MODY3 in the children and adolescents: the molecular-genetic basis and clinico-laboratory manifestations
https://doi.org/10.14341/probl201561316-22
Abstract
The present study of HNF1А gene involved 121 children suspected to have the nonimmune-mediated form of diabetes mellitus. Diagnosis of MODY3 was verified in 18 (19.4%) probands. Disturbances of carbohydrate metabolism in one of the parents were documented in 94.5% of the cases. Metabolic disorders were revealed in the probands at the mean age of 11.65 years (9.8; 14.6), the clinical manifestations of diabetes mellitus (DM) were apparent in 16.7% of the children, the fasting blood glucose level was 7.5 mmol/l, HbA1c 6.6% (6.5; 7.7), 66.7% of the children had a history of glucosuria and 33.3% suffered obesity. The normal fasting blood glucose and HbA1c levels were found in 22.2% of the children. In 100% of the cases, results of OGTT suggested diabetes despite insulin secretion. Low titers of anti-GAD and anti-IA2 antibodies were detected in 20.0 and 22.2% of the children respectively. The most common mutation was p.P291fs.
About the Authors
E A Sechko
Sechenov First Moscow State Medical University
T L Kuraeva
Sechenov First Moscow State Medical University; Endocrinology Research Centre
L I Zil’berman
Sechenov First Moscow State Medical University; Endocrinology Research Centre
O N Ivanova
Endocrinology Research Centre
V A Peterkova
Sechenov First Moscow State Medical University; Endocrinology Research Centre
References
1. Tattersall RB. Mild familial diabetes with dominant inheritance. Q J Med. 1974;43(170):339-357.
2. Tattersall RB, Fajans SS, Arbor A. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes. 1975;24(1):44-53. doi: 10.2337/diab.24.1.44.
3. Fajans SS, Conn JW. Tolbutamide-induced improvement in carbohydrate tolerance of young people with mild diabetes mellitus. Diabetes. 1960;9(2):83-88. doi:10.2337/diab.9.2.83.
4. Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic β-cell diabetes. Nat Clin Pract Endoc. 2008;4(4):200-213. doi:10.1038/ncpendmet0778.
5. Hattersley A, Bruining J, Shield J, et al. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2009;10:33-42. doi:10.1111/j.1399-5448.2009.00571.x.
6. Shields BM, Hicks S, Shepherd MH, et al. Maturity-onset diabetes of the young (mody): how many cases are we missing? Diabetologia. 2010;53(12):2504-2508. doi: 10.1007/s00125-010-1799-4.
7. Pihoker C, Gilliam LK, Ellard S, et al. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A and glucokinase: results from the search for diabetes in youth. J Clin Endocrinol Metabol. 2013;98(10):4055-4062. doi: 10.1210/jc.2013-1279.
8. Ellard S, Bellanné-Chantelot C, Hattersley AT. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia. 2008;51(4):546-553. doi: 10.1007/s00125-008-0942-y.
9. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2011;35:S64-S71. doi: 10.2337/dc12-s064.
10. Kuraeva TL, Sechko EA, Eremina IA, et al. MODY3 in the child with type 2 diabetes mellitus phenotype: case report. Diabetes mellitus. 2013;16(2):88-93. doi: 10.14341/2072-0351-3762.
11. Зубкова Н.А., Арбатская Н.Ю., Петряйкина Е.Е, и др. Сахарный диабет типа MODY٣: клиническая и молекулярно-генетическая характеристика ٩ случаев заболевания. Проблемы эндокринологии. 2014;60(1):51-56. [Zubkova NA, Arbatskaya NYu, Petryaikina EE, et al. Type 3 form of MODY: the clinical and molecular-genetic characteristic. Nine cases of the disease. Probl Endocrinol. (Mosk.). 2014;60(1):51-56. (in Russ.)]. doi: 10.14341/probl201460151-56.
12. Yamagata K, Oda N, Kaisaki PJ, et al. Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3). Nature. 1996;384(6608):455-458. doi:10.1038/384455a0.
13. Vaxillaire M, Boccio V, Philippi A, et al. A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q. Nat Genet. 1995;9(4):418-423. doi: 10.1038/ng0495-418.
14. Pontoglio M, Barra J, Hadchouel M, et al. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal fanconi syndrome. Cell. 1996;84(4):575-585. doi: 10.1016/s0092-8674(00)81033-8.
15. Bach I, Yaniv M. More potent transcriptional activators or a transdominant inhibitor of the HNF1 homeoprotein family are generated by alternative RNA processing. EMBO J. 1993;12(11):4229-4242. PMC413717.
16. Colclough K, Bellanne-Chantelot C, Saint-Martin C, et al. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat. 2013;34(5):669-685. doi:10.1002/humu.22279.
17. Harries LW. Isomers of the tcf1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes. Hum Mol Genet. 2006;15(14):2216-2224. doi:10.1093/hmg/ddl147.
18. Дедов И.И., Мельниченко Г.А., Петеркова В.А., Ремизов О.В. Ожирение. М.:МИА. 2004;456. [Dedov II, Mel’nichenko GA, Peterkova VA, Remizov OV. Obesity. Moscow: MIA. 2004;456. (In Russ.)].
19. Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med. 2001;345(13):971-980. doi: 10.1056/nejmra002168.
20. Bellanné-Chantelot C, Lévy DJ, Carette C, et al. Clinical characteristics and diagnostic criteria of maturity-onset diabetes of the young (MODY) due to molecular anomalies of thehnf1agene. J Clin Endocrinol Metab. 2011;96(8):E1346-E1351. doi: 10.1210/jc.2011-0268.
21. Fajans SS, Bell GI. Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees. Diabetologia. 2006;49(5):1106-1108. doi: 10.1007/s00125-006-0158-y.
22. Bellanne-Chantelot C, Carette C, Riveline JP, et al. The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes. 2007;57(2):503-508. doi:0.2337/db07-0859.
23. Stanik J, Dusatkova P, Cinek O, et al. De novo mutations of GSK, HNF1α and HNF4A may be more frequent in MODY than previously assumed. Diabetologia. 2013;57(3):480-484. doi:10.1007/s00125-013-3119-2.
24. Bellanne-Chantelot C, Iafusco D, Blanche H, et al. Screening for mutations in the glucokinase (MODY2/GCK) and hepatocyte nuclear factor 1-alpha (MODY3/HNF1-alpha) genes in south-italian families. Diabetologia. 1998;41:(suppl 1):A115,422.
25. Glucksmann MA, Lehto M, Tayber O. et al. Novel mutations and a mutational hotspot in the MODY3 gene. Diabetes. 1997;46(6):1081-1086. doi:10.2337/diab.46.6.1081.
26. Schober E, Rami B, Grabert M. et al. Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database. Diabet Med. 2009;26(5):466-473. doi:10.1111/j.1464-5491.2009.02720.x.
27. Kondrashova A, Viskari H, Kulmala P, et al. Signs of β-cell autoimmunity in nondiabetic schoolchildren: a comparison between Russian Karelia with a low incidence of type 1 diabetes and finland with a high incidence rate. Diabetes Care. 2006;30(1):95-100. doi: 10.2337/dc06-0711.
28. Pontoglio M, Prié D, Cheret C, et al. HNF1α controls renal glucose reabsorption in mouse and man. EMBO Reports. 2000;1(4):359-365. doi:10.1093/embo-reports/kvd071.
29. Stride A, Ellard S, Clark P, et al. Beta-cell dysfunction, insulin sensitivity, and glycosuria precede diabetes in hepatocyte nuclear factor-1 mutation carriers. Diabetes Care. 2005;28(7):1751-1756. doi: 10.2337/diacare.28.7.1751.
Review
For citations:
Sechko E.A., Kuraeva T.L., Zil’berman L.I., Ivanova O.N., Peterkova V.A. MODY3 in the children and adolescents: the molecular-genetic basis and clinico-laboratory manifestations. Problems of Endocrinology. 2015;61(3):16-22. (In Russ.) https://doi.org/10.14341/probl201561316-22
Views:
729
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0).
Email this article 
.jpg){kind=logo}
