Monogenic obesity in children in Slovakia
Authors:
D. Staníková 1,2; M. Sůrová 1; Ľ. Tichá 2; D. Lobotková 2; D. Gabčová 1; M. Škopková 1; I. Klimeš 1; J. Staník 1,2; D. Gašperíková 1
Authors‘ workplace:
DIABGENE a Laboratórium diabetu a porúch metabolizmu, Ústav experimentálnej endokrinológie
Biomedicínske centrum SAV, Bratislava
1; Detská klinika LFUK a DFNsP, Bratislava
2
Published in:
Čes-slov Pediat 2017; 72 (5): 293-300.
Category:
Original Papers
Overview
Background:
Monogenic obesity is caused by a mutation in on of the genes regulating leptin-melanocortin pathway, which is playing a key role by maintaining energetic homeostasis of organism, mainly inducing a feeling of satiety.
Aim:
The aim of this work is to conclude results of DNA analysis of monogenic obesity in laboratorium DIABGENE in years 2009–2015. This work is focused on etiology and epidemiology of the most frequent types of monogenic obesity in children.
Patients and methods:
DNA analysis of varios genes was performed together in 565 patients with a clinical suspicion of monogenic obesity to date. The suggested most frequent type of monogenic obesity (due to a mutation in melanocortin receptor 4 gene – MC4R) was analysed in 268 patients with obesity onset up to 11. years, without other specific clinical signs. In patients with more specific clinical signs (endocrinopathies, infections, decreased growth, red hair, hypocorticism and other) was performed DNA analysis of other genes (SIM1, LEP, LEPR, POMC) causing monogenic obesity.
Results:
We have found 2 probands (0.7%) with a MC4R mutation in our study. One mutation was found in SIM1 gene and no mutations in LEP, LEPR and POMC gene to date, reffering Slovakia to European countries with probably the lowest prevalence of monogenic obesity.
Conclusion:
Monogenic obesity is a rare cause of childhood obesity in Slovakia, however searching and diagnosing of these patients is very important, because of the need of specific management as well as real possibility of causal treatment today or in the future.
Key words:
monogenic obesity, MC4R, children, Slovak republik
Sources
1. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of childhood and adult obesity in the United States, 2011–2012. JAMA 2014; 311 (8): 806–814.
2. Ahrens W, Pigeot I, Pohlabeln H, et al. Prevalence of overweight and obesity in European children below the age of 10. Int J Obes (Lond) 2014; 38 (Suppl 2): S99–107.
3. Volkovova K, Chorvathova V, Jurcovicova M, et al. Antioxidative state of the myocardium and kidneys in acute diabetic rats. Physiol Res 1993; 42 (4): 251–255.
4. Freedman DS, Khan LK, Serdula MK, et al. The relation of childhood BMI to adult adiposity: the Bogalusa Heart Study. Pediatrics 2005; 115 (1): 22–27.
5. Farooqi S. Obesity genes-it‘s all about the parents! Cell Metab 2009; 9 (6): 487–488.
6. Skytthe A, Kyvik K, Holm NV, et al. The Danish Twin Registry: 127 birth cohorts of twins. Twin Res 2002; 5 (5): 352–357.
7. Stunkard AJ, Sorensen TI, Hanis C, et al. An adoption study of human obesity. N Engl J Med 1986; 314 (4): 193–198.
8. Farooqi IS, O‘Rahilly S. New advances in the genetics of early onset obesity. Int J Obes (Lond) 2005; 29 (10): 1149–1152.
9. Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and human adiposity. Behav Genet 1997; 27 (4): 325–351.
10. Meyre D, Lecoeur C, Delplanque J, et al. A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. Diabetes 2004; 53 (3): 803–811.
11. Boissel S, Reish O, Proulx K, et al. Loss-of-function mutation in the dioxygenase-encoding FTO gene causes severe growth retardation and multiple malformations. Am J Hum Genet 2009; 85 (1): 106–111.
12. Dina C, Meyre D, Gallina S, et al. Variation in FTO contributes to child-hood obesity and severe adult obesity. Nat Genet 2007; 39 (6): 724–726.
13. O‘Rahilly S, Farooqi IS. Genetics of obesity. Philos Trans R Soc Lond B Biol Sci 2006; 361 (1471): 1095–1105.
14. Ramachandrappa S, Raimondo A, Cali AM, et al. Rare variants in single-minded 1 (SIM1) are associated with severe obesity. J Clin Invest 2013; 123 (7): 3042–3050.
15. Farooqi IS, O‘Rahilly S. Monogenic obesity in humans. Annu Rev Med 2005; 56: 443–458.
16. Ranadive SA, Vaisse C. Lessons from extreme human obesity: monogenic disorders. Endocrinol Metab Clin North Am 2008; 37 (3): 733–751.
17. Montague CT, Farooqi IS, Whitehead JP, et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 1997; 387 (6636): 903–908.
18. Wabitsch M, Funcke JB, Lennerz B, et al. Biologically inactive leptin and early-onset extreme obesity. N Engl J Med 2015; 372 (1): 48–54.
19. Wabitsch M, Funcke JB, von Schnurbein J, et al. Severe early-onset obesity due to bioinactive leptin caused by a p.N103K mutation in the leptin gene. J Clin Endocrinol Metab 2015; 100 (9): 3227–3230.
20. Dubern B, Clement K. Leptin and leptin receptor-related monogenic obesity. Biochimie 2012; 94 (10): 2111–2115.
21. Farooqi IS, Wangensteen T, Collins S, et al. Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor. N Engl J Med 2007; 356 (3): 237–247.
22. Kuhnen P, Clement K, Wiegand S, et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med 2016; 375 (3): 240–246.
23. Gray J, Yeo GS, Cox JJ, et al. Hyperphagia, severe obesity, impaired cognitive function, and hyperactivity associated with functional loss of one copy of the brain-derived neurotrophic factor (BDNF) gene. Diabetes 2006; 55 (12): 3366–3671.
24. Farooqi IS, Keogh JM, Yeo GS, et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003; 348 (12): 1085–1095.
25. Hainerova I, Larsen LH, Holst B, et al. Melanocortin 4 receptor mutations in obese Czech children: studies of prevalence, phenotype development, weight reduction response, and functional analysis. J Clin Endocrinol Metab 2007; 92 (9): 3689–3696.
26. Tao YX. The melanocortin-4 receptor: physiology, pharmacology, and pathophysiology. Endocr Rev 2010; 31 (4): 506–543.
27. Fani L, Bak S, Delhanty P, et al. The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options. Int J Obes (Lond) 2014; 38 (2): 163–169.
28. Hainerova IA, Lebl J. Treatment options for children with monogenic forms of obesity. World Rev Nutr Diet 2013; 106: 105–112.
29. Bonnefond A, Raimondo A, Stutzmann F, et al. Loss-of-function mutations in SIM1 contribute to obesity and Prader-Willi-like features. J Clin Invest 2013; 123 (7): 3037–3041.
30. Montagne L, Raimondo A, Delobel B, et al. Identification of two novel loss-of-function SIM1 mutations in two overweight children with developmental delay. Obesity (Silver Spring) 2014; 22 (12): 2621–2624.
31. Huvenne H, Dubern B, Clement K, et al. Rare genetic forms of obesity: Clinical approach and current treatments in 2016. Obes Facts 2016; 9 (3): 158–173.
32. Stanikova D, Surova M, Ticha L, et al. Melanocortin-4 receptor gene mutations in obese Slovak children. Physiol Res 2015; 64 (6): 883–890.
33. Hinney A, Schmidt A, Nottebom K, et al. Several mutations in the melanocortin-4 receptor gene including a nonsense and a frameshift mutation associated with dominantly inherited obesity in humans. J Clin Endocrinol Metab 1999; 84 (4): 1483–1486.
34. Rosmond R, Chagnon M, Bouchard C, et al. A missense mutation in the human melanocortin-4 receptor gene in relation to abdominal obesity and salivary cortisol. Diabetologia 2001; 44 (10): 1335–1338.
35. Polak E, Vitariusova E, Celec P, et al. The prevalence of melanocortin-4 receptor gene mutations in Slovak obese children and adolescents. J Pediatr Endocrinol Metab 2016; 29 (1): 55–61.
36. Santoro N, Cirillo G, Xiang Z, et al. Prevalence of pathogenetic MC4R mutations in Italian children with early onset obesity, tall stature and familial history of obesity. BMC Med Genet 2009; 10: 25.
37. Dubern B, Clement K, Pelloux V, et al. Mutational analysis of melanocortin-4 receptor, agouti-related protein, and alpha-melanocyte-stimulating hormone genes in severely obese children. J Pediatr 2001; 139 (2): 204–209.
38. van den Berg L, van Beekum O, Heutink P, et al. Melanocortin-4 receptor gene mutations in a Dutch cohort of obese children. Obesity (Silver Spring) 2011; 19 (3): 604–611.
39. Stanikova D, Surova M, Buzga M, et al. Age of obesity onset in MC4R mutation carriers. Endocr Regul 2015; 49 (3): 137–140.
40. Yiannakouris N, Yannakoulia M, Melistas L, et al. The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability. J Clin Endocrinol Metab 2001; 86 (9): 4434–4439.
Labels
Neonatology Paediatrics General practitioner for children and adolescentsArticle was published in
Czech-Slovak Pediatrics
2017 Issue 5
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