Béatrice Dubern

Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.

Objective Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1–5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency. Methods We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants. Results In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls. Conclusions Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.

Metabolic and Adipose Tissue Signatures in Adults With Prader-Willi Syndrome: A Model of Extreme Adiposity

CONTEXTnPrader-Willi syndrome (PWS), the most frequent syndrome of obesity, is a model of early fat mass (FM) development, but scarce data exist on adipose tissue characteristics.nnnOBJECTIVEnThe objective of the study was to compare metabolic, fat distribution, and transcriptomic signatures of sc adipose tissue (scAT) in PWS adults, with matched obese adults with primary obesities.nnnMAIN OUTCOMES AND MEASURESnHormonal and metabolic assessments, systemic inflammation, and gene expression in scAT were compared between PWS patients and obese controls (OCs). Each 42nd PWS patient was matched with one randomly paired control with primary obesity. Matching factors were age, gender, fat mass (percentage), and diabetic status.nnnRESULTSnCompared with OCs, the PWS group had a decreased percentage of trunk FM and a better metabolic profile with decreased insulin and homeostasis model assessment, an index of insulin-resistance, and increased concentrations of serum adiponectin and ghrelin. Adipocyte size relative to body fat was significantly higher in PWS vs OCs. scAT in PWS patients was characterized by a transcriptomic functional signature with enrichment of themes related to immunoinflammation, the extracellular matrix, and angiogenesis. A RT-PCR targeted study revealed that candidate genes encoding proinflammatory markers and remodeling molecules, CD68, CD3e, IL-1β, chemokine (C-C motif) ligand 5, collagen type 4-α, and lysyl oxidase, were down-regulated.nnnCONCLUSIONnMatched for FM, PWS subjects have a better metabolic profile, a phenotype that could be linked to changes in scAT remodeling and promotion of adipocyte growth.

Chromosome 14q32.2 Imprinted Region Disruption as an Alternative Molecular Diagnosis of Silver-Russell Syndrome

ContextnSilver-Russell syndrome (SRS) (mainly secondary to 11p15 molecular disruption) and Temple syndrome (TS) (secondary to 14q32.2 molecular disruption) are imprinting disorders with phenotypic (prenatal and postnatal growth retardation, early feeding difficulties) and molecular overlap.nnnObjectivenTo describe the clinical overlap between SRS and TS and extensively study the molecular aspects of TS.nnnPatientsnWe retrospectively collected data on 28 patients with disruption of the 14q32.2 imprinted region, identified in our center, and performed extensive molecular analysis.nnnResultsnSeventeen (60.7%) patients showed loss of methylation of the MEG3/DLK1 intergenic differentially methylated region by epimutation. Eight (28.6%) patients had maternal uniparental disomy of chromosome 14 and three (10.7%) had a paternal deletion in 14q32.2. Most patients (72.7%) had a Netchine-Harbison SRS clinical scoring system ≥4/6, and consistent with a clinical diagnosis of SRS. The mean age at puberty onset was 7.2 years in girls and 9.6 years in boys; 37.5% had premature pubarche. The body mass index of all patients increased before pubarche and/or the onset of puberty. Multilocus analysis identified multiple methylation defects in 58.8% of patients. We identified four potentially damaging genetic variants in genes encoding proteins involved in the establishment or maintenance of DNA methylation.nnnConclusionsnMost patients with 14q32.2 disruption fulfill the criteria for a clinical diagnosis of SRS. These clinical data suggest similar management of patients with TS and SRS, with special attention to their young age at the onset of puberty and early increase of body mass index.

Combined Immunodeficiency in Patients With Trichohepatoenteric Syndrome

The syndromic diarrhea/trichohepatoenteric syndrome (SD/THE) is a rare and multi-system genetic disorder caused by mutation in SKIV2L or in TTC37, two genes encoding subunits of the putative human SKI complex involved in RNA degradation. The main features are intractable diarrhea of infancy, hair abnormalities, facial dysmorphism, and intrauterine growth restriction. Immunologically this syndrome is associated with a hypogammaglobulinemia leading to an immunoglobulin supplementation. Our immune evaluation of a large French cohort of SD/THE patient revealed several immunological defects. First, switched memory B lymphocytes count is very low. Second, IFN-γ production by T and NK cells is impaired and associated with a reduced degranulation of NK cells. Third, T cell proliferation was abnormal in 3/6 TTC37-mutated patients. These three patients present with severe EBV infection and a transient hemophagocytosis which may be related to these immunological defects. Moreover, an immunological screening of patients with clinical features of SD/THE could facilitate both diagnosis and therapeutic management of these patients.

P310: Étude du comportement alimentaire des enfants ayant un syndrome de Silver-Russell

Introduction et but de l’etude Le syndrome de Silver-Russell (SSR) est une maladie epigenetique rare caracterisee par un retard de croissance intra-uterin avec perimetre crânien relativement preserve, une petite taille post-natale associee a une dysmorphie et une asymetrie corporelle inconstante. Des difficultes alimentaires majeures sont souvent decrites pouvant necessiter le recours a une nutrition enterale prolongee. A ce jour, aucune etude n’a decrit precisement les troubles du comportement alimentaire de ces enfants. Le but de notre travail etait donc de caracteriser les differentes composantes du comportement alimentaire d’enfants ayant un SSR. Materiel et methodes Un questionnaire valide evaluant la sensibilite tactile orale, le comportement, les preferences et les habitudes alimentaires a ete complete pour 21 enfants ayant un SSR (âge moyen 6,0xa0±xa03,9 ans), 59 enfants ayant des troubles de l’oralite (TO) d’autres etiologies (âge moyen 4,9 ans ± 2,4 ans) et 101 enfants temoins sans troubles de l’oralite (STO) (âge moyen 5,2xa0±xa01,8 ans). Les reponses des SSR, TO et STO ont ete comparees par des t-tests. Resultats et Analyse statistique La sensibilite tactile orale etait significativement alteree chez les enfants SSR par rapport aux enfants STO (pxa0 Conclusion Notre travail decrit pour la premiere fois le comportement alimentaire des enfants ayant un SSR et montre qu’il est proche, mais pas identique, de celui des enfants ayant un TO d’autre cause. Ces resultats permettent donc d’adapter la prise en charge nutritionnelle des enfants SSR chez lesquels la denutrition est particulierement frequente en raison des troubles alimentaires.