Diagnosis and Treatment of MODY: Comparison
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Maturity-Onset Diabetes of the Young (MODY) is a monogenic type of diabetes, resultant from single gene mutations. MODY is characterized by mild hyperglycemia, autosomal dominant inheritance, early onset of diabetes (<25 years), insulin resistance, and preservation of endogenous insulin secretion. The genes involved are crucial for the development, function and regulation of beta cells and can cause glucose sensing and insulin secretion disorders.

  • maturity onset diabetes of the young
  • diabetes
  • genetic testing
  • gene mutations
  • glucokinase

1. Introduction

Maturity-Onset Diabetes of the Young (MODY) is a monogenic type of diabetes, resultant from single gene mutations [1]. MODY is characterized by mild hyperglycemia, autosomal dominant inheritance, early onset of diabetes (<25 years), insulin resistance, and preservation of endogenous insulin secretion [2,3,4][2][3][4]. The genes involved are crucial for the development, function and regulation of beta cells and can cause glucose sensing and insulin secretion disorders [5,6][5][6]. MODY is classified into several subtypes based on the genes involved and clinical phenotypes. Fourteen MODY subtypes have been identified thus far, each caused by a distinct gene mutation ( Table 1 ) [7]. Among the 14 MODY subtypes, mutations in hepatocyte nuclear factor 1-α ( HNF1A ), glucokinase (GCK) , HNF4A , and HNF1B are the underlying cause in more than 95% of MODY cases; the other mutations are uncommon in the Caucasian population [2,8,9,10][2][8][9][10]. These mutations differ in terms of prevalence, clinical features, the severity of diabetes and related complications, and treatment response. Each mutation encodes proteins involved in glucose homeostasis of pancreatic β-cells [11,12][11][12].

TypeGene NameLocusClinical FeaturesReference
1HNF4A20q13.12Mild - increased fasting and postprandial plasma glucose, sensitivity to sulfonylurea derivatives, low levels of apolipoproteins and triglycerides, neonatal macrosomia, neonatal hypoglycemic events[11,21]
2GCK7p13Mild fasting hyperglycemia, impaired fasting glucose and impaired glucose tolerance, HbA1c is usually 7.3–7.5%[11,22,23]
3HNF1A12q24.31Diminished renal threshold for glycosuria, sensitivity to sulfonylurea derivatives, transient neonatal hyperinsulinemic hypoglycemia[24]
4IPF/PDXI13q12.2Pancreatic agenesis, permanent neonatal diabetes in homozygote[9,25]
5HNF1B17q12Characterized by renal disease and urogenital tract abnormalities in females, exocrine pancreatic dysfunction, hyperuricemia[2,25]
6NEUROD12q31.3Characterized by obesity and insulin resistance, neonatal diabetes, child or adult-onset diabetes neurological abnormalities[26,27]
7KLF112p25.1Pancreatic malignancy[26]
8CEL9q34.13Associated with both endocrine and exocrine pancreatic dysfunction, lipomatosis and fibrosis[25,26]
9PAX47q32.1Important for transcription for beta cell development[26]
10INS11p15.5Associated with neonatal diabetes[2]
11BLK8p23.1Contributes to control of beta signaling[2]
12ABCC811p15.1Associated with renal diabetes[2]
13KCNJ1111p15.1Associated with renal diabetes[2]
14APPL13p14.3Associated with Wolfram or DIDMOAD syndrome[2]

Table 1. Summary of MODY subtypes, gene names, locus, and their clinical features.

TypeGene NameLocusClinical FeaturesReference
1HNF4A20q13.12Mild - increased fasting and postprandial plasma glucose, sensitivity to sulfonylurea derivatives, low levels of apolipoproteins and triglycerides, neonatal macrosomia, neonatal hypoglycemic events[11][13]
2GCK7p13Mild fasting hyperglycemia, impaired fasting glucose and impaired glucose tolerance, HbA1c is usually 7.3–7.5%[11][14][15]
3HNF1A12q24.31Diminished renal threshold for glycosuria, sensitivity to sulfonylurea derivatives, transient neonatal hyperinsulinemic hypoglycemia[16]
4IPF/PDXI13q12.2Pancreatic agenesis, permanent neonatal diabetes in homozygote[9][17]
5HNF1B17q12Characterized by renal disease and urogenital tract abnormalities in females, exocrine pancreatic dysfunction, hyperuricemia[2][17]
6NEUROD12q31.3Characterized by obesity and insulin resistance, neonatal diabetes, child or adult-onset diabetes neurological abnormalities[18][19]
7KLF112p25.1Pancreatic malignancy[18]
8CEL9q34.13Associated with both endocrine and exocrine pancreatic dysfunction, lipomatosis and fibrosis[17][18]
9PAX47q32.1Important for transcription for beta cell development[18]
10INS11p15.5Associated with neonatal diabetes[2]
11BLK8p23.1Contributes to control of beta signaling[2]
12ABCC811p15.1Associated with renal diabetes[2]
13KCNJ1111p15.1Associated with renal diabetes[2]
14APPL13p14.3Associated with Wolfram or DIDMOAD syndrome[2]

GCK: Glucokinase, HNF1A, HNF4A, HNF1B: Hepatic nuclear factor alpha/beta, PDX1/IPF1: Pancreatic and duodenal homeobox 1/Insulin promoter factor 1, NEUROD1: Neurogenic differentiation factor 1, KLF11: Krueppel-like factor 11, CEL: Carboxyl ester lipase, PAX4: Paired Box 4, INS: Insulin, BLK: BLK proto-oncogenes, Src family tyrosine kinase, ABCC8: ATP binding cassette subfamily C member 8, KCNJ11: Potassium voltage-gated channel subfamily J member 11, APPL1: Adaptor protein, phosphotyrosine interacting with PH domain and leucine Zipper 1, DIDMOAD: Diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.

2. Diagnosis of MODY

Misdiagnosis of MODY with type 1 (T1DM) or type 2 diabetes mellitus (T2DM) can be avoided if clinicians can establish a correct molecular diagnosis, and with advances in genetic testing, aided by the development of new techniques (for example.g., Next Generation Sequencing) and increased access to genetic testing facilities, diagnosis of MODY can be performed accurately [13][20]. However, in order to ensure an accurate diagnosis, specific criteria must be met before administering genetic tests [2]. MODY can be distinguished from other types of diabetes based on the age at which the disease first manifested. MODY subtypes with variable age of onset, low penetrance, or atypical presentation may fail to meet the diagnostic criteria for the disease [14,15,16,17][21][22][23][24]. Additionally, while a family history of diabetes is highly suggestive of MODY, some mutations in MODY-associated genes can occur at high frequencies in individuals without a family history of diabetes, demonstrating the critical nature of genetic testing in individuals without a family history of diabetes [18][25]. According to the MODY diagnostic guidelines, genetic testing should be performed on individuals diagnosed with diabetes at a young age (25 years), as well as those with a familial history of diabetes, evidence of endogenous insulin secretion, detectable levels of c-peptide, and negative antibody results [19][26]. Direct sequencing with sensitivity close to 100% and next generation sequencing methods can be successfully used to identify MODY gene mutations [1,9,20][1][9][27]. According to a model proposed by Shields et al., a diagnosis before the age of 30 years is a useful discriminator between MODY and T2DM, whereas a parental history of diabetes produces a 23-fold increased chance that a patient previously diagnosed with T1DM may be diagnosed with MODY at a later stage [9].

3. Significance of MODY Diagnosis

Although MODY accounts for only 1-5% of all diabetes cases, it has significant implications [28]. The diagnosis of MODY is crucial for patients and their families; therefore, it is important to characterize each MODY subtype and distinguish these from other types of diabetes. MODY patients are often misdiagnosed with either T1DM or T2DM, resulting in patients receiving inappropriate treatment [26][18]. This could be due to overlapping clinical features, which are more common in diabetes, the high cost of genetic testing, and clinicians’ lack of awareness [29]. Accurate diagnosis would enable optimal therapeutic management and treatment strategies that differ significantly from those used for T1DM or T2DM [7]. Patients who had been receiving T1DM treatment can switch to oral agents (i.for example., sulfonylureas), which will improve their quality of life and glycemic control [30]. For example, HNF1AHNF1A -MODY -MODY (MODY 3) and HNF4AHNF4A -MODY -MODY (MODY 1) patients are best managed with oral sulfonylureas and can avoid the unnecessary insulin therapy that is generally prescribed before MODY diagnosis [31]. MODY diagnosis is key to providing accurate counselling regarding the predicted clinical outcome, genetic counselling, and identification of affected family members [32].

4. MODY Subtypes and Their Treatments

The pancreatic and duodenal homeobox 1 ( PDXI PDXI ) gene is a homeodomain-containing transcriptional factor, which regulates insulin gene expression and pancreatic development [40,56,57][33][34][35]. PDX1 PDX1 -MODY is a rare type of MODY caused by heterozygous mutations in the PDX1 gene. It is important in the regulation of genes that code for glucagon, insulin, glucose transporter 2 ( GLUT2 ), and glucokinase ( GCK ) enzymes [58][36]. It acts as the master switch for the pancreas’ hormonal and enzymatic functions [59][37]. Heterozygous PDX1 mutations can result in defective insulin secretion, whereas homozygous mutations result in permanent neonatal diabetes (PND) and exocrine pancreatic insufficiency [56,60,61][34][38][39]. Patients with PDX1 –MODY present with type 2 diabetes with early onset and no extra-pancreatic involvement. Metformin [62][40] and dipeptidyl peptidase-4 (DPP-4) inhibitors [63][41] have been shown to be effective in case reports. Diet, oral anti-diabetes drugs (OADs), and insulin are all options to treat individuals with MODY 4 [34,51][42][43].

MODY 11 is caused by heterozygous tyrosine-protein kinase ( BLK BLK ) gene mutations. The BLK gene, which belongs to the SRC proto-oncogenes family, encodes a tyrosine receptor protein that stimulates β-cells to produce and secrete insulin [40][33]. The BLK gene is expressed in β-cells and is essential for thymopoiesis in immature T cells [91][44]. BLK -MODY has incomplete penetrance, and as a result not all carriers present with diabetes. Heterozygous mutations in this gene reduce BLK expression and/or activity, leading to PDX1 and NKX6.1 deficiency, impaired glucose-stimulated insulin secretion, and decreased beta cell mass [92][45]. Environmental and genetic factors are thought to play a role in BLK -MODY, and the most important factor that causes hyperglycemia is excessive body weight [93][46]. Hyperglycemia is also likely to be influenced by pregnancy [94][47]. Although insulin is required for the vast majority of patients, some may be treated with diet or oral anti-diabetes drugs (OADs), [34,50][42][48].

MODY 12 is caused by heterozygous ATP binding cassette subfamily C member 8 ( ABCC8 ) gene mutations. ABCC8 encodes for sulfonyl-urea receptor 1 (SUR1), a subunit of an ATP-sensitive potassium (K-ATP) channel found in β-cell membranes [40,65][33][49]. ABCC8 is responsible for the secretion of insulin, which controls blood sugar levels [95][50]. ABCC8 gene mutations can result in congenital hyperinsulinism, which can be caused by dominantly inherited inactivating mutations. As a result of activating mutations or recessive loss-of-function mutations, ABCC8 gene mutations can lead to permanent or transient neonatal diabetes (PNDM or TNDM, respectively) [95][50]. The majority of patients with MODY 12 are misdiagnosed as having diabetes of a different kind and are mistreated with insulin, resulting in poor control and hypoglycemia episodes [34][42]. Rafiq et al. proposed that in adulthood, all ABCC8 mutation carriers could be switched to sulfonylureas [96][51].

MODY 14 is a rare subtype caused by mutations in the adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 ( APPL1 ) gene, which regulates cell proliferation and interaction between the adiponectin and insulin signaling pathways [101,102][52][53]. Heterozygous loss-of-function mutations in this gene result in impaired insulin secretion in response to glucose stimulation and decreased beta cell survival [101,102,103][52][53][54]. APPL1 APPL1 mutations can cause apoptosis in highly expressed tissues; overexpression causes dysmorphic phenotypes and developmental delays [101][52]. Diet, OADs, and insulin are all possible APPL1 -MODY treatments [34,50][42][48].

References

  1. Pihoker, C.; Gilliam, L.K.; Ellard, S.; Dabelea, D.; Davis, C.; Dolan, L.M.; Greenbaum, C.J.; Imperatore, G.; Lawrence, J.M.; Marcovina, S.M.; 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. Metab. 2013, 98, 4055–4062.
  2. Anik, A.; Çatli, G.; Abaci, A.; Böber, E. Maturity-onset diabetes of the young (MODY): An update. J. Pediatr. Endocrinol. Metab. 2015, 28, 251–263.
  3. McDonald, T.J.; Colclough, K.; Brown, R.; Shields, B.; Shepherd, M.; Bingley, P.; Williams, A.; Hattersley, A.T.; Ellard, S. Islet autoantibodies can discriminate maturity-onset diabetes of the young (MODY) from Type 1 diabetes. Diabet. Med. 2011, 28, 1028–1033.
  4. Owen, K.R.; Roland, J.; Smith, K.; Hattersley, A.T. Adolescent onset Type 2 diabetes in a non-obese Caucasian patient with an unbalanced translocation. Diabet. Med. 2003, 20, 483–485.
  5. Chambers, C.; Fouts, A.; Dong, F.; Colclough, K.; Wang, Z.; Batish, S.D.; Jaremko, M.; Ellard, S.; Hattersley, A.; Klingensmith, G.; et al. Characteristics of maturity onset diabetes of the young in a large diabetes center. Pediatr. Diabetes 2016, 17, 360–367.
  6. Naylor, R.; Philipson, L.H. Who should have genetic testing for maturity-onset diabetes of the young? Clin. Endocrinol. 2011, 75, 422–426.
  7. Kim, S.H. Maturity-Onset Diabetes of the Young: What Do Clinicians Need to Know? Diabetes Metab. J. 2015, 39, 468–477.
  8. Shepherd, M.; Shields, B.; Hammersley, S.; Hudson, M.; McDonald, T.J.; Colclough, K.; Oram, R.A.; Knight, B.; Hyde, C.; Cox, J.; et al. Systematic Population Screening, Using Biomarkers and Genetic Testing, Identifies 2.5% of the U.K. Pediatric Diabetes Population With Monogenic Diabetes. Diabetes Care 2016, 39, 1879–1888.
  9. Shields, B.M.; Hicks, S.; Shepherd, M.H.; Colclough, K.; Hattersley, A.T.; Ellard, S. Maturity-onset diabetes of the young (MODY): How many cases are we missing? Diabetologia 2010, 53, 2504–2508.
  10. Fajans, S.S.; Bell, G.I.; Polonsky, K.S. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N. Engl. J. Med. 2001, 345, 971–980.
  11. Heuvel-Borsboom, H.; de Valk, H.W.; Losekoot, M.; Westerink, J. Maturity onset diabetes of the young: Seek and you will find. Neth. J. Med. 2016, 74, 193–200.
  12. Barrio, R.; Bellanné-Chantelot, C.; Moreno, J.C.; Morel, V.; Calle, H.; Alonso, M.; Mustieles, C. Nine novel mutations in maturity-onset diabetes of the young (MODY) candidate genes in 22 Spanish families. J. Clin. Endocrinol. Metab. 2002, 87, 2532–2539.
  13. Arya, V.B.; Rahman, S.; Senniappan, S.; Flanagan, S.E.; Ellard, S.; Hussain, K. HNF4A mutation: Switch from hyperinsulinaemic hypoglycaemia to maturity-onset diabetes of the young, and incretin response. Diabet. Med. 2014, 31, e11–e15.
  14. Steele, A.M.; Wensley, K.J.; Ellard, S.; Murphy, R.; Shepherd, M.; Colclough, K.; Hattersley, A.; Shields, B.M. Use of HbA1c in the Identification of Patients with Hyperglycaemia Caused by a Glucokinase Mutation: Observational Case Control Studies. PLoS ONE 2013, 8, e65326.
  15. Delvecchio, M.; Salzano, G.; Bonura, C.; Cauvin, V.; Cherubini, V.; d’Annunzio, G.; Franzese, A.; Giglio, S.; Grasso, V.; Graziani, V.; et al. Can HbA1c combined with fasting plasma glucose help to assess priority for GCK-MODY vs. HNF1A-MODY genetic testing? Acta Diabetol. 2018, 55, 981–983.
  16. Nkonge, K.M.; Nkonge, D.K.; Nkonge, T.N. The epidemiology, molecular pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY). Clin. Diabetes Endocrinol. 2020, 6, 20.
  17. Skoczek, D.; Dulak, J.; Kachamakova-Trojanowska, N. Maturity Onset Diabetes of the Young-New Approaches for Disease Modelling. Int. J. Mol. Sci. 2021, 22, 7553.
  18. Thanabalasingham, G.; Owen, K.R. Diagnosis and management of maturity onset diabetes of the young (MODY). BMJ 2011, 343, d6044.
  19. Urakami, T. Maturity-onset diabetes of the young (MODY): Current perspectives on diagnosis and treatment. Diabetes Metab. Syndr. Obes. 2019, 12, 1047–1056.
  20. Malik, R.A.; Shaikh, S. Monogenic diabetes: Importance of genetic testing. Middle East J. Fam. Med. 2020, 18, 78–86.
  21. Peixoto-Barbosa, R.; Reis, A.F.; Giuffrida, F.M.A. Update on clinical screening of maturity-onset diabetes of the young (MODY). Diabetol. Metab. Syndr. 2020, 12, 50.
  22. Urbanová, J.; Brunerová, L.; Brož, J. Hidden MODY-Looking for a Needle in a Haystack. Front. Endocrinol. 2018, 9, 355.
  23. Pinelli, M.; Acquaviva, F.; Barbetti, F.; Caredda, E.; Cocozza, S.; Delvecchio, M.; Mozzillo, E.; Pirozzi, D.; Prisco, F.; Rabbone, I.; et al. Identification of candidate children for maturity-onset diabetes of the young type 2 (MODY2) gene testing: A seven-item clinical flowchart (7-iF). PLoS ONE 2013, 8, e79933.
  24. Lizarzaburu-Robles, J.C.; Gomez-de-la-Torre, J.C.; Castro-Mujica, M.D.C.; Vento, F.; Villanes, S.; Salsavilca, E.; Guerin, C. Atypical hyperglycemia presentation suggests considering a diagnostic of other types of diabetes: First reported GCK-MODY in Perú. Clin. Diabetes Endocrinol. 2020, 6, 3.
  25. Stanik, J.; Dusatkova, P.; Cinek, O.; Valentinova, L.; Huckova, M.; Skopkova, M.; Dusatkova, L.; Stanikova, D.; Pura, M.; Klimes, I.; et al. De novo mutations of GCK, HNF1A and HNF4A may be more frequent in MODY than previously assumed. Diabetologia 2014, 57, 480–484.
  26. Ellard, S.; Bellanné-Chantelot, C.; Hattersley, A.T. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 2008, 51, 546–553.
  27. Johansson, S.; Irgens, H.; Chudasama, K.K.; Molnes, J.; Aerts, J.; Roque, F.S.; Jonassen, I.; Levy, S.; Lima, K.; Knappskog, P.M.; et al. Exome sequencing and genetic testing for MODY. PLoS ONE 2012, 7, e38050.
  28. Gardner, D.S.; Tai, E.S. Clinical features and treatment of maturity onset diabetes of the young (MODY). Diabetes Metab. Syndr. Obes. 2012, 5, 101–108.
  29. Thanabalasingham, G.; Huffman, J.E.; Kattla, J.J.; Novokmet, M.; Rudan, I.; Gloyn, A.; Hayward, C.; Adamczyk, B.; Reynolds, R.; Muzinic, A.; et al. Mutations in HNF1A Result in Marked Alterations of Plasma Glycan Profile. Diabetes 2012, 62, 1329–1337.
  30. Pearson, E.R.; Starkey, B.J.; Powell, R.J.; Gribble, F.M.; Clark, P.M.; Hattersley, A.T. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 2003, 362, 1275–1281.
  31. Timsit, J.; Saint-Martin, C.; Dubois-Laforgue, D.; Bellanné-Chantelot, C. Searching for Maturity-Onset Diabetes of the Young (MODY): When and What for? Can. J. Diabetes 2016, 40, 455–461.
  32. Amed, S.; Oram, R. Maturity-Onset Diabetes of the Young (MODY): Making the Right Diagnosis to Optimize Treatment. Can. J. Diabetes 2016, 40, 449–454.
  33. Kanwal, A.; Fazal, S.; Ismail, M.; Naureen, N. A narrative insight to maturity-onset diabetes of the young. Clin. Rev. Opin. 2011, 3, 6–13.
  34. Ahlgren, U.; Jonsson, J.; Jonsson, L.; Simu, K.; Edlund, H. β-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the β-cell phenotype and maturity onset diabetes. Genes Dev. 1998, 12, 1763–1768.
  35. Stoffers, D.A.; Thomas, M.K.; Habener, J.F. Homeodomain protein IDX-1: A master regulator of pancreas development and insulin gene expression. Trends Endocrinol. Metab. 1997, 8, 145–151.
  36. Kim, S.K.; Selleri, L.; Lee, J.S.; Zhang, A.Y.; Gu, X.; Jacobs, Y.; Cleary, M.L. Pbx1 inactivation disrupts pancreas development and in Ipf1-deficient mice promotes diabetes mellitus. Nat. Genet. 2002, 30, 430–435.
  37. Schwitzgebel, V.; Mamin, A.; Brun, T.; Ritz-Laser, B.; Zaiko, M.; Maret, A.; Jornayvaz, F.R.; Theintz, G.E.; Michielin, O.; Melloul, D.; et al. Agenesis of Human Pancreas due to Decreased Half-Life of Insulin Promoter Factor 1. J. Clin. Endocrinol. Metab. 2003, 88, 4398–4406.
  38. Stoffers, D.A.; Zinkin, N.T.; Stanojevic, V.; Clarke, W.L.; Habener, J.F. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat. Genet. 1997, 15, 106–110.
  39. Jonsson, J.; Carlsson, L.; Edlund, T.; Edlund, H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 1994, 371, 606–609.
  40. Deng, M.; Xiao, X.; Zhou, L.; Wang, T. First Case Report of Maturity-Onset Diabetes of the Young Type 4 Pedigree in a Chinese Family. Front. Endocrinol. 2019, 10, 406.
  41. Mangrum, C.; Rush, E.; Shivaswamy, V. Genetically Targeted Dipeptidyl Peptidase-4 Inhibitor Use in a Patient with a Novel Mutation of MODY type 4. Clin. Med. Insights Endocrinol. Diabetes 2015, 8, 83–86.
  42. Delvecchio, M.; Pastore, C.; Giordano, P. Treatment Options for MODY Patients: A Systematic Review of Literature. Diabetes Ther. 2020, 11, 1667–1685.
  43. Dickens, L.T.; Naylor, R.N. Clinical Management of Women with Monogenic Diabetes during Pregnancy. Curr. Diab. Rep. 2018, 18, 12.
  44. Islam, K.B.; Rabbani, H.; Larsson, C.; Sanders, R.; Smith, C.I. Molecular cloning, characterization, and chromosomal localization of a human lymphoid tyrosine kinase related to murine Blk. J. Immunol. 1995, 154, 1265–1272.
  45. Borowiec, M.; Liew, C.W.; Thompson, R.; Boonyasrisawat, W.; Hu, J.; Mlynarski, W.M.; El Khattabi, I.; Kim, S.; Marselli, L.; Rich, S.S.; et al. Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc. Natl. Acad. Sci. USA 2009, 106, 14460–14465.
  46. Bonnefond, A.; Yengo, L.; Philippe, J.; Dechaume, A.; Ezzidi, I.; Vaillant, E.; Gjesing, A.P.; Andersson, E.A.; Czernichow, S.; Hercberg, S.; et al. Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes. Diabetologia 2013, 56, 492–496.
  47. Doddabelavangala Mruthyunjaya, M.; Chapla, A.; Hesarghatta Shyamasunder, A.; Varghese, D.; Varshney, M.; Paul, J.; Inbakumari, M.; Christina, F.; Varghese, R.T.; Kuruvilla, K.A.; et al. Comprehensive Maturity Onset Diabetes of the Young (MODY) Gene Screening in Pregnant Women with Diabetes in India. PLoS ONE 2017, 12, e0168656.
  48. Naylor, R.; Johnson, A.K. Maturity-Onset Diabetes of the Young Overview 1. Clinical Characteristics of MODY 2. Genetic Causes of MODY. Gene Rev. 2019, 1–20.
  49. Firdous, P.; Nissar, K.; Ali, S.; Ganai, B.A.; Shabir, U.; Hassan, T.; Masoodi, S.R. Genetic Testing of Maturity-Onset Diabetes of the Young Current Status and Future Perspectives. Front. Endocrinol. 2018, 9, 253.
  50. Kapoor, R.R.; Flanagan, S.E.; James, C.; Shield, J.; Ellard, S.; Hussain, K. Hyperinsulinaemic hypoglycaemia. Arch. Dis. Child. 2009, 94, 450–457.
  51. Rafiq, M.; Flanagan, S.E.; Patch, A.-M.; Shields, B.M.; Ellard, S.; Hattersley, A.T. Effective treatment with oral sulfonylureas in patients with diabetes due to sulfonylurea receptor 1 (SUR1) mutations. Diabetes Care 2008, 31, 204–209.
  52. Schenck, A.; Goto-Silva, L.; Collinet, C.; Rhinn, M.; Giner, A.; Habermann, B.; Brand, M.; Zerial, M. The endosomal protein Appl1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell 2008, 133, 486–497.
  53. Prudente, S.; Jungtrakoon, P.; Marucci, A.; Ludovico, O.; Buranasupkajorn, P.; Mazza, T.; Hastings, T.; Milano, T.; Morini, E.; Mercuri, L.; et al. Loss-of-Function Mutations in APPL1 in Familial Diabetes Mellitus. Am. J. Hum. Genet. 2015, 97, 177–185.
  54. Ivanoshchuk, D.; Shakhtshneider, E.; Rymar, O.; Ovsyannikova, A.; Mikhailova, S.; Orlov, P.; Ragino, Y.; Voevoda, M. Analysis of APPL1 Gene Polymorphisms in Patients with a Phenotype of Maturity Onset Diabetes of the Young. J. Pers. Med. 2020, 10, 100.
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