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Genetic and clinical characteristics of Turkish children with Maturity Onset Diabetes of the Young Type 2 (MODY2): A single center experience

Year 2023, , 51 - 56, 30.04.2023
https://doi.org/10.17944/interdiscip.1285735

Abstract

Objective: The aim of the study was to investigate the clinical and molecular genetic characteristics of children with maturity-onset diabetes of the youth-glucokinase (MODY-GCK, MODY type 2).

Method: Medical files of 21 patients with suspected MODY-GCK were reviewed retrospectively. The file records of the clinical findings, laboratory results and the suspected clinical diagnoses of MODY were based on (1) asymptomatic fasting hyperglycemia (glucose ≥100mg/dl, HbA1c < 7.5% (at least twice measurement) 2) parents with a history of diabetes without complications or mild fasting hyperglycemia (100-144mg/dL).

Results: The mean age at diagnosis was 11.5±4.3 years (min-max, 1.9-17.2). The mean (SD) fasting blood glucose level was 119.1 (9.8) mg/dL. The mean (SD) fasting C-peptide level was 1.3 (0.7) ng/mL, the mean (SD) insulin level was 5.9 (2.3) IU/ml, and the mean (SD) HbA1c level at diagnosis was 6.2 (0.5) %. Among 12 variants detected in the GCK gene, 8 were missense mutation, 2 were non-sense mutation, 1 of them was splice site and 1 of them was frameshift mutation. Eight of them (p. Val227Met, p. Ser282Ala, p.Val183Met, p.Met239Thr, p.Arg304Gln, p.Thr229Met, p.Gly163Asp, p.Cys130Ter) have been previously reported in the literature and 4 variants (c.582+4delA, p.Glu436Ter, p.His106ThrfsTer11, p.Asp133Gly) were novel.

Conclusion: We found similar phenotype characteristic of children with GCK-MODY among the children with different variants. The most common mutation type was missense and followed by nonsense, splice site and frameshift mutations. Detection of the molecular defect in patients with MODY is vital for the implementation of appropriate treatment approaches.

References

  • Fajans SS, Bell GI. MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care. 2011;34:1878–84. https://doi.org/10.2337/dc11-0035.
  • Ledermann, H.M. Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia. 1995;38(12):1482. https://doi.org/10.1007/BF00400611.
  • Kavvoura FK, Owen KR. Maturity onset diabetes of the young: clinical characteristics, diagnosis and management. Pediatr Endocrinol Rev. 2013;10(2):234–42.
  • Hoffman LS, Jialal I. Diabetes, maturity onset in the young (MODY). In: StatPearls. Treasure Island: StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532900/.
  • Kim SH. Maturity-onset diabetes of the young: what do clinicians need to know? Diabetes Metab J. 2015;39:468–77. https://doi.org/10.4093/dmj.2015.39.6.468
  • Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes of the young (MODY). Brit Med J 2011;343:d6044. https://doi.org/10.1136/bmj.d6044
  • Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009;30:1512–26. https://doi.org/10.1002/humu.21110.
  • Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007;4:e 118. https://doi.org/10.1371/journal.pmed.0040118.
  • Tattersall RB, Fajans SS. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes. 1975;18(8):44–53. https://doi.org/10.2337/diab.24.1.44.
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. https://doi.org/10.1038/gim.2015.30.
  • Feigerlová E, Pruhová S, Dittertová L, Lebl J, Pinterová D, Kolostová K, et al. Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. Eur J Pediatr. 2006;165:446–52. https://doi.org/10.1007/s00431-006-0106-3.
  • Codner E, Rocha A, Deng L, Martínez-Aguayo A, Godoy C, Mericq V, et al. Mild fasting hyperglycemia in children: high rate of glucokinase mutations and some risk of developing Type 1 diabetes mellitus. Pediatr Diabetes. 2009;10:382–8. https://doi.org/10.1111/j.1399-5448.2009.00499.x.
  • Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med. 1993;328(10):697-702. https://doi.org/10.1056/NEJM199303113281005.
  • Velho G, Blanché H, Vaxillaire M, Bellanné-Chantelot C, Pardini VC, Timsit J, et al. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia. 1997;40(2):217-24. https://doi.org/10.1007/s001250050666.
  • Costa A, Bescós M, Velho G, Chêvre J, Vidal J, Sesmilo G, et al. Genetic and clinical characterisation of maturity-onset diabetes of the young in Spanish families. Eur J Endocrinol. 2000;142(4):380-6. https://doi.org/10.1530/eje.0.1420380.
  • Ağladıoğlu SY, Aycan Z, Çetinkaya S, Baş VN, Önder A, Peltek Kendirci HN, et al. Maturity onset diabetes of youth (MODY) in Turkish children: sequence analysis of 11 causative genes by next generation sequencing. J Pediatr Endocrinol Metab. 2016;29(4):487-96. https://doi.org/10.1515/jpem-2015-0039.
  • Anık A, Çatlı G, Abacı A, Sarı E, Yeşilkaya E, Korkmaz HA, et al. Molecular diagnosis of maturity-onset diabetes of the young (MODY) in Turkish children by using targeted next-generation sequencing. J Pediatr Endocrinol Metab. 2015;28(11-12):1265-71. https://doi.org/10.1515/jpem-2014-0430.
  • Aykut A, Karaca E, Onay H, Gökşen D, Çetinkalp Ş, Eren E, et al. Analysis of the GCK gene in 79 MODY type 2 patients: A multicenter Turkish study, mutation profile and description of twenty novel mutations. Gene. 2018;641:186-189. https://doi.org/10.1016/j.gene.2017.10.057.
  • Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff: GCK Gene: http://www.hgmd.cf.ac.uk
  • Valentínová L, Beer NL, Staník J, Tribble ND, van de Bunt M, Hučková M, et al. Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia. PLoS One. 2012;7(4):e34541. https://doi.org/10.1371/journal.pone.0034541.
  • Gasperíková D, Tribble ND, Staník J, Hucková M, Misovicová N, van de Bunt M, et al. Identifcation of a novel beta-cell glucokinase [GCK] promoter mutation [- 71G.C] that modulates GCK gene expression through loss of allele-specific Spl binding causing mild fasting hyperglycemia in humans. Diabetes. 2009;58:1929-35.
  • Bolu S, Eroz R, Dogan M, Arslanoglu I, Dundar I. Genotype-Phenotype Characteristics of Turkish Children With Glucokinase Mutations Associated Maturity-Onset Diabetes of the Young. Indian Pediatr. 2020;57(11):1037-1039.
  • Craig ME, Jefferies C, Dabelea D, Balde N, Seth A, Donaghue KC. International Society for Pediatric and Adolescent Diabetes. ISPAD clinical practice consensus guidelines 2014. Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes. 2014; 15(S20):4–17. https://doi.org/10.1111/pedi.12186.
  • Wei X, Ju X, Yi X, Zhu Q, Qu N, Liu T, et al. Identification of sequence variants in genetic disease-causing genes using targeted next-generation sequencing. PLoS One. 2011;6(12):e29500. https://doi.org/10.1371/journal.pone.002950
Year 2023, , 51 - 56, 30.04.2023
https://doi.org/10.17944/interdiscip.1285735

Abstract

References

  • Fajans SS, Bell GI. MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care. 2011;34:1878–84. https://doi.org/10.2337/dc11-0035.
  • Ledermann, H.M. Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia. 1995;38(12):1482. https://doi.org/10.1007/BF00400611.
  • Kavvoura FK, Owen KR. Maturity onset diabetes of the young: clinical characteristics, diagnosis and management. Pediatr Endocrinol Rev. 2013;10(2):234–42.
  • Hoffman LS, Jialal I. Diabetes, maturity onset in the young (MODY). In: StatPearls. Treasure Island: StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532900/.
  • Kim SH. Maturity-onset diabetes of the young: what do clinicians need to know? Diabetes Metab J. 2015;39:468–77. https://doi.org/10.4093/dmj.2015.39.6.468
  • Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes of the young (MODY). Brit Med J 2011;343:d6044. https://doi.org/10.1136/bmj.d6044
  • Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat. 2009;30:1512–26. https://doi.org/10.1002/humu.21110.
  • Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med 2007;4:e 118. https://doi.org/10.1371/journal.pmed.0040118.
  • Tattersall RB, Fajans SS. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes. 1975;18(8):44–53. https://doi.org/10.2337/diab.24.1.44.
  • Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-24. https://doi.org/10.1038/gim.2015.30.
  • Feigerlová E, Pruhová S, Dittertová L, Lebl J, Pinterová D, Kolostová K, et al. Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. Eur J Pediatr. 2006;165:446–52. https://doi.org/10.1007/s00431-006-0106-3.
  • Codner E, Rocha A, Deng L, Martínez-Aguayo A, Godoy C, Mericq V, et al. Mild fasting hyperglycemia in children: high rate of glucokinase mutations and some risk of developing Type 1 diabetes mellitus. Pediatr Diabetes. 2009;10:382–8. https://doi.org/10.1111/j.1399-5448.2009.00499.x.
  • Froguel P, Zouali H, Vionnet N, Velho G, Vaxillaire M, Sun F, et al. Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med. 1993;328(10):697-702. https://doi.org/10.1056/NEJM199303113281005.
  • Velho G, Blanché H, Vaxillaire M, Bellanné-Chantelot C, Pardini VC, Timsit J, et al. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia. 1997;40(2):217-24. https://doi.org/10.1007/s001250050666.
  • Costa A, Bescós M, Velho G, Chêvre J, Vidal J, Sesmilo G, et al. Genetic and clinical characterisation of maturity-onset diabetes of the young in Spanish families. Eur J Endocrinol. 2000;142(4):380-6. https://doi.org/10.1530/eje.0.1420380.
  • Ağladıoğlu SY, Aycan Z, Çetinkaya S, Baş VN, Önder A, Peltek Kendirci HN, et al. Maturity onset diabetes of youth (MODY) in Turkish children: sequence analysis of 11 causative genes by next generation sequencing. J Pediatr Endocrinol Metab. 2016;29(4):487-96. https://doi.org/10.1515/jpem-2015-0039.
  • Anık A, Çatlı G, Abacı A, Sarı E, Yeşilkaya E, Korkmaz HA, et al. Molecular diagnosis of maturity-onset diabetes of the young (MODY) in Turkish children by using targeted next-generation sequencing. J Pediatr Endocrinol Metab. 2015;28(11-12):1265-71. https://doi.org/10.1515/jpem-2014-0430.
  • Aykut A, Karaca E, Onay H, Gökşen D, Çetinkalp Ş, Eren E, et al. Analysis of the GCK gene in 79 MODY type 2 patients: A multicenter Turkish study, mutation profile and description of twenty novel mutations. Gene. 2018;641:186-189. https://doi.org/10.1016/j.gene.2017.10.057.
  • Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff: GCK Gene: http://www.hgmd.cf.ac.uk
  • Valentínová L, Beer NL, Staník J, Tribble ND, van de Bunt M, Hučková M, et al. Identification and functional characterisation of novel glucokinase mutations causing maturity-onset diabetes of the young in Slovakia. PLoS One. 2012;7(4):e34541. https://doi.org/10.1371/journal.pone.0034541.
  • Gasperíková D, Tribble ND, Staník J, Hucková M, Misovicová N, van de Bunt M, et al. Identifcation of a novel beta-cell glucokinase [GCK] promoter mutation [- 71G.C] that modulates GCK gene expression through loss of allele-specific Spl binding causing mild fasting hyperglycemia in humans. Diabetes. 2009;58:1929-35.
  • Bolu S, Eroz R, Dogan M, Arslanoglu I, Dundar I. Genotype-Phenotype Characteristics of Turkish Children With Glucokinase Mutations Associated Maturity-Onset Diabetes of the Young. Indian Pediatr. 2020;57(11):1037-1039.
  • Craig ME, Jefferies C, Dabelea D, Balde N, Seth A, Donaghue KC. International Society for Pediatric and Adolescent Diabetes. ISPAD clinical practice consensus guidelines 2014. Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes. 2014; 15(S20):4–17. https://doi.org/10.1111/pedi.12186.
  • Wei X, Ju X, Yi X, Zhu Q, Qu N, Liu T, et al. Identification of sequence variants in genetic disease-causing genes using targeted next-generation sequencing. PLoS One. 2011;6(12):e29500. https://doi.org/10.1371/journal.pone.002950
There are 24 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research Articles
Authors

Özlem Nalbantoğlu 0000-0002-0410-5761

Semra Gürsoy This is me 0000-0002-6795-3012

Tarık Kırkgöz This is me 0000-0003-3450-9780

Filiz Hazan This is me 0000-0002-0382-3446

Behzat Özkan This is me 0000-0002-9153-8409

Early Pub Date April 30, 2023
Publication Date April 30, 2023
Submission Date June 15, 2022
Published in Issue Year 2023

Cite

Vancouver Nalbantoğlu Ö, Gürsoy S, Kırkgöz T, Hazan F, Özkan B. Genetic and clinical characteristics of Turkish children with Maturity Onset Diabetes of the Young Type 2 (MODY2): A single center experience. Interdiscip Med J. 2023;14(48):51-6.