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[The genetics of obesity - pathogenetic, clinical and diagnostic aspects].

ABSTRACT: Due to its prevalence and its health-related, economic and social consequences, childhood and adult obesity is a complex, medical and civilizational problem, which has been on the increase in the last decade. The results of multi-center investigations reveal that genetic factors play an essential role in the etiopathogenesis of obesity, particularly in the case of extreme cases with very early onset. The Body Mass Index (BMI) is one of the most frequently used indicators of obesity and shows a strong genetic component with a 40-70% degree of heritability. The three types of genetically conditioned obesity are: (1) isolated (nonsyndromic) monogenic obesity, (2) syndromic monogenic obesity associated with dysmorphic features and/or congenital defects, caused by mutations in specific gene(s), (3) chromosomal aberrations, including submicroscopic changes. The most prevalent common (complex) obesity is linked to the presence of various changes in different genomic loci, which are subject to interactions and modifications by environmental (ethnic, dietary, lifestyle, bacterial flora, oxidative stress), as well as epigenetic (i.e., associated with DNA methylation, histone modification) and epistatic (gene-gene interaction) factors. Recent investigations using the modern methods of genome-wide association studies (GWAS), bioinformatics and proteomics, have made it possible to elucidate 8 key genes among the 97 genes most likely to play significant roles in the metabolic effects of obesity. The results of investigations on the pathogenesis of complex obesity do not as yet clarify the potential pathogenic significance of these genomic changes in humans. This article discusses the neuro-endocrinological regulation of the sensation of hunger and thirst, the clinical consequences of mutations in genes associated with the melanocortin pathway, and the features of the most common obesity syndromes, including syndromes conditioned by genomic imprinting. A diagnostic algorithm for cases of suspected syndromic obesity is proposed.

SUBMITTER: Barczyk A

PROVIDER: S-EPMC8522950 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Primary ciliary dyskinesia (PCD) is an orphan disease (MIM 244400), autosomal recessive inherited, characterized by motile ciliary dysfunction. The estimated prevalence of PCD is 1:10,000 to 1:20,000 live-born children, but true prevalence could be even higher. PCD is characterized by chronic upper and lower respiratory tract disease, infertility/ectopic pregnancy, and situs anomalies, that occur in ≈50% of PCD patients (Kartagener syndrome), and these may be associated with congenital heart abnormalities. Most patients report a daily year-round wet cough or nose congestion starting in the first year of life. Daily wet cough, associated with recurrent infections exacerbations, results in the development of chronic suppurative lung disease, with localized-to-diffuse bronchiectasis. No diagnostic test is perfect for confirming PCD. Diagnosis can be challenging and relies on a combination of clinical data, nasal nitric oxide levels plus cilia ultrastructure and function analysis. Adjunctive tests include genetic analysis and repeated tests in ciliary culture specimens. There are currently 33 known genes associated with PCD and correlations between genotype and ultrastructural defects have been increasingly demonstrated. Comprehensive genetic testing may hopefully screen young infants before symptoms occur, thus improving survival. Recent surprising advances in PCD genetic designed a novel approach called "gene editing" to restore gene function and normalize ciliary motility, opening up new avenues for treating PCD. Currently, there are no data from randomized clinical trials to support any specific treatment, thus, management strategies are usually extrapolated from cystic fibrosis. The goal of treatment is to prevent exacerbations, slowing the progression of lung disease. The therapeutic mainstay includes airway clearance maneuvers mainly with nebulized hypertonic saline and chest physiotherapy, and prompt and aggressive administration of antibiotics. Standardized care at specialized centers using a multidisciplinary approach that imposes surveillance of lung function and of airway biofilm composition likely improves patients' outcome. Pediatricians, neonatologists, pulmonologists, and ENT surgeons should maintain high awareness of PCD and refer patients to the specialized center before sustained irreversible lung damage develops. The recent creation of a network of PCD clinical centers, focusing on improving diagnosis and treatment, will hopefully help to improve care and knowledge of PCD patients.

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[The genetics of obesity - pathogenetic, clinical and diagnostic aspects].

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