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Hormone Research in Paediatrics Feb 2024Childhood obesity is a global concern and has both nutritional and genetic causative factors. One of the most common monogenic causes of obesity is heterozygous...
INTRODUCTION
Childhood obesity is a global concern and has both nutritional and genetic causative factors. One of the most common monogenic causes of obesity is heterozygous mutations in the Melanocortin 4 receptor (MC4R), which are found in 5.7% to 8.6% of individuals with early-onset obesity. We report, the effect of Semaglutide, a long-acting Glucagon like peptide (GLP1) analogue, in the treatment of severe obesity in an adolescent boy with a heterozygous mutation in MC4R.
CASE PRESENTATION
A 13-year-old boy with a history of excessive weight gain since infancy was referred to the specialised weight management team. He was born at full-term with a birth weight of 3.57kg (50th centile), but his weight consistently exceeded the 99.6th percentile after the age of one year. At the age of five years, he was diagnosed with autism spectrum disorder (ASD). Diagnostic investigations revealed insulin resistance, and dyslipidaemia, while genetic testing confirmed a heterozygous mutation in MC4R (E61K), inherited from his mother. Managing his condition was challenging due to his rapid weight gain, needle phobia, and behavioural difficulties. Despite intense multidisciplinary lifestyle interventions, he continued to gain weight, reaching a peak weight of 187.5kg [+16.65 standard deviation score (SDS)], body mass index (BMI) of 56.9kg/m2 (+4.19 SDS), body fat 63.9%] at the age of 13 years. Due to severe ASD and needle phobia, he was not keen on daily GLP-1 injections. He was commenced on Semaglutide subcutaneous injection at a dose of 0.25mg weekly, gradually increasing to the maximum dose of 1mg weekly. Over the course of 12 weeks, his BMI decreased to 52.2kg/m2 (+4.08SDS) and weight dropped to 176.8kg (+14.76SDS, body fat: 52.7%). At the 3-month and 12-month reviews post treatment, he achieved weight loss of 5.7% and 11% respectively. Quality of life questionnaire (QoL) showed improved scores from 35.95 to 60.36 at 12-month review indicating enhanced well-being. The CGM (continuous glucose monitor) demonstrated an improvement in TIR (time in range).
CONCLUSION
Semaglutide, is approved by the FDA for weight management in adolescents aged 12 years and above in December 2022. A recent case series underscored the benefits of therapy with Liraglutide, a short-acting GLP-1 analogue, in rare genetic cases of early-onset obesity. To our knowledge, this is the first case report to highlight the efficacy and safety of Semaglutide in an adolescent with heterozygous MC4R mutation. Semaglutide could be a potential treatment option for monogenic obesity and will benefit from further research.
PubMed: 38402868
DOI: 10.1159/000537921 -
Children (Basel, Switzerland) Jan 2024Obesity is a significant health problem with a continuously increasing prevalence among children and adolescents that has become a modern pandemic during the last... (Review)
Review
Obesity is a significant health problem with a continuously increasing prevalence among children and adolescents that has become a modern pandemic during the last decades. Nowadays, the genetic contribution to obesity is well-established. For this narrative review article, we searched PubMed and Scopus databases for peer-reviewed research, review articles, and meta-analyses regarding the genetics of obesity and current pharmacological treatment, published in the English language with no time restrictions. We also screened the references of the selected articles for possible additional articles in order to include most of the key recent evidence. Our research was conducted between December 2022 and December 2023. We used the terms "obesity", "genetics", "monogenic", "syndromic", "drugs", "autosomal dominant", "autosomal recessive", "leptin-melanocortin pathway", and "children" in different combinations. Recognizing the genetic background in obesity can enhance the effectiveness of treatment. During the last years, intense research in the field of obesity treatment has increased the number of available drugs. This review analyzes the main categories of syndromic and monogenic obesity discussing current data on genetic-based pharmacological treatment of genetic obesity and highlighting the necessity that cases of genetic obesity should follow specific, pharmacological treatment based on their genetic background.
PubMed: 38397265
DOI: 10.3390/children11020153 -
Genes Jan 2024Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute... (Review)
Review
Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in , , , and triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism. Hypertriglyceridemia resulting from such genetic abnormalities can be categorized as monogenic or polygenic. Monogenic hypertriglyceridemia, also known as familial chylomicronemia syndrome, is caused by homozygous or compound heterozygous pathogenic variants in the five canonical genes. Polygenic hypertriglyceridemia, also known as multifactorial chylomicronemia syndrome in extreme cases of hypertriglyceridemia, is caused by heterozygous pathogenic genetic variants with variable penetrance affecting the canonical genes, and a set of common non-pathogenic genetic variants (polymorphisms, using the former nomenclature) with well-established association with elevated triglyceride levels. We further address recent progress in triglyceride-lowering treatments. Understanding the genetic basis of hypertriglyceridemia opens new translational opportunities in the scope of genetic screening and the development of novel therapies.
Topics: Humans; Lipoprotein Lipase; Acute Disease; Pancreatitis; Hypertriglyceridemia; Triglycerides
PubMed: 38397180
DOI: 10.3390/genes15020190 -
Diabetes, Metabolic Syndrome and... 2024The objective of this study was to clarify the phenotypic characteristics of monogenic diabetes abnormalities in Thai children with autoantibody-negative insulin.
PURPOSE
The objective of this study was to clarify the phenotypic characteristics of monogenic diabetes abnormalities in Thai children with autoantibody-negative insulin.
PATIENTS AND METHODS
Two hundred and thirty-one Thai type 1 diabetes (T1D) patients out of 300 participants with recent-onset diabetes were analyzed for GAD65 and IA2 pancreatic autoantibodies. A total of 30 individuals with T1D patients with negative autoantibody were screened for 32 monogenic diabetes genes by whole-exome sequencing (WES).
RESULTS
All participants were ten men and twenty women. The median age to onset of diabetes was 8 years and 3 months. A total of 20 people with monogenic diabetes carried genes related to monogenic diabetes. The (rs2233580) in ten patients with monogenic diabetes was found. Seven variants of (Val412Ala, Glu737Lys, Gly576Ser, Cys673Tyr, Arg456His, Lys424Glu, and Gly736fs) were investigated in patients in this study. Furthermore, the pathogenic variant, rs115099192 (Pro407Gln) in gene was found. Most patients who carried (c.575G>A, rs2233580) did not have a history of DKA. The pathogenic variant variant (c.1220C>A, rs115099192) was found in a patient with a history of DKA.
CONCLUSION
This study demonstrated significant genetic overlap between autoantibody-negative diabetes and monogenic diabetes using WES. All candidate variants were considered disease risk with clinically significant variants. WES screening was the first implemented to diagnose monogenic diabetes in Thai children, and fourteen novel variants were identified in this study and need to be investigated in the future.
PubMed: 38375489
DOI: 10.2147/DMSO.S409713 -
International Journal of Obesity (2005) Feb 2024Pediatric obesity is a highly prevalent chronic disease, which has traditionally been treated with lifestyle therapy alone. Yet for many youth, lifestyle intervention as... (Review)
Review
Pediatric obesity is a highly prevalent chronic disease, which has traditionally been treated with lifestyle therapy alone. Yet for many youth, lifestyle intervention as a monotherapy is often insufficient for achieving clinically significant and durable BMI reduction. While metabolic/bariatric surgery achieves robust and long-lasting outcomes, it is neither widely accessible nor wanted by most pediatric patients and families. In the past 3 years, this treatment gap between lifestyle therapy and metabolic/bariatric surgery has been filled with a number of landmark clinical trials examining the safety and efficacy of anti-obesity medication (AOM) for use in children and adolescents. These trials include studies of liraglutide, phentermine/topiramate ER, semaglutide, and setmelanotide, all of which have led to FDA and/or EMA approval. Concurrent with this developing evidence base, in 2023, the American Academy of Pediatrics published their first Clinical Practice Guideline on the assessment and management of childhood obesity. The Guideline includes the recommendation that pediatric health care providers should offer AOM to youth ages ≥12 years with obesity. Recognizing that AOM use in the pediatric population will likely become the standard of care and to provide perspective on the recently generated data regarding new AOM, this narrative review summarizes the published randomized controlled trials (RCTs) from the past 10 years that examine AOM for the pediatric population. This report additionally includes RCTs examining AOM for special populations of pediatric obesity including monogenic obesity, Bardet Biedl syndrome, Prader Willi syndrome, and hypothalamic obesity. Finally, the clinical application of AOM for children and adolescents, as well as future directions and challenges are discussed.
PubMed: 38321079
DOI: 10.1038/s41366-024-01465-y -
Diabetes, Obesity & Metabolism Apr 2024Bardet-Biedl syndrome (BBS) is a rare, monogenic, multisystem disorder characterized by retinal dystrophy, renal abnormalities, polydactyly, learning disabilities, as... (Review)
Review
Bardet-Biedl syndrome (BBS) is a rare, monogenic, multisystem disorder characterized by retinal dystrophy, renal abnormalities, polydactyly, learning disabilities, as well as metabolic dysfunction, including obesity and an increased risk of type 2 diabetes. It is a primary ciliopathy, and causative mutations in more than 25 different genes have been described. Multiple cellular mechanisms contribute to the development of the metabolic phenotype associated with BBS, including hyperphagia as a consequence of altered hypothalamic appetite signalling as well as alterations in adipocyte biology promoting adipocyte proliferation and adipogenesis. Within this review, we describe in detail the metabolic phenotype associated with BBS and discuss the mechanisms that drive its evolution. In addition, we review current approaches to the metabolic management of patients with BBS, including the use of weight loss medications and bariatric surgery. Finally, we evaluate the potential of targeting hypothalamic appetite signalling to limit hyperphagia and induce clinically significant weight loss.
Topics: Humans; Bardet-Biedl Syndrome; Diabetes Mellitus, Type 2; Kidney; Hyperphagia; Weight Loss
PubMed: 38302651
DOI: 10.1111/dom.15480 -
International Journal of Obesity (2005) Jun 2024The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when...
BACKGROUND/OBJECTIVE
The genetic architecture of extreme non-syndromic obesity in adults remains to be elucidated. A range of genes are known to cause monogenic obesity, but even when pathogenic mutations are present, there may be variable penetrance.
METHODS
Whole-exome sequencing (WES) was carried out on a 15-year-old male proband of Pakistani ancestry who had severe obesity. This was followed by family segregation analysis, using Sanger sequencing. We also undertook re-analysis of WES data from 91 unrelated adults with severe obesity (86% white European ancestry) from the Personalised Medicine for Morbid Obesity (PMMO) cohort, recruited from the UK National Health Service.
RESULTS
We identified an oligogenic mode of inheritance of obesity in the proband's family-this provided the impetus to reanalyze existing sequence data in a separate dataset. Analysis of PMMO participant data revealed two further patients who carried more than one rare, predicted-deleterious mutation in a known monogenic obesity gene. In all three cases, the genes involved had known autosomal dominant inheritance, with incomplete penetrance.
CONCLUSION
Oligogenic inheritance may explain some of the variable penetrance in Mendelian forms of obesity. We caution clinicians and researchers to avoid confining sequence analysis to individual genes and, in particular, not to stop looking when the first potentially-causative mutation is found.
Topics: Humans; Male; Adolescent; Obesity, Morbid; Adult; Exome Sequencing; Pedigree; Female; Genetic Predisposition to Disease; Mutation; Penetrance; United Kingdom; Pakistan; Multifactorial Inheritance
PubMed: 38297031
DOI: 10.1038/s41366-024-01476-9 -
Nature Metabolism Feb 2024The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily, producing a growing public health concern that disproportionately...
The prevalence of youth-onset type 2 diabetes (T2D) and childhood obesity has been rising steadily, producing a growing public health concern that disproportionately affects minority groups. The genetic basis of youth-onset T2D and its relationship to other forms of diabetes are unclear. Here we report a detailed genetic characterization of youth-onset T2D by analysing exome sequences and common variant associations for 3,005 individuals with youth-onset T2D and 9,777 adult control participants matched for ancestry, including both males and females. We identify monogenic diabetes variants in 2.4% of individuals and three exome-wide significant (P < 2.6 × 10) gene-level associations (HNF1A, MC4R, ATXN2L). Furthermore, we report rare variant association enrichments within 25 gene sets related to obesity, monogenic diabetes and β-cell function. Many youth-onset T2D associations are shared with adult-onset T2D, but genetic risk factors of all frequencies-and rare variants in particular-are enriched within youth-onset T2D cases (5.0-fold increase in the rare variant and 3.4-fold increase in common variant genetic liability relative to adult-onset cases). The clinical presentation of participants with youth-onset T2D is influenced in part by the frequency of genetic risk factors within each individual. These findings portray youth-onset T2D as a heterogeneous disease situated on a spectrum between monogenic diabetes and adult-onset T2D.
Topics: Male; Adult; Female; Humans; Adolescent; Child; Diabetes Mellitus, Type 2; Pediatric Obesity; Exome; Genome-Wide Association Study; Biology
PubMed: 38278947
DOI: 10.1038/s42255-023-00970-0 -
European Journal of Pediatrics Apr 2024The prevalence of obesity in children and adolescents is increasing, and it is recognised as a complex disorder that often begins in early childhood and persists... (Review)
Review
The prevalence of obesity in children and adolescents is increasing, and it is recognised as a complex disorder that often begins in early childhood and persists throughout life. Both polygenic and monogenic obesity are influenced by a combination of genetic predisposition and environmental factors. Rare genetic obesity forms are caused by specific pathogenic variants in single genes that have a significant impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway. Genetic testing is recommended for patients who exhibit rapid weight gain in infancy and show additional clinical features suggestive of monogenic obesity as an early identification allows for appropriate treatment, preventing the development of obesity-related complications, avoiding the failure of traditional treatment approaches. In the past, the primary recommendations for managing obesity in children and teenagers have been focused on making multiple lifestyle changes that address diet, physical activity, and behaviour, with the goal of maintaining these changes long-term. However, achieving substantial and lasting weight loss and improvements in body mass index (BMI) through lifestyle interventions alone is rare. Recently the progress made in genetic analysis has paved the way for innovative pharmacological treatments for different forms of genetic obesity. By understanding the molecular pathways that contribute to the development of obesity, it is now feasible to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms. Conclusion: However, additional preclinical research and studies in the paediatric population are required, both to develop more personalised prevention and therapeutic programs, particularly for the early implementation of innovative and beneficial management options, and to enable the translation of these novel therapy approaches into clinical practice. What is Known: • The prevalence of obesity in the paediatric population is increasing, and it is considered as a multifaceted condition that often begins in early childhood and persists in the adult life. Particularly, rare genetic forms of obesity are influenced by a combination of genetic predisposition and environmental factors and are caused by specific pathogenic variants in single genes showing a remarkable impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway. • Patients who present with rapid weight gain in infancy and show additional clinical characteristics indicative of monogenic obesity should undergo genetic testing, which, by enabling a correct diagnosis, can prevent the development of obesity-related consequences through the identification for appropriate treatment. What is New: • In recent years, advances made in genetic analysis has made it possible to develop innovative pharmacological treatments for various forms of genetic obesity. In fact, it is now achievable to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms by understanding the molecular pathways involved in the development of obesity. • As demonstrated over the last years, two drugs, setmelanotide and metreleptin, have been identified as potentially effective interventions in the treatment of certain rare forms of monogenic obesity caused by loss-of-function mutations in genes involved in the leptin-melanocortin pathway. Recent advancements have led to the development of novel treatments, including liraglutide, semaglutide and retatrutide, that have the potential to prevent the progression of metabolic abnormalities and improve the prognosis of individuals with these rare and severe forms of obesity. However, extensive preclinical research and, specifically, additional studies in the paediatric population are necessary to facilitate the translation of these innovative treatment techniques into clinical practice.
Topics: Child; Adult; Adolescent; Humans; Child, Preschool; Pediatric Obesity; Leptin; Genetic Predisposition to Disease; alpha-MSH; Weight Gain
PubMed: 38227053
DOI: 10.1007/s00431-024-05427-4