MRAP2, all of which were heterozygous. Moreover, enrichment of a heterozygous ADCY3 variant (c.1658C>T; p.A553V) appeared to cause severe obesity in an autosomal dominant manner. Conclusion: These findings highlight the importance of implementing routine testing for genetic variants that predispose for MO in Qatar. Clearly, additional studies of this nature on populations not yet examined are required. At the same time, functional investigations, both in vitro and in vivo, are necessary in order to better understand the role of the variants identified in the pathogenesis of obesity.

Genomic analysis to screen potential genes and mutations in children with non-syndromic early onset severe obesity: a multicentre study in Turkey.

Obesity is a complex genetic-based pediatric disorder which triggers life-threatening conditions. Therefore, the understanding the molecular mechanisms of obesity has been a significant approach in medicine. Computational methods allow rapid and comprehensive pathway analysis, which is important for generation of diagnosis and treatment of obesity. Aims of our study are to comprehensively investigate genetic characteristics of obesity in children with non-syndromic, early-onset (< 7years), and severe obesity (BMI-SDS > 3) through computational approaches. First, the mutational analyses of 41 of obesity-related genes in 126 children with non-syndromic early-onset severe obesity and 76 healthy non-obese controls were performed using the next generation sequencing (NGS) technique, and the NGS data analyzed by using bioinformatics methods. Then, the relationship between pathogenic variants and anthropometric/biochemical parameters was further evaluated. Obtained results demonstrated that the 15 genes (ADIPOQ, ADRB2, ADRB3, IRS1, LEPR, NPY, POMC, PPARG, PPARGC1A, PPARGC1B, PTPN1, SLC22A1, SLC2A4, SREBF1 and UCP1) which directly related to obesity found linked together via biological pathways and/or functions. Among these genes, IRS1, PPARGC1A, and SLC2A4 stand out as the most central ones. Furthermore, 12 of non-synonymous pathogenic variants, including six novels, were detected on ADIPOQ (G90S and D242G), ADRB2 (V87M), PPARGC1A (E680G, A477T, and R656H), UCP1 (Q44R), and IRS1 (R302Q, R301H, R301C, H250P, and H250N) genes. We propose that 12 of non-synonymous pathogenic variations detected on ADIPOQ, ADRB2, PPARGC1A, UCP1, and IRS1 genes might have a cumulative effect on the development and progression of obesity.

Molecular modelling of novel ADCY3 variantpredicts a molecular target for tackling obesity.

Severe early-onset obesity is mainly attributed to single gene variations of the hypothalamic leptin-melanocortin system, which is critical for controlling the balance between appetite and energy expenditure. Adenylate cyclase 3 (ADCY3), a transmembrane enzyme localized in primary neuronal cilia, is a key genetic candidate, which appears to have an essential role in regulating body weight. The present study aimed to identify ADCY3 genetic variants in severely obese young patients of Greek-Cypriot origin by genomic sequencing. Apart from previously reported variants, the novel and probably pathogenic variant c.349T>A, causing a p.Leu117Met substitution within one of the two pseudo-symmetric halves of the transmembrane part of the protein, was reported. Molecular modelling analysis used to delineate bonding interactions within the mutated protein structure strongly suggested a change in interactive forces and energy levels affecting the pseudo-twofold symmetry of the transmembrane domain of the protein and probably its catalytic function. These results support the involvement of ADCY3 in the pathology of the disease and point towards the requirement of defining protein function and evaluating the clinical significance of the detected variants.

Severe obesity, hypogonadotropic hypogonadism and a WDR11 gene mutation.

Abstract Congenital hypogonadotropic hypogonadism (CHH) is a rare genetic disease characterized by gonadotropin- releasing hormone (GnRH) deficiency. A number of variants were proved to be the pathogenesis gene of CHH, and a proportion of the patients of CHH were accompanied with severe early-onset obesity. We report on one adult male patient who manifested as CHH caused by WDR11 gene deletion mutation and severe obesity related to SH2B1 gene missense mutation, as well as early onset nasopharyngeal carcinoma (NPC). Our case emphasizes the importance of recognizing the heterogeneous underling diseases of the symptoms of morbid obesity and hypogonadism.

Rôle de la génétique et de l’épigénétique dans l’obésité de l’enfant et de l’adolescent

Obesity is a complex, multifactorial disease due to a dysfunction of the hypothalamic control of weight and food intake. The contribution of genetics is constant, but its impact is variable depending on the situations ranging from rare genetic obesities (around 5% of cases) to more frequently polygenic obesity (or common obesity) (95% of cases). Other factors as pre- and post-natal, societal or psychological determinants always interact closely with these genetic factors explaining the high variability of the phenotype and the complex pathophysiology. A true continuum exists between all these situations through the involvement of more or less rare genetic variants located in genes encoding key proteins in the central regulation of food intake. Rare forms of obesity are characterized by their common phenotype including a very early-onset severe obesity (BMI Z score greater than+3 SD early before the age of 3 years) with resistance to medical treatment, and major eating disorders characterized by difficulties in voluntary control of food intake. Central endocrine abnormalities such as hypogonadotropic hypogonadism or GH deficiency for example, and metabolic abnormalities due to abnormal adipose tissue distribution are also associated with variable degrees (Alström syndrome for example). Neuropsychological abnormalities are also present such as neurodevelopmental disorders (intellectual disability with variable intensity and/or adaptive development disorders which are part of many syndromes such as in Prader-Wili Syndrome; autism spectrum disorders (in SH2B1 or MYT1L deficiency for example), cognitive disorders with difficulties in emotional regulation (eg: Bardet-Biedl Syndrome or specific rare variants located on genes of the melanocortin pathway), behavioral or psychiatric disorders, sleep disorders and major hypothalamic dysfunctions (eg: Prader-Willi Syndrome, Smith Magenis syndrome). This better understanding of the mechanisms has made it possible to better precise the associated phenotypes and, recently, to lead to therapeutic innovations targeting these key genes. This evolution helps to quickly envisage the development of a real personalized medicine in early onset obesity using the combination of drug treatments targeted according to the identified genetic anomaly and/or a multidisciplinary global approach targeting the patient's phenotype or even the bariatric surgery in specific situations.

Generation of the iPSC line CUIMCi003-A derived from a patient with severe early onset obesity

Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a basic helix-loop-helix (bHLH/PAS) transcription factor involved in the development of paraventricular nucleus of the hypothalamus (PVH) through the heterodimerization with Single-minded 1 (SIM1) (Michaud et al., 2000). Using a Sendai virus-based approach, the four reprogramming factors OCT3/4, SOX2, KLF4 and C-MYC were delivered into Peripheral Blood Mononuclear Cell (PBMCs) from a 14-year-old girl with early onset obesity carrying a de novo variant (p.P130A) in ARNT2. The resulting iPSC line CUIMCi003-A had a normal karyotype, showed pluripotency and three germ layer differentiation capacity in vitro and was heterozygous for the de novo ARNT2 variant.

Implication of Heterozygous Variants in Genes of the Leptin-Melanocortin Pathway in Severe Obesity.

Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established. To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity. In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities. The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI. Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway.

A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway

Background and Objectives: Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist setmelanotide in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with setmelanotide, changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. Methods: In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist setmelanotide. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. Results: We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of setmelanotide treatment. Discussion: Setmelanotide treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.

Long-term outcomes of bariatric surgery in patients with bi-allelic mutations in the POMC, LEPR, and MC4R genes.

Gene mutations in the leptin-melanocortin signaling cascade lead to hyperphagia and severe early onset obesity. In most cases, multimodal conservative treatment (increased physical activity, reduced caloric intake) is not successful to stabilize body weight and control hyperphagia. To examine bariatric surgery as a therapeutic option for patients with genetic obesity. Three major academic, specialized medical centers. In 3 clinical centers, we retrospectively analyzed the outcomes of bariatric surgery performed in 8 patients with monogenic forms of obesity with bi-allelic variants in the genes LEPR (n = 5), POMC (n = 2), and MC4R (n = 1). In this group of patients with monogenic obesity, initial bariatric surgery was performed at a median age of 19 years (interquartile range [IQR], 16-23.8 yr). All patients initially experienced weight loss after each bariatric surgery, which was followed by substantial weight regain. In total, bariatric surgery led to a median maximum reduction of body weight of -21.5 kg (IQR, -36.3 to -2.9 kg), median percent excess weight loss (%EWL) of -47.5 %EWL (IQR, -57.6 to -28.9 %EWL). This body weight reduction was followed by median weight regain of 24.1 kg (IQR: 10.0 to 42.0 kg), leading to a final weight change of -24.2 % EWL (IQR: -37.6 to -5.4 %EWL) after a maximum duration of 19 years post surgery. In one patient, bariatric surgery was accompanied by significant complications, including vitamin deficiencies and hernia development. The indication for bariatric surgery in patients with monogenic obesity based on bi-allelic gene mutations and its benefit/risk balance has to be evaluated very cautiously by specialized centers. Furthermore, to avoid an unsuccessful operation, preoperative genetic testing of patients with a history of early onset obesity might be essential, even more since novel pharmacological treatment options are expected.

Severe Early-Onset Obesity in Three Adult Patients Harboring Inactivating Mutations of the Leptin Receptor Gene

Background: Leptin is secreted by white adipocytes in response to fat storage and binds to leptin receptors (LEPR) expressed all over the body particularly in hypothalamic neurons. This hormone regulates several physiologic functions including energy expenditure and appetite. Clinical Case: We describe the clinical and hormonal findings in 3 adult brothers with body mass index (BMI) of 36.7, 50.7, and 46.1 kg/m2, respectively. There is no history of consanguinity in the family and none of the patients exhibited dysmorphic features. A rapid weight gain was noticed during their first few months of life, associated with permanent hyperphagia. At 2 years old, their BMI was already above 25 kg/m2 (> +3SD), and at 10 years old, it was over 40 kg/m2 (> +3SD). The linear growth was within the expected target heights for their parents. They did not seem to present cognitive impairment. The pubertal development began at 16 to 18 years old, and since then they maintained levels and FSH and LH above the upper limit of normal (15.6±3.7mUI/mL and 12.3±2.2mUI/mL, reference range 1.5–12.4 and 1.7–8.6, respectively), but with normal sexual steroids (estradiol 36.4±16.1pg/mL and total testosterone 445±401ng/dL, reference range 11–44 and 249–836, respectively). The thyroid function was normal and none of the patients suffered from dyslipidemia or diabetes, despite high serum insulin levels 26.4±15.8 mU/L (normal 5–10). Genetic sequencing identified a homozygous mutation of the leptin receptor gene in the 3 brothers: c.2357T> C, p. (Leu786Pro). Their parents were heterozygous for the mutation as well as the patients’ daughters. Homozygous carriers of the mutation presented a significantly higher BMI than their heterozygous family members, 44.5±7.1 Kg/m2 vs 32.2±1.7 Kg/m2 (p=0.023), a significantly increased leptin levels, 80±36.4 ng/ml vs 26.3±9.3 ng/ml (p=0.028), and significantly higher weight, 134.6±16.9 vs 89.2±15,2 kg (p=0.021), respectively. Women had higher BMI than men (42.0 ±12.2 Kg/m2 vs 37.9±7.5 Kg/m2, p=0.496) and also higher percentage of fat (46.4±3.1% vs 34.9±6.8%, p=0.108). Serum levels of leptin in homozygous patients were not significantly higher than those measured in 10 patients with adult-onset morbid obesity, 80± 36.4 ng/ml vs 53.8±24.1 ng/ml, respectively (p=0.149). Therefore, serum leptin is not a useful discriminative maker of LEPR gene mutations. Conclusion: Patients with severe early-onset obesity should have a genetic diagnosis workup. Firstly, because clinical trials with MC4R-agonists have raised expectations regarding the treatment of patients with mutations of the LEPR gene. Secondly, and in contradiction to other reports in the literature, our patients were fertile. Therefore, identification of the mutation allows genetic counseling of these patients and their families, including the possibility of Pre-Natal Diagnosis or Pre-Implantation Genetic Diagnosis.

A novel MYT1L mutation in a boy with syndromic obesity: Case report and literature review

BackgroundPathogenic variants involving the MYT1L gene lead to an autosomal dominant form of syndromic obesity, characterized by polyphagia, intellectual disability/developmental delay, and behavioral problems, and that a characteristic facial phenotype does not seem to be recognizable. MethodsTrio whole exome sequencing was performed in a 10-year-old Brazilian male presenting polyphagia, severe early-onset obesity, intellectual disability, speech delay, macrocephaly, frontal bossing, telecanthus, strabismus, and hypogenitalism. Additionally, we performed a literature review of patients carrying non-copy number MYT1L variants. ResultsA de novo genetic variant not previously reported in MYT1L (NM_015025.4:c.2990C>A) was identified in the proband and classified as pathogenic. From a literature search, 22 further patients carrying non-copy number MYT1L variants were identified, evidencing that although the associated phenotype is quite variable, intellectual disability/developmental and speech delays are always present. Further, most patients have obesity or overweight due to polyphagia. Macrocephaly, strabismus, behavioral problems, and hand/feet malformations are also recurrent features. ConclusionsWe described the first Brazilian case of MYT1L related syndrome and highlighted clinical characteristics based on the literature. Other syndromic forms of obesity such as Prader-Willi, Bardet-Biedl, Börjeson-Forssman-Lehmann, MORM, Cohen, Alstrom, and Kleefstra type 1 syndromes should be considered in the differential diagnosis. Further, although obesity is frequent, it is not an obligatory feature of all carriers of MYT1L mutations.

Clinical Assessment and Treatment of Early-Onset Severe Obesity.

This review describes clinical management of early-onset severe obesity, defined here as severe obesity in children ≤ 5years old. It summarizes current information regarding (1) assessment, specifically growth, genetics, cardiometabolic risk, health behaviors, developmental considerations, and psychosocial factors, and (2) treatment, focusing on lifestyle modification including parent training and a brief summary of pharmacotherapy. Prevalence of severe obesity in young children has remained stable yet most of these children will become adults with obesity. Interventions that address multiple health domains, such as eating habits, physical activity, and parenting skills, are necessary for addressing early-onset severe obesity. Research into pharmacotherapy remains limited but may provide future strategies for management. Early-onset severe obesity significantly influences children's long-term health and management should focus on intervention to promote BMI reduction. Further research into effective strategies is necessary to address the needs of this high-risk population.

A novel compound heterozygous leptin receptor mutation causes more severe obesity than in Leprdb/db mice

The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-LeprL536Hfs*6-1NKB), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, LeprL536Hfs*6 develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the LeprL536Hfs*6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Leprdb/wt with LeprL536Hfs*6/wt mice results in compound heterozygous LeprL536Hfs*6/db mice, which develop even higher body weight and fat mass than both homozygous Leprdb/db and LeprL536Hfs*6 mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.

A Rare Potential Pathogenic Variant in the BDNF Gene is Found in a Brazilian Patient with Severe Childhood-Onset Obesity.

BackgroundBrain-derived neurotrophic factor (BDNF) is a pro-survival factor in the brain that also regulates energy balance. BDNF loss-of-function point mutations are responsible for haploinsufficiency, causing severe early-onset obesity. Up to date, only a few studies have sequenced this gene to search for rare mutations related to obesity. In this study, we aimed to investigate the prevalence of BDNF variants in a cohort of adults with severe obesity from Brazil.Material and MethodsThis study comprised 201 adults with severe obesity (BMI ≥ 35.0 kg/m2) with onset during childhood- or adolescence/youth. As controls, 73 subjects with normal weight (18.5 ≤ BMI ≤ 24.9 kg/m2) were selected. The exclusion criteria were pregnancy, lactation, the use of medication to lose or gain weight, and the presence of symptoms suggestive of syndromic obesity (only for the case group). The coding region of the BDNF gene was screened by Sanger sequencing. Demographic, anthropometric, and blood pressure parameters were obtained from the participants as well as serum hormone and cytokines concentrations and biochemical values.ResultsAs a result, three missense variants [p.(Thr2Ile), p.(Val66Met), and p.(Arg209Gln)] and four synonymous variants (p.Leu107=, p.Thr149=, p.Ala150=, and p.Ser213=) were identified. The p.(Arg209Gln) was predicted as pathogenic by all in silico algorithms used and was not observed in the control group. The individuals carrying the p.(Val66Met) mutated allele had higher waist circumference, HDL-cholesterol and MCP1 levels, and reduced risk of developing metabolic syndrome.ConclusionWe observed that the common BDNF p.(Val66Met) variant has influenced waist circumference, HDL-cholesterol, and MCP1 levels. This polymorphism has also a protective effect on metabolic syndrome susceptibility. Additionally, we described for the first time a rare potentially pathogenic BDNF variant in a Brazilian patient with severe obesity and childhood-onset.

Screening of MC4R, LEP, LEPR, POMC, SH2B1, and SIM1 genes in Turkish children with severe early-onset obesity

Screening of MC4R, LEP, LEPR, POMC, SH2B1, and SIM1 genes in Turkish children with severe early-onset obesity

Executive Function and BMI Trajectories Among Rural, Poor Youth at High Risk for Obesity.

The aim of this study was to identify longitudinal trajectories of conjoint development of executive function (EF) and obesity among a diverse sample of poor, rural youth and to evaluate individual differences in infant growth, parental BMI, and cumulative risk. Participants included 948 youth from the Family Life Project. Child anthropometrics were measured at 2 and 6 months and at 2, 3, 4, 5, 7, and 12 years. EF tasks were administered at 3, 4, and 5 years. Mothers reported youth birth weight, parental height and weight, and cumulative risk indicators. Multidimensional growth mixture modeling identified three classes: "High EF - High Obesity Resilience"; "Low EF - Delayed-Onset Severe Obesity"; and "Low EF - Early-Onset Severe Obesity." Youth in the low-EF, early-onset class displayed higher birth weight and BMI at 6 months, whereas the low-EF, delayed-onset class had rapid weight gain during infancy, parents with class II obesity, and greater cumulative risk and was more likely to be Black and female. Despite increased obesity risk among this sample, the majority of youth exhibited higher EF and some degree of obesity resilience. Youth with EF deficits displayed the greatest risk for severe obesity but had differing BMI trajectories and obesity risk profiles, which has implications for obesity intervention.

A Novel Loss of Function Melanocortin-4-Receptor Mutation (MC4R-F313Sfs*29) in Morbid Obesity.

Melanocortin receptor-4 (MC4R) gene mutations are associated with early-onset severe obesity, and the identification of potential pathological variants is crucial for the clinical management of patients with obesity. To explore whether and how a novel heterozygous MC4R variant (MC4R-F313Sfs*29), identified in a young boy (body mass index [BMI] 38.8 kg/m2) during a mutation analysis conducted in a cohort of patients with obesity, plays a determinant pathophysiological role in the obesity development. The genetic screening was carried out in a total of 209 unrelated patients with obesity (BMI ≥ 35 kg/m2). Structural and functional characterization of the F313Sfs*29-mutated MC4R was performed using computational approaches and in vitro, using HEK293 cells transfected with genetically encoded biosensors for cAMP and Ca2+. The F313Sfs*29 was the only variant identified. In vitro experiments showed that HEK293 cells transfected with the mutated form of MC4R did not increase intracellular cAMP or Ca2+ levels after stimulation with a specific agonist in comparison with HEK293 cells transfected with the wild type form of MC4R (∆R/R0 = -90% ± 8%; P < 0.001). In silico modeling showed that the F313Sfs*29 mutation causes a major reorganization in the cytosolic domain of MC4R, thus reducing the affinity of the putative GalphaS binding site. The newly discovered F313Sfs*29 variant of MC4R may be involved in the impairment of α-MSH-induced cAMP and Ca2+ signaling, blunting intracellular G protein-mediated signal transduction. This alteration might have led to the dysregulation of satiety signaling, resulting in hyperphagia and early onset of obesity.

Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity

BackgroundDeficiency in the leptin-leptin receptor (LEPR) axis leads to severe, and potentially treatable, obesity in humans. To guide clinical decision-making, the functional relevance of variants in the LEPR gene needs to be carefully investigated. Cases and methodsWe characterized the functional impact of LEPR variants identified in two patients with severe early-onset obesity (1: compound heterozygous for the novel variant p.Tyr411del and p.Trp664Arg; 2: heterozygous for p.Arg612His) by investigating leptin-mediated signaling, leptin binding, receptor expression on cell surfaces, and receptor dimerization and activation for either wild-type and/or mutant LEPR. ResultsLeptin-induced STAT3-phosphorylation was blunted the novel p.Tyr411del or the p.Trp664Arg variant and mildly reduced with the p.Arg612His variant. Computational structure prediction suggested impaired leptin binding for all three LEPR variants. Experimentally, reduced leptin binding of all mutant proteins was due to diminished LEPR expression on the cell surface, with the p.Trp664Arg mutations being the most affected. Considering the heterozygosity in our patients, we assessed the heterodimerization capacity with the wild-type LEPR, which was retained for the p.Tyr411del and p.Arg612His variants. Finally, mimicking (compound) heterozygosity, we confirmed abolished STAT3-phosphorylation for the variant combination [p.Tyr411del + p.Trp664Arg] as found in patient 1, whereas it was retained for [p.Arg612His + wilde type] as found in patient 2. ConclusionsThe novel p.Tyr411del mutation causes complete loss of function alone (and combined with p.Trp664Arg) and is likely the cause for the early onset obesity, qualifying the patient for pharmacologic treatment. Heterozygosity for the p.Arg612His variant, however, appears unlikely to be solely responsible for the phenotype.

Diagnostic and therapeutic odyssey of two patients with compound heterozygous leptin receptor deficiency

BackgroundRare genetic variations in the leptin-melanocortin signalling pathway can severely impair appetite regulation and cause extreme obesity in early childhood.Case presentationOur case reports describe the diagnostic and therapeutic procedures in a girl as well as in a non-related boy of non-consanguineous, German parents with severe early-onset obesity, pronounced hyperphagia, and permanent food-seeking behaviour. Excessive weight gain within the first year of life initiated extensive diagnostics without finding a causal diagnosis. Furthermore, a wide range of intensive, interdisciplinary, and behavioural therapies for weight control were unsuccessful. Prior to bariatric surgery, the 18-year-old girl and the 14-year-old boy reached a BMI of 67.7 kg/m2 and 55.2 kg/m2, respectively. However, even surgical outcomes were unsatisfactory. A subsequently initiated genetic analysis including sequencing of the leptin receptor gene revealed compound heterozygous variants as a cause of the severe early-onset obesity in both patients (c.2598-3_2607delTAGAATGAAAAAG and c.2227 T>C; c.1874G>A and c.2051A>C). Both patients were enrolled in the clinical study RM-493-015 and treated with melanocortin receptor agonist setmelanotide. Currently, they are still on setmelanotide treatment in the extension trial RM-493-022.ConclusionOur case report illustrates the urgent necessity of early genetic diagnostics in children with severe early-onset obesity to avoid frustrating and potentially damaging therapies. Thus, genetic examination should precede bariatric surgery. In the future, several pharmacological therapies will be available for some forms of monogenetic obesity.