Rare genetic causes of obesity: Diagnosis and management in clinical care

International audienceRare genetic forms of obesity are linked to impaired energy balance (i.e., eating behaviour and energy expenditure) involving hypothalamic pathways. More than 60 genes coding for proteins located in the hypothalamic leptin/melanocortin pathway contribute to the development of these rare forms of obesity. The ambition of the French National Protocol for the Diagnosis and Care (PNDS) of Obesity of Rare Causes was to establish practical recommendations for assessment and management at all ages. This report is available on the website of the French Health Authority (HAS). In addition to severe obesity, patients often display obesity-related comorbidities and neuropsychological/psychiatric disorders. These complex conditions make clinical management particularly challenging. Early diagnosis is critical for the organization of coordinated specialized multidisciplinary care, with mandatory interaction between caregivers, social partners and families. Strategies to prevent aggravation of obesity consist in limiting access to food, establishing a reassuring daily eating environment, and the practice of sustained adapted supervised daily physical activity. The implementation of genetic diagnosis in clinical practice now enables a personalized medicine approach with access to new drug therapies, and improves the analysis of the risk/benefit ratio of bariatric surgery

Récepteur MC4R : actualités de la recherche dans l’obésité et potentiels développements thérapeutiques

International audienceLe récepteur aux mélanocortines de type 4 (MC4R) a un rôle central dans la voie leptine/mélanocortines et dans la régulation de l’homéostasie énergétique. Les mutations hétérozygotes du gène MC4R sont la cause la plus fréquente d’obésité sévère et précoce. Néanmoins, aucun élément phénotypique spécifique ne différencie les patients adultes porteurs de variants de MC4R de ceux ayant une obésité d’origine polygénique. Leur prise en charge reste multidisciplinaire et précoce, intégrant les mêmes traitements conventionnels médicaux et éventuellement chirurgicaux ; ces derniers ayant des résultats variables selon le type de variant génétique. De nouvelles stratégies thérapeutiques se développent avec des molécules comme les agonistes du récepteur au glucagon-like peptide-1 (GLP1) ou avec de nouvelles molécules plus ciblées comme les agonistes pharmacologiques de MC4R afin de restaurer l’activité des variants pathogènes

Physical Activity in Patients with Prader-Willi Syndrome—A Systematic Review of Observational and Interventional Studies

International audiencePhysical activity (PA) is an important aspect of the management of patients with Prader-Willi syndrome (PWS). However, the day-to-day implementation of PA programs is particularly challenging in these patients. This systematic review aimed (1) to describe habitual PA and sedentary behavior and (2) to assess the effects of PA interventions and to describe their implementation process, in children and adults with PWS. A systematic search of controlled trials, single-group interventions, observational, and qualitative studies published up to December 2020 was performed. Twenty-five studies were included. Habitual PA was found to be lower in patients with PWS compared to controls without obesity or with non-syndromic obesity. Habitual PA was positively associated with lean body mass and bone parameters in children with PWS, and these finding were strengthened by intervention studies reporting an increase in both outcomes after a PA program. PA programs also improved physical function (muscle strength, walking distance, and coordination), without significant effect on weight and fat mass. Attendance to exercise sessions was usually high and no serious adverse effect was reported. In conclusion, supervised PA programs are beneficial for children and adults with PWS. Support should be provided to families to facilitate their implementation in real-life setting

Diabetes Mellitus in Prader-Willi Syndrome: Natural History during the Transition from Childhood to Adulthood in a Cohort of 39 Patients

International audienceType 2 diabetes mellitus (T2DM) affects 20% of patients with Prader-Willi syndrome (PWS), with many cases diagnosed during the transition period. Our aim was to describe the natural history of T2DM in patients with PWS before the age of 25 years and to develop screening and preventive strategies. Thirty-nine patients followed in the French PWS Reference Center were included (median age 25.6 years [23.7; 31.7]). Twenty-one had been treated with growth hormone (GH), fifteen had not, and three had an unknown status. The median age at T2DM diagnosis was 16.8 years (11–24) and the median BMI was 39 kg/m2 [34.6; 45], with 34/35 patients living with obesity. The patients displayed frequent psychiatric (48.3% hospitalization,) and metabolic (56.4% hypertriglyceridemia,) comorbidities and a parental history of T2DM (35.7%) or overweight (53.6%) compared to the PWS general population. There was no difference in BMI and metabolic complications between the GH-treated and non-GH-treated groups at T2DM diagnosis. Patients with PWS who develop early T2DM have severe obesity, a high frequency of psychiatric and metabolic disorders, and a family history of T2DM and overweight. These results underline the need for early identification of patients at risk, prevention of obesity, and repeated blood glucose monitoring during the transition period

Diagnostic et parcours de soin chez les patients avec lipodystrophies et syndromes rares d'insulino-résistance: point d'étape à partir d'un centre de référence National

International audienceBACKGROUND:Rare syndromes of lipodystrophy and insulin-resistance display heterogeneous clinical expressions. Their early recognition, diagnosis and management are required to avoid long-term complications. OBJECTIVE:We aimed to evaluate the patients’ age at referral to our dedicated national reference center in France and their elapsed time from first symptoms to diagnosis and access to specialized care. PATIENTS AND METHODS:We analyzed data from patients with rare lipodystrophy and insulin-resistance syndromes referred to the coordinating PRISIS reference center (Adult Endocrine Department, Saint-Antoine Hospital, AP-HP, Paris), prospectively recorded between 2018 and 2023 in the French National Rare Disease Database (BNDMR, Banque Nationale de Données Maladies Rares ). RESULTS:A cohort of 292 patients was analyzed, including 208 women, with the following diagnosis: Familial Partial LipoDystrophy (FPLD, n = 124, including n = 67 FPLD2/Dunnigan Syndrome); Acquired lipodystrophy syndromes ( n = 98, with n = 13 Acquired Generalized Lipodystrophy, AGL); Symmetric cervical adenolipomatosis (n = 27, Launois-Bensaude syndrome, LB), Congenital generalized lipodystrophy (n = 18, CGL) and other rare severe insulin-resistance syndromes (n = 25). The median age at referral was 47.6 years [IQR: 31–60], ranging from 25.2 (CGL) to 62.2 years old (LB). The median age at first symptoms of 27.6 years old [IQR: 16.8–42.0]) and the median diagnostic delay of 6.4 years [IQR: 1.3–19.5] varied among diagnostic groups. The gender-specific expression of lipodystrophy is well-illustrated in the FPLD2 group (91% of women), presenting with first signs at 19.3 years [IQR: 14.4–27.8] with a diagnostic delay of 10.5 years [IQR: 1.8–27.0].CONCLUSION:The national rare disease database provides an important tool for assessment of care pathways in patients with lipodystrophy and rare insulin-resistance syndromes in France. Improving knowledge to reduce diagnostic delay is an important objective of the PRISIS reference center.CONTEXTE :Les syndromes rares de lipodystrophies et de résistance à l'insuline présentent des expressions cliniques hétérogènes. Leur reconnaissance, leur diagnostic et leur prise en charge précoces sont nécessaires pour éviter les complications à long terme. OBJECTIF :Nous avons cherché à évaluer l'âge des patients au moment où ils sont adressés dans notre centre national de référence en France et le temps écoulé entre les premiers symptômes et le diagnostic et l'accès à des soins spécialisés. PATIENTS et METHODES :Nous avons analysé les données des patients atteints de syndromes rares de lipodystrophie et d'insulino-résistance adressés au centre de référence PRISIS coordonnateur (service d'endocrinologie adulte, hôpital Saint-Antoine, AP-HP, Paris), enregistrés prospectivement entre 2018 et 2023 dans la Banque Nationale de Données Maladies Rares (BNDMR). RÉSULTATS :Une cohorte de 292 patients a été analysée, dont 208 femmes, avec les diagnostics suivants : LipoDystrophie partielle familiale (FPLD, n = 124, dont n = 67 FPLD2/syndrome de Dunnigan) ; syndromes de lipodystrophie acquise (n = 98, dont n = 13 lipodystrophie généralisée acquise, AGL) ; Adénolipomatose cervicale symétrique (n = 27, syndrome de Launois-Bensaude, LB), lipodystrophie congénitale généralisée (n = 18, CGL) et autres syndromes rares de résistance sévère à l'insuline (n = 25). L'âge médian au moment de la consultation était de 47,6 ans [IQR : 31-60], allant de 25,2 ans (CGL) à 62,2 ans (LB). L'âge médian des premiers symptômes (27,6 ans [IQR : 16,8-42,0]) et le délai médian de diagnostic (6,4 ans [IQR : 1,3-19,5]) varient d'un groupe de diagnostic à l'autre. L'expression sexe-spécifique de la lipodystrophie est bien illustrée dans le groupe FPLD2 (91% de femmes), présentant les premiers signes à 19,3 ans [IQR : 14,4-27,8] avec un retard diagnostic de 10,5 ans [IQR : 1,8-27,0].CONCLUSION :La base de données nationale sur les maladies rares constitue un outil important pour l'évaluation des parcours de soins des patients atteints de lipodystrophies et de syndromes rares de résistance à l'insuline en France. L'amélioration des connaissances pour réduire le retard diagnostique est un objectif important du centre de référence PRISIS

Molecular and Cellular Bases of Lipodystrophy Syndromes

International audienceLipodystrophy syndromes are rare diseases originating from a generalized or partial loss of adipose tissue. Adipose tissue dysfunction results from heterogeneous genetic or acquired causes, but leads to similar metabolic complications with insulin resistance, diabetes, hypertriglyceridemia, nonalcoholic fatty liver disease, dysfunctions of the gonadotropic axis and endocrine defects of adipose tissue with leptin and adiponectin deficiency. Diagnosis, based on clinical and metabolic investigations, and on genetic analyses, is of major importance to adapt medical care and genetic counseling. Molecular and cellular bases of these syndromes involve, among others, altered adipocyte differentiation, structure and/or regulation of the adipocyte lipid droplet, and/or premature cellular senescence. Lipodystrophy syndromes frequently present as systemic diseases with multi-tissue involvement. After an update on the main molecular bases and clinical forms of lipodystrophy, we will focus on topics that have recently emerged in the field. We will discuss the links between lipodystrophy and premature ageing and/or immuno-inflammatory aggressions of adipose tissue, as well as the relationships between lipomatosis and lipodystrophy. Finally, the indications of substitutive therapy with metreleptin, an analog of leptin, which is approved in Europe and USA, will be discussed

Mucosal-associated invariant T (MAIT) cells are depleted and prone to apoptosis in cardiometabolic disorders

International audienceThe disruption of systemic immune homeostasis is a key mediator in the progression of cardiometabolic diseases (CMDs). We aimed to extend knowledge regarding the clinical relevance of CMD-associated variation of circulating mucosal-associated invariant T (MAIT) cell abundance and to explore underlying cellular mechanisms. We analyzed cross-sectional data from 439 participants of the Metagenomics in Cardiometabolic Diseases (MetaCardis) study, stratified into 6 groups: healthy control subjects and patients with metabolic syndrome (MS), obesity, type 2 diabetes mellitus (T2DM), and coronary artery disease (CAD) without, or with congestive heart failure (CAD-CHF). Blood MAIT cell frequency was significantly decreased in all CMD groups, including early (MS) and later (CAD and CAD-CHF) stages of disease progression. Reduced MAIT cell abundance was associated with increased glycosylated hemoglobin, inflammation markers, and deterioration of cardiac function. Glucose dose dependently promoted MAIT cell apoptosis in vitro, independently of anti-CD3 and cytokine-mediated activation. This outcome suggests the prominence of metabolic over an antigenic or cytokine-rich environment to promote MAIT cell reduction in patients with CMD. In summary, all stages of CMDs are characterized by reduced circulating MAIT cells. Chronically elevated blood glucose levels could contribute to this decline. These data extend the pathologic relevance of MAIT cell loss and suggest that MAIT cell abundance may serve as an indicator of cardiometabolic health.-Touch, S

Paradoxical low severity of COVID-19 in Prader-Willi syndrome: data from a French survey on 647 patients

International audienceBackground: Patients with Prader-Willi syndrome (PWS) often have comorbidities, especially obesity, that may constitute a risk factor for severe forms of COVID-19. We aimed to assess prevalence and medical course of SARS-CoV-2 infection in children and adults with PWS. From November 2020 to January 2021, we performed a detailed medical survey on 342 adults and 305 children with PWS followed in the French reference center.Results: We obtained responses from 288 adults (84%) and 239 children (78%). From March 2020 to January 2021, 38 adults (13.2%) and 13 children (5.4%) with PWS had SARS-CoV-2 infection. Mean age of adults was 34.1 ± 11.9 years and mean body mass index was 40.6 ± 12.7 kg/m2; 82% had obesity and 37% had diabetes. Only 3 children (23%) had obesity and none had diabetes. Similar to the general population, the most frequent symptoms of COVID-19 were asthenia, fever, cough, headache and shortness of breath. All patients had a favorable outcome.Conclusion: PWS itself is not a risk factor for severe COVID-19 in children and adults. On the contrary, evolution of SARS-CoV-2 infection in adults with PWS seems more favorable than expected, given their comorbidities

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

International audienceVariants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects. A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing. View Full-Tex

MFN2-associated lipomatosis: Clinical spectrum and impact on adipose tissue

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