Obesity results from a synergistic relationship between genes and the environment. The phenotypic expression of genetic factors involved in obesity is variable, allowing to distinguish several ...clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. This is mainly due to autosomal recessive mutations in genes of the leptin-melanocortin pathway which plays a key role in the hypothalamic control of food intake. Melanocortin 4 receptor(MC4R)-linked obesity is characterized by the variable severity of obesity and no notable additional phenotypes. Mutations in the MC4R gene are involved in 2-3% of obese children and adults; the majority of these are heterozygous. Syndromic obesity is associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities. Additional genes participating in the development of hypothalamus and central nervous system have been regularly identified. But to date, not all involved genes have been identified so far. New diagnostic tools, such as whole-exome sequencing, will probably help to identify other genes. Managing these patients is challenging. Indeed, specific treatments are available only for specific types of monogenic obesity, such as leptin deficiency. Data on bariatric surgery are limited and controversial. New molecules acting on the leptin-melanocortin pathway are currently being developed.
Current Treatments for Patients with Genetic Obesity Faccioli, Nathan; Poitou, Christine; Clément, Karine ...
Journal of clinical research in pediatric endocrinology,
05/2023, Letnik:
15, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Obesity derives from impaired central control of body weight, implying interaction between environment and an individual genetic predisposition. Genetic obesities, including monogenic and syndromic ...obesities, are rare and complex neuro-endocrine pathologies where the genetic contribution is predominant. Severe and early-onset obesity with eating disorders associated with frequent comorbidities make these diseases challenging. Their current estimated prevalence of 5-10% in severely obese children is probably underestimated due to the limited access to genetic diagnosis. A central alteration of hypothalamic regulation of weight implies that the leptin-melanocortin pathway is responsible for the symptoms. The management of genetic obesity has so far been only based, above all, on lifestyle intervention, especially regarding nutrition and physical activity. New therapeutic options have emerged in the last years for these patients, raising great hope to manage their complex situation and improve quality of life. Implementation of genetic diagnosis in clinical practice is thus of paramount importance to allow individualized care. This review describes the current clinical management of genetic obesity and the evidence on which it is based. Some insights will also be provided into new therapies under evaluation.
The determinants of early-onset obesity (< 6 years) are not completely elucidated, however eating behavior has a central role. To date no study has explored eating behavior in children with severe, ...early-onset obesity. Self-administered questionnaire data from these children were examined to evaluate eating behavior and the etiology of early-onset obesity.
Children with severe, early-onset obesity (body mass index BMI > International Obesity Task Force IOTF 30) of different etiologies (hypothalamic obesity HO, intellectual disability with obesity IDO, common polygenic obesity CO) were prospectively included. BMI history and responses from the Dykens' Hyperphagia Questionnaire and an in-house Impulsivity Questionnaire at first visit were compared between groups.
This cohort of 75 children (39 girls; mean age ± standard deviation SD 10.8 ± 4.4 years) had severe, early-onset obesity at an age of 3.8 ± 2.7 years, with a BMI Z-score of 4.9 ± 1.5. BMI history varied between the 3 groups, with earlier severe obesity in the HO group versus 2 other groups (BMI > IOTF40 at 3.4 ± 1.6 vs. 4.6 ± 1.6 and 8.4 ± 4.1 years for the IDO and CO groups, respectively P < 0.01). Absence of adiposity rebound was more prevalent in the HO group (87% vs. 63% and 33% for the IDO and CO groups, respectively P < 0.01). The Dykens' mean total score for the cohort was 22.1 ± 7.2 with no significant between-group differences. Hyperphagia (Dykens' score > 19) and impulsivity (score > 7) were found in 50 (67%) and 11 children (15%), respectively, with no difference between the HO, IDO and CO groups regarding the number of patients with hyperphagia (10 67%, 14 74%, and 26 63% children, respectively) or impulsivity (2 13%, 1 7%, and 8 19% children, respectively). Children with food impulsivity had significantly higher total and severity scores on the Dykens' Questionnaire versus those without impulsivity.
The Dykens' and Impulsivity questionnaires can help diagnose severe hyperphagia with/without food impulsivity in children with early-onset obesity, regardless of disease origin. Their systematic use can allow more targeted management of food access control in clinical practice and monitor the evolution of eating behavior in the case of innovative therapeutic targeting hyperphagia.
Rare 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.
Certaines formes rares de l’obésité sont liées à une altération de l’équilibre énergétique (comportements alimentaires et dépenses énergétiques) impliquant les voies hypothalamiques. Il y a plus de 60 gènes qui codent pour des protéines localisées dans la voie leptine-mélanocortine qui contribuent au développement de ces formes rares. L’ambition du Protocole Nationale de Diagnostic et de Soins (PNDS) Générique Obésité de Causes Rares est d’établir des recommandations pratiques pour l’évaluation et la prise en charge à toute âge. Le rapport est disponible sur le site web de la Haute Autorité de santé (HAS). En association à l’obésité sévère, les patients présentent souvent des comorbidités et des troubles neuropsychologiques ou psychiatriques liés à l’obésité. Ces situations complexes représentent un défi pour la prise en charge clinique. Le diagnostic précoce est essentiel pour mettre en place une prise en charge pluridisciplinaire spécialisée et bien coordonnée, où l’interaction entre les professionnels de santé, les acteurs sociaux et les familles est fondamentale. Les stratégies pour prévenir l’aggravation de l’obésité consistent à limiter l’accès à la nourriture, à créer un environnement alimentaire quotidien qui est rassurant, et à mettre en place des activités physiques supervisées, soutenues et adaptées. L’intégration du diagnostic génétique dans la pratique clinique dorénavant permet d’adopter une approche de médecine personnalisée et améliore l’analyse du rapport risque/bénéfice de la chirurgie bariatrique.
The objective was to establish new diagnostic criteria for undernutrition for the French population, concordant for children aged <18 years and adults aged <70 years, easy to use by health ...professionals and applicable whatever the situation (in and outpatients). A multi-disciplinary working and a reading group were involved. The procedure was divided into four phases: (1) systematic review and synthesis of the literature; (2) writing of the initial version of the guidelines; (3) reading and (4) finalisation. The literature search included international guidelines, meta-analyses, systematic reviews and randomised control trials from January 2007 to 31 July 2018. A two-step approach was selected: diagnosing undernutrition and then grading its severity. For diagnosis at least one phenotypic criterion associated with at least one aetiologic criterion were required for both children and adults. Phenotypic criteria for children were weight loss, Body Mass Index (BMI) < International Obesity Task Force curve 18·5, weight stagnation, reduction of muscle mass/function; for adults: weight loss, BMI < 18·5 and reduction of muscle mass/function. Aetiological criteria for children and adults were reduction in dietary intake, reduced absorption and hypercatabolism. Phenotypic metrics were used in both children and adults for grading severity (moderate or severe). These new French recommendations integrate the proposals of recent international recommendations combining aetiologic with phenotypic criteria, but for the first time, they are concordant for children and adults. The WHO threshold of 18·5 for BMI was kept as phenotypic criteria because epidemiological data show an increased mortality for that threshold.
To evaluate the intermediate-term efficacy and tolerance of statins in children and adolescents with familial hypercholesterolemia.
A total of 131 children or adolescents treated with statins for ...familial hypercholesterolemia were prospectively included. The efficacy of treatment was established by the percentage of children who achieved low density lipoprotein-cholesterol (LDL-C) levels <160 mg/dL during treatment. Treatment tolerance was evaluated by the occurrence of clinical or laboratory side effects, regularity of increases in height and weight, and pubertal development.
The median duration of treatment with statins was 4 years. A median decrease of 32% in LDL-C levels was observed (P < .0001). The therapeutic target (LDL-C <160 mg/dL) was achieved in 67% of cases. Increases in height and weight and sexual maturation were not affected by the treatment. Minor side effects were reported for 24 (18.4%) patients including 3 cases of a clinically asymptomatic increase in creatine phosphokinase (CPK) levels, 2 cases of an increase in CPK levels with muscular symptoms, 14 cases of myalgia without an increase in CPK levels, 3 cases of abdominal pain, 1 case of dysuria, and 1 case of diffuse pain. None of these side effects led to the discontinuation of statin therapy, although a change of statin was required in 7 cases. This new statin was tolerated in all cases. No patients had abnormal liver function during treatment.
The results of this large cohort confirm the intermediate-term safety and efficacy of statin therapy in children with familial hypercholesterolemia.
Renal and/or urinary manifestations (RUM) have been reported in pediatric patients with inflammatory bowel disease (IBD) but their incidence is unknown. The aims of this study were to assess the ...prevalence and causes of these manifestations in children with IBD and determine the causal link with 5-aminosalicylic acid (5-ASA) treatment.
A retrospective observational study was performed with children with diagnosis of IBD. All children with RUM during follow-up and/or impaired renal function estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m 2 were identified.
Of 228 included patients, 9 (3.9%) had a RUM during follow-up follow-up: 5 years (1-12 years) at a median age of 16 years (8-17 years). It concerned 7 of 171 patients with Crohn disease and 2 of 57 with ulcerative colitis. Seven patients were taking 5-ASA at the time of the RUM. Only 1 of them had an iatrogenic renal complication related to this treatment. Patients with RUM had a more severe disease with increased anti-tumor necrosis factor-α use ( P = 0.031), more abscesses ( P = 0.003), and a higher rate of digestive surgery ( P = 0.04). For the whole cohort, a significant decrease in eGFR was found during follow-up (121 vs 107 mL/min/1.73 m 2 , P < 0.001). At the end of follow-up, 38 of 202 (19%) patients had an eGFR < 90 mL/min/1.73 m 2 .
In children with IBD, RUM can occur, independently of treatment with 5-ASA. During follow-up, a significant decrease in eGFR was observed. We suggest monitoring renal function in all patients with IBD.
Home Parenteral Nutrition (HPN) is the cornerstone management for children suffering from chronic intestinal failure (CIF). In France, HPN is organized from a network of 7 certified centers located ...in University Hospitals spread across the national territory. This study aims to review the data involving children on HPN over a 6-years period in France to outline the global and continuous improvement in care.
This cross-sectional study included all children enrolled in any of the 7 French HPN certified centers from January 1st, 2014 to December 31st, 2019. Data was recorded from annual databases provided by each center regarding: age at inclusion, indication and duration of HPN, type of intravenous lipid emulsion (ILE), outcome PN weaning off, transfer to adult center, death, intestinal transplantation (ITx), rate of catheter-related bloodstream infections (CRSBIs) for 1000 days of HPN, Taurolidine lock procedure (TLP) use and prevalence of cholestasis defined as conjugated bilirubin ≥20 μmol/l.
The number of patients increased by 43.6% from 268 in 2014 to 385 in 2019. According to the year of follow up, the indications for HPN were short bowel syndrome (SBS) (42.3–46.6%), congenital enteropathies (CE) (18.5–22.8%), chronic intestinal pseudo-obstruction syndrome (CIPOS) (13.0–16.3%), long segment Hirschsprung's disease (LSHD) (9.7–13.3%), Crohn's disease (CD) (1.6–2.6%) and other non-primary digestive diseases (NPDD) such as immune deficiency, cancer or metabolic disease (4.0–9.2%). The median age at discharge on HPN decreased from 11.7 months in 2014 to 8.3 months in 2019 (p < .001). By December 31st, 2019, 44.8% of children had left the HPN program after a median duration ranging between 39.9 and 66.4 months. Among these patients, 192 (74.2%) were weaned off PN (94.7% SBS), 41 (15.8%) were transferred to adult centers for CIPOS (42%), SBS (31%) or CE (27%), 21 died (8.1%) – mostly in relation to cancer or immune deficiency – and 5 were transplanted (1.9%): 4 underwent combined liver-intestine transplantation for LSHD (n = 2), SBS, CE and one multivisceral Tx for CIPOS. The use of a composite fish-oil based ILE increased from 67.4% in 2014 to 88.3% in 2019 (p < 0.001). CRBSIs dropped from 1.04 CRSBIs per 1000 days HPN in 2014 to 0.61 in 2019 (p < 0.001) while meantime, the percentage of children receiving TLP increased from 29.4% to 63.0% (p < 0.001). The prevalence of cholestasis (conjugated bilirubin ≥ 20 μmol/l) was low and stable between 4.1 and 5.9% of children during the study period.
In France, the number of children enrolled in a HPN program continuously increased over a 6 years period. SBS is the leading cause of CIF requiring HPN. The rate of CRBSIs dropped dramatically as the use of TLP increased. Mortality rate was low and mainly in relation to the underlying disease (cancer, immune deficiency). Cholestasis and intestinal Tx remained very rare.
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.
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