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European Journal of Endocrinology Oct 2023Mutations in genes encoding proteins located in the leptin/melanocortin pathway have been identified in the rare cases of genetic obesities. Heterozygous variants of...
Mutations in genes encoding proteins located in the leptin/melanocortin pathway have been identified in the rare cases of genetic obesities. Heterozygous variants of MRAP2, encoding a G coupled-protein receptor accessory protein implicated in energy control notably via the melanocortin-4 receptor, have been recently identified. A 24-year-old patient with early-onset severe obesity (body mass index [BMI]: 64 kg/m2) associated with hypertension, respiratory complications, nonalcoholic fatty liver disease, and type 2 diabetes was referred to our department. Sleeve gastrectomy was successful. A new heterozygous variant in MRAP2 (NM_138409.4: c.154G>C/p.G52R) variant was identified in the patient DNA. Functional assessment confirmed that this new variant was pathogenic. We report a new pathogenic loss-of-function mutation in MRAP2 in a patient suffering from a severe multicomplicated obesity. This confirms the metabolic phenotype in patients with this monogenic form of obesity. Longer follow-up will be necessary. Our finding will allow a personalized medicine.
Topics: Humans; Young Adult; Adaptor Proteins, Signal Transducing; Bariatric Surgery; Carrier Proteins; Diabetes Mellitus, Type 2; Obesity; Receptor, Melanocortin, Type 4
PubMed: 37888144
DOI: 10.1093/ejendo/lvad132 -
BMC Endocrine Disorders Oct 2023New-onset diabetes in youth encompasses type 1 diabetes, type 2 diabetes, monogenic diabetes, and rarer subtypes like Type B insulin resistance syndrome and...
BACKGROUND
New-onset diabetes in youth encompasses type 1 diabetes, type 2 diabetes, monogenic diabetes, and rarer subtypes like Type B insulin resistance syndrome and ketosis-prone atypical diabetes in African populations. Some cases defy classification, posing management challenges. Here, we present a case of a unique, reversible diabetes subtype.
CASE PRESENTATION
We describe an adolescent African girl recently diagnosed with systemic lupus erythematosus. At age 15, she presented with ketoacidosis, HbA1c of 108.7 mmol/mol (12.1%), and positive anti-insulin antibodies. Initially diagnosed with type 1 diabetes, insulin was prescribed. Due to the presence of obesity and signs of insulin resistance, we added metformin. Concurrently, she received treatment for lupus with hydroxychloroquine, mycophenolate mofetil, and prednisone. After discharge, she stopped insulin due to cultural beliefs. Five months later, her glycemia and HbA1c normalized (37 mmol/mol or 5.5%) without insulin, despite corticosteroid therapy and weight gain. Autoantibodies normalized, and lupus activity decreased. Genetic testing for monogenic diabetes was negative, and the type 1 genetic risk score was exceptionally low.
CONCLUSIONS
We present a complex, reversible diabetes subtype. Features suggest an autoimmune origin, possibly influenced by overlapping HLA risk haplotypes with lupus. Lupus treatment or immunomodulation may have impacted diabetes remission. Ancestry-tailored genetic risk scores are currently designed to improve diagnostic accuracy.
Topics: Humans; Adolescent; Female; Diabetes Mellitus, Type 2; Insulin Resistance; Remission, Spontaneous; Glycated Hemoglobin; Lupus Erythematosus, Systemic; Insulin; Diabetes Mellitus, Type 1
PubMed: 37864241
DOI: 10.1186/s12902-023-01478-0 -
Journal of Clinical Research in... Oct 2023Adenylate cyclase 3 (ADCY3) gene alterations have been found to be associated with obesity. However, few patients with homozygous mutations have been reported so far,...
Adenylate cyclase 3 (ADCY3) gene alterations have been found to be associated with obesity. However, few patients with homozygous mutations have been reported so far, and the follow-up procedure and treatment options have not been clarified. A 10-month-old female presented with increased appetite and weight gain. She was born from a consanguineous marriage. Weight, height, head circumference measurements and standard deviation scores (SDS) were 19 kg (+6.98 SDS), 82 cm (+3.53 SDS), and 49 cm (+3.07 SDS), respectively. Laboratory tests revealed a fasting glucose level of 103 mg/dL (5.7 mmol/L), insulin level of 25.39 µIU/mL, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) value of 6.43. Whole-exome sequencing revealed a novel, homozygous c.1102G>A(p.Asp368Asn) variant in ADCY3. Her parents and healthy sister were heterozygous for the variant. At the age of 2.5 years, neurodevelopmental delay was observed. At the age of 3.5 years, the patient's weight, height, and body mass index values were 49.5 kg (+8.16 SDS), 111 cm (+2.59 SDS), and 40.18 kg/m2 (+6.48 SDS), respectively. Signs of Blount's disease and acanthosis nigricans were distinctive, and she had hyperphagia. She was undergoing speech therapy. Homozygous ADCY3 variants may present with early onset, severe obesity, insulin resistance, and neurodevelopmental delay in children. Severe complications may occur even at young ages. More data regarding the follow-up process and treatment of these patients are needed.
PubMed: 37855273
DOI: 10.4274/jcrpe.galenos.2023.2023-7-2 -
Obesity Science & Practice Oct 2023While obesity is common in the United States, monogenic obesity is rare, accounting for approximately 5% of individuals with obesity. New targeted therapies for genetic...
BACKGROUND
While obesity is common in the United States, monogenic obesity is rare, accounting for approximately 5% of individuals with obesity. New targeted therapies for genetic forms of obesity are available but there is limited guidance on who requires testing. The aims of this study were to evaluate the prevalence of potentially clinically significant variants among individuals in Pediatric Endocrinology or Medical Weight Center clinics at a single center and to identify clinical characteristics that may make genetic obesity more likely.
METHODS
Children and adults who had a genetic test for obesity, Uncovering Rare Obesity Gene panel, ordered during routine clinic visits from December 2019 to March 2021 were identified.
RESULTS
Of the 139 patients with testing ordered, 117 had available results and clinical data. Over 40% (52/117, 44%) had at least one positive result (variant) with a variant that is considered pathogenic, likely pathogenic, or a variant of uncertain significance. No association was detected between age, sex, race, and body mass index (BMI) or BMI -score with a variant. Twenty-six individuals (22%) had one or more variants in genes associated with Bardet Biedl Syndrome, and 8 (6.8%) of them had pathogenic variants, higher than expected.
CONCLUSION
Overall, clinical suspicion for genetic obesity is important in determining who requires genetic testing but no clinical factors were found to predict results. While obesity is multifactorial, novel medications for genetic forms of obesity indicate the need for evidence-based guidelines for who requires genetic testing for obesity.
PubMed: 37810530
DOI: 10.1002/osp4.671 -
Nature Medicine Oct 2023Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical... (Review)
Review
Precision medicine is part of the logical evolution of contemporary evidence-based medicine that seeks to reduce errors and optimize outcomes when making medical decisions and health recommendations. Diabetes affects hundreds of millions of people worldwide, many of whom will develop life-threatening complications and die prematurely. Precision medicine can potentially address this enormous problem by accounting for heterogeneity in the etiology, clinical presentation and pathogenesis of common forms of diabetes and risks of complications. This second international consensus report on precision diabetes medicine summarizes the findings from a systematic evidence review across the key pillars of precision medicine (prevention, diagnosis, treatment, prognosis) in four recognized forms of diabetes (monogenic, gestational, type 1, type 2). These reviews address key questions about the translation of precision medicine research into practice. Although not complete, owing to the vast literature on this topic, they revealed opportunities for the immediate or near-term clinical implementation of precision diabetes medicine; furthermore, we expose important gaps in knowledge, focusing on the need to obtain new clinically relevant evidence. Gaps include the need for common standards for clinical readiness, including consideration of cost-effectiveness, health equity, predictive accuracy, liability and accessibility. Key milestones are outlined for the broad clinical implementation of precision diabetes medicine.
Topics: Humans; Precision Medicine; Consensus; Diabetes Mellitus; Evidence-Based Medicine
PubMed: 37794253
DOI: 10.1038/s41591-023-02502-5 -
Frontiers in Endocrinology 2023Hypothalamic obesity (HO) is a complex and rare disorder affecting multiple regulatory pathways of energy intake and expenditure in the brain as well as the regulation... (Review)
Review
Hypothalamic obesity (HO) is a complex and rare disorder affecting multiple regulatory pathways of energy intake and expenditure in the brain as well as the regulation of the autonomic nervous system and peripheral hormonal signaling. It can be related to monogenic obesity syndromes which often affect the central leptin-melanocortin pathways or due to injury of the hypothalamus from pituitary and hypothalamic tumors, such as craniopharyngioma, surgery, trauma, or radiation to the hypothalamus. Traditional treatments of obesity, such as lifestyle intervention and specific diets, are still a therapeutic cornerstone, but often fail to result in meaningful and sustained reduction of body mass index. This review will give an update on pharmacotherapies of HO related to hypothalamic injury. Recent obesity drug developments are promising for successful obesity intervention outcomes.
Topics: Humans; Hypothalamic Diseases; Hypothalamus; Obesity; Craniopharyngioma; Brain Injuries, Traumatic; Pituitary Neoplasms
PubMed: 37780616
DOI: 10.3389/fendo.2023.1256514 -
Pediatric Endocrinology, Diabetes, and... 2023Monogenic obesity can be caused by a mutation in one of the single genes involved in hunger and satiety. The most common mutations affect melanocortin 4 (MC4) followed...
Monogenic obesity can be caused by a mutation in one of the single genes involved in hunger and satiety. The most common mutations affect melanocortin 4 (MC4) followed by the leptin gene and its receptor. Leptin receptor (LEPR) gene mutation is an extremely rare endocrine disease characterized by early-onset obesity, hyperphagia in addition to pituitary hormone deficiency, and metabolic abnormalities. We report the case of a 12-month-old male infant born of a non-consanguineous marriage. He presented to us with rapid weight gain from 2 months of age along with hyperphagia. Biochemistry revealed a deranged lipid profile, elevated transaminases, and markedly raised serum leptin levels. On genetic analysis, a novel mutation was detected, which was a homozygous variation In exon 12 of the LEPR gene (chr1:g.65608901G>A) that resulted in the synonymous amino acid change of lysine at codon 584 proximal to donor splice site (p.Lys584). The in silico prediction of the variant was 'damaging' by MutationTaster2. The mutation was classified as a 'variant of uncertain significance' due to a lack of published literature and had to be correlated carefully with the clinical symptoms. It was recommended to do Sanger sequencing of the parents and other family members. However, due to financial constraints, the family could not afford the same. At the time of writing, funds were being arranged for procuring setmelanotide, which is a novel and effective therapy for monogenic obesity due to LepR mutation.
Topics: Infant; Male; Humans; Leptin; Receptors, Leptin; Hyperphagia; Exons; Obesity
PubMed: 37728464
DOI: 10.5114/pedm.2023.129344 -
NPJ Parkinson's Disease Sep 2023The Global Parkinson's Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in...
The Global Parkinson's Genetics Program (GP2) will genotype over 150,000 participants from around the world, and integrate genetic and clinical data for use in large-scale analyses to dramatically expand our understanding of the genetic architecture of PD. This report details the workflow for cohort integration into the complex arm of GP2, and together with our outline of the monogenic hub in a companion paper, provides a generalizable blueprint for establishing large scale collaborative research consortia.
PubMed: 37699923
DOI: 10.1038/s41531-023-00533-w -
Cell Reports. Medicine Sep 2023The long-term clinical outcomes of severe obesity due to leptin signaling deficiency are unknown. We carry out a retrospective cross-sectional investigation of a large...
The long-term clinical outcomes of severe obesity due to leptin signaling deficiency are unknown. We carry out a retrospective cross-sectional investigation of a large cohort of children with leptin (LEP), LEP receptor (LEPR), or melanocortin 4 receptor (MC4R) deficiency (n = 145) to evaluate the progression of the disease. The affected individuals undergo physical, clinical, and metabolic evaluations. We report a very high mortality in children with LEP (26%) or LEPR deficiency (9%), mainly due to severe pulmonary and gastrointestinal infections. In addition, 40% of surviving children with LEP or LEPR deficiency experience life-threatening episodes of lung or gastrointestinal infections. Although precision drugs are currently available for LEP and LEPR deficiencies, as yet, they are not accessible in Pakistan. An appreciation of the severe impact of LEP or LEPR deficiency on morbidity and early mortality, educational attainment, and the attendant stigmatization should spur efforts to deliver the available life-saving drugs to these children as a matter of urgency.
Topics: Child; Humans; Cross-Sectional Studies; Leptin; Morbidity; Obesity, Morbid; Retrospective Studies
PubMed: 37659411
DOI: 10.1016/j.xcrm.2023.101187 -
Frontiers in Endocrinology 2023Over the past 50 years, the number of overweight/obese people increased significantly, making obesity a global public health challenge. Apart from rare monogenic forms,... (Review)
Review
Over the past 50 years, the number of overweight/obese people increased significantly, making obesity a global public health challenge. Apart from rare monogenic forms, obesity is a multifactorial disease, most likely resulting from a concerted interaction of genetic, epigenetic and environmental factors. Although recent studies opened new avenues in elucidating the complex genetics behind obesity, the biological mechanisms contributing to individual's risk to become obese are not yet fully understood. Non-genetic factors such as eating behaviour or physical activity are strong contributing factors for the onset of obesity. These factors may interact with genetic predispositions most likely epigenetic mechanisms. Epigenome-wide association studies or methylome-wide association studies are measuring DNA methylation at single CpGs across thousands of genes and capture associations to obesity phenotypes such as BMI. However, they only represent a snapshot in the complex biological network and cannot distinguish between causes and consequences. Intervention studies are therefore a suitable method to control for confounding factors and to avoid possible sources of bias. In particular, intervention studies documenting changes in obesity-associated epigenetic markers during lifestyle driven weight loss, make an important contribution to a better understanding of epigenetic reprogramming in obesity. To investigate the impact of lifestyle in obesity state specific DNA methylation, especially concerning the development of new strategies for prevention and individual therapy, we reviewed 19 most recent human intervention studies. In summary, this review highlights the huge potential of targeted interventions to alter disease-associated epigenetic patterns. However, there is an urgent need for further robust and larger studies to identify the specific DNA methylation biomarkers which influence obesity.
Topics: Humans; DNA Methylation; Life Style; Weight Loss; Epigenesis, Genetic; Obesity
PubMed: 37614712
DOI: 10.3389/fendo.2023.1181002