MODY in Siberia – molecular genetics and clinical characteristics

The diagnosis of maturity onset diabetes of the young (MODY) has high clinical significance in young patients (no absolute need for exogenous insulin; normoglycaemia in most patients achieved by dieting or taking oral hypoglycaemic agents) and their relatives (high probability of first-degree relatives being carriers of mutations, which requires a thorough collection of family history and determination of the parameters of carbohydrate metabolism).

Aim. This study aimed was to determine the clinical characteristics of different subtypes of MODY in a Siberian region.

Materials and Methods. We performed an examination, biochemical and hormonal blood tests, ultrasound and molecular genetic testing of 20 patients with a clinical diagnosis of MODY.

Results. Four subtypes of MODY were verified: MODY2 in 11 patients, MODY3 in two, MODY8 in one and MODY12 in two. Eleven patients (69%) exhibited no clinical manifestations of carbohydrate metabolism disorders, and one patient showed weight loss during early stage of the disease. Comorbidities included dyslipidemia, thyroid gland disorders and arterial hypertension. One patient (6%) exhibited diabetic nephropathy; two (13%), diabetic retinopathy and three (19%), peripheral neuropathy of lower legs. All patients achieved the target carbohydrate metabolism; the level of C-peptide was within the reference range.

Conclusion. Four different subtypes of MODY (2, 3, 8, 12) were diagnosed in the present study, which differed in their clinical characteristics, presence of complications and treatment strategies. Our knowledge of monogenic forms of diabetes is expanding with the development in molecular genetics, but several aspects related to them require further study.

diabetes mellitus, MODY, genes, mutations, molecular genetic testing

1. Fajans SS, Bell GI. MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care. 2011;34(8):1878-1884. doi: 10.2337/dc11-0035

2. Петеркова В.А., Кураева Т.Л., Прокофьев С.А. и др. Молекулярная генетика и клинические особенности моногенных форм сахарного диабета. // Вестник РАМН. – 2012. – №1 – С. 81-86. [Peterkova VA, Kuraeva TL, Prokof'ev SA, et al. Molecular genetics and clinical aspects of monogenic diabetes mellitus. Annals of the Russian academy of medical sciences. 2012;(1):81-86. (In Russ).] doi: 10.15690/vramn.v67i1.115.

3. Рымар О.Д., Овсянникова А.К., Сазонова О.В., и др. Клинико-генетические аспекты MODY диабета. – Новосибирск: Издательство Сибирского отделения Российской Академии Наук; ٢٠١٥. [Rymar OD, Ovsyannikova AK, Sazonova OV, et al. Kliniko-geneticheskieaspekty MODY diabeta. Novosibirsk: Izdatel'stvo Sibirskogo otdeleniya Rossiiskoi Akademii Nauk; 2015. (InRuss).].

4. Кураева Т.Л., Сечко Е.А., Еремина И.А., и др. Особенности течения MODY3 у ребенка с фенотипом сахарного диабета 2 типа // Сахарный диабет. – 2013. – Т. 16. – №2. – C. 88-93. [Kuraeva TL, Sechko EA, Eremina IA, Ivanova ON, Prokof’ev SA. MODY3 in the child with type 2 diabetes mellitus phenotype: case report. Diabetes mellitus. 2013;16(2):88-93. (In Russ).] doi: 10.14341/2072-0351-3762

5. Hattersley AT. Diagnosis of Maturity-Onset Diabetes of the Young in the Pediatric Diabetes Clinic. Journal of Pediatric Endocrinology and Metabolism. 2000;13(Supplement). doi: 10.1515/jpem-2000-s615

6. Bonnefond A, Philippe J, Durand E. et al. Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoSONE. 2012;7(6), p.e37423.doi: 10.1371/journal.pone.0037423.

7. Bonnefond A, Philippe J, Durand E, et al. Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One. 2012;7(6):e37423. doi: 10.1371/journal.pone.0037423

8. Орлов А.И. Прикладная статистика. – Москва: Экзамен; ٢٠٠٤. [Orlov AI. Prikladnaya statistika. Moscow: Ekzamen; 2004. (In Russ)].

9. Gardner DS, Tai ES. Clinical features and treatment of maturity onset diabetes of the young (MODY). Diabetes Metab Syndr Obes. 2012;5:101-108. doi: 10.2147/DMSO.S23353

10. Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes of the young (MODY). BMJ. 2011;343:d6044. doi: 10.1136/bmj.d6044

11. Кураева Т.Л., Сечко Е.А., Зильберман Л.И., и др. Молекулярно-генетические и клинические варианты MODY2 и MODY3 у детей в России. // Проблемы Эндокринологии. – 2015. – Т. 61. – №5. – C. 14-25. [Kuraeva TL, Sechko EA, Zilberman LI, Ivanova ON, Mayorov AY, Koksharova EO, et al. Molecular genetic and clinical variants MODY2 and MODY3 in children in Russia. Problems of Endocrinology. 2016;61(5):14-25. (InRuss).] doi: 10.14341/probl201561514-25

12. Петеркова В.А., Кураева Т.Л., Зильберман Л.И., и др. Моногенные формы сахарного диабета у детей и подростков. Сахарный диабет: диагностика, лечение, профилактика. / Под редакцией академика РАН и РАМН Дедова ИИ, профессора Шестаковой МВ. – М: Медицинское информационное агентство; ٢٠١١. [Peterkova VA, Kuraeva TL, Zil'berman LI, et al. Monogennye formy sakharnogo diabeta u detei I podrostkov. Sakharnyi diabet: diagnostika, lechenie, profilaktika. Ed by akademik RAN i RAMN Dedova II, professor Shestakovoi MV. Moscow: Meditsinskoe informatsionnoe agentstvo; 2011. (In Russ)].

13. Henzen C. Monogenic diabetes mellitus due to defects in insulin secretion. Swiss Med Wkly. 2012;142:w13690. doi: 10.4414/smw.2012.13690

14. Сечко Е.А., Кураева Т.Л., Зильберман Л.И., и др. MODY3 у детей и подростков: молекулярно-генетическая основа и клинико-лабораторные проявления // Проблемы Эндокринологии. – 2015. – Т. 61. – №3. – C. 16-22. [Sechko EA, Kuraeva TL, Zil’berman LI, Ivanova ON, Peterkova VA. MODY3 in the children and adolescents: the molecular-genetic basis and clinico-laboratory manifestations. Problems of Endocrinology. 2015;61(3):16-22. (In Russ.)] doi: 10.14341/probl201561316-22.

15. Thanabalasingham G, Kaur K, Talbot F, et al. Atypical phenotype associated with reported GCK exon 10 deletions: Clinical judgement is needed alongside appropriate genetic investigations. Diabet Med. 2013;30(8):e233-238. doi: 10.1111/dme.12210

16. Steele AM, Shields BM, Shepherd M, et al. Increased all-cause and cardiovascular mortality in monogenic diabetes as a result of mutations in the HNF1A gene. Diabet Med. 2010;27(2):157-161. doi: 10.1111/j.1464-5491.2009.02913.x

17. Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab. 2008;4(4):200-213. doi: 10.1038/ncpendmet0778

18. Habeb AM, George ET, Mathew V, Hattersley AL. Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young. Ann Saudi Med. 2011;31(2):190-193. doi: 10.4103/0256-4947.75590

19. Зубкова Н.А., Арбатская Н.Ю., Петряйкина Е.Е., и др. Сахарный диабет типа MODY3: клиническая и молекулярно-генетическая характеристика 9 случаев заболевания // Проблемы Эндокринологии. – 2014. – Т. 60. – №1. – C. 51-56. [Zubkova NA, Arbatskaya NY, Petryaikina EE, Malievsky OA, Tulpakov AN. Type 3 form of MODY: the clinical and molecular-genetic characteristic. Nine cases of the disease. Problems of Endocrinology. 2014;60(1):51-56. (InRuss.)] doi: 10.14341/probl201460151-56.

20. Воевода М.И., Иванова А.А, Шахтшнейдер Е.В., и др. Молекулярно-генетические основы MODY-диабета. // Терапевтический архив. – 2016. – Т. 88. – №4 – С. 117-124. [Voevoda MI, Ivanova AA, Shakhtshneider EV, et al. Molekulyarno-geneticheskie osnovy MODY-diabeta. Terapevticheskii arkhiv. 2016;88(4):117-124. (In Russ).].

21. Tjora E, Wathle G, Engjom T, et al. Severe pancreatic dysfunction but compensated nutritional status in monogenic pancreatic disease caused by carboxyl-ester lipase mutations. Pancreas. 2013;42(7):1078-1084. doi: 10.1097/MPA.0b013e3182920e9c

22. Raeder H, McAllister FE, Tjora E, et al. Carboxyl-ester lipase maturity-onset diabetes of the young is associated with development of pancreatic cysts and upregulated MAPK signaling in secretin-stimulated duodenal fluid. Diabetes. 2014;63(1):259-269. doi: 10.2337/db13-1012

23. D'Amato E, Tammaro P, Craig TJ, et al. Variable phenotypic spectrum of diabetes mellitus in a family carrying a novel KCNJ11 gene mutation. Diabet Med. 2008;25(6):651-656. doi: 10.1111/j.1464-5491.2008.02443.x

24. Haghverdizadeh P, Sadat Haerian M, Haghverdizadeh P, Sadat Haerian B. ABCC8 genetic variants and risk of diabetes mellitus. Gene. 2014;545(2):198-204. doi: 10.1016/j.gene.2014.04.040