A number of single gene disorders predisposing to diabetes have been identified in recent decades. In this group a single, usually autosomal and dominantly inherited gene defect leads to diabetes, which can manifest itself at various ages. The first to be identified was a syndrome of early onset dominantly inherited diabetes titled MODY (maturity onset diabetes of the young), which accounts for up to 2% of all young patients with diabetes. Mutations in thirteen different genes can cause a MODY-like phenotype, of which the most common in clinical practice are mutations in the hepatocyte nuclear factor 1-alpha (HNF1A) and glucokinase (GCK) genes. It is important to make the diagnosis of MODY, since this has important implications for management and prognosis, but this can be a diagnostic challenge for the clinician, due to the overlap between its clinical features and those of the much great majority of cases with type 1 or type 2 diabetes.

Historical aspects

Elliot Joslin observed before the discovery of insulin that some young patients with diabetes and a strong family history of the condition survived much longer than expected. Similar clinical reports may be traced in the subsequent literature, but the history of MODY really began in 1974 when Tattersall1described three families with early onset diabetes transmitted as an autosomal dominant trait, responsive to sulphonylureas, and with a relatively benign prognosis. Fajans had independently described a group of patients diagnosed with diabetes under the age 25 years who had not progressed to insulin after many years on sulphonylureas. Tattersall and Fajans joined forces to coin the somewhat unfortunate term maturity onset diabetes of the young (MODY), which they defined as 'fasting hyperglycaemia diagnosed under age 25 which could be treated without insulin for more than two years'.

It was believed at one time that people with MODY were unusually resistant to the development of late complications, stimulating the quest for a gene that might protect against complications. Subsequent analysis confirmed that GCK-MODY does indeed have a good long term prognosis, mainly because the metabolic defect is mild. Typical complications can and do develop with other forms of MODY, and the quest for good control should not be relaxed.

Clinical features

MODY is a heterogeneous group of monogenic disorders causing beta cell dysfunction. The key feature thay have in common is onset of diabetes in adolescence or young adulthood in conjunction with a family history of the disease, especially when this suggests an autosomal dominant mode of transmission. Delayed diagnosis into later adulthood can occur, particularly with GCK-MODY (MODY 2), in which hyperglycaemia is relatively mild.

Mutations in thirteen different genes have been associated with a MODY phenotype (see table): GCK, HNF1A, HNF4A, , IPF1, HNF1B, NEUROD1, CEL, ABCC8, KCNJ11, INS, PAX4, KLF11, BLK.[1][2][3][4][5][6][7][8][9]

Clinical features shared by the different MODY subgroups are:

  • Onset of diabetes in the 2nd–5th decades of life

  • Insulin independence (although insulin may be required for optimal control)

  • Frequent strong family history of diabetes (of any type)

  • Usually absence of features of insulin resistance

  • Usually absence of beta cell autoimmunity

Different genetic subtypes of MODY have different clinical presentation, prognosis and treatment response. In clinical practice, mutations in the genes encoding the enzyme glucokinase (GCK) and the nuclear transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and hepatocyte nuclear factor 4 alpha (HNF4A) are the most frequent causes of MODY. The relative proportions of MODY cases associated with GCK or HNF1A mutations differs between countries; GCK mutations are more common in countries where glucose testing of asymptomatic individuals occurs (e.g. France, Spain and Italy), whereas in other countries HNF1A-MODY is most frequent.[10][11][12][13][14][15] In the UK HNF1A mutations are the most common, representing 52% of cases. GCK-MODY accounts for 32% of cases and HNF4A mutations for 10%.[16]

Prevalence of MODY

MODY has been estimated to account for up to 2% of diabetes patients; however, exact prevalence figures will remain unavailable until large population screening studies are performed.[17] A recent report from the UK diagnostic testing centre estimated the minimum UK population prevalence of all MODY subtypes as 68–108 cases per million.17 This figure was derived by looking at the clinical centres where most cases had been identified and extrapolating this UK-wide. Although based on a number of assumptions, this figure was comparable with population-based cross-sectional studies in Oxfordshire (UK) and the Nord-Trondelag county of Norway, which estimated minimum prevalences for HNF1A-MODY at 84 and 63 cases per million respectively.[18][19] From these data and the number of confirmed MODY cases in the UK, the authors estimated that more than 80% of MODY cases are currently misdiagnosed as more common types of diabetes.17 This may in itself be an underestimate.


  1. ^ Froguel P, Velho G. Non-sense mutation of glucokinase gene [letter; comment] [see comments]. Lancet 1993;341(8841):385

  2. ^ Yamagata K, Furuta H, Oda N, et al. Mutations in the hepatocyte nuclear factor 4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature 1996; 384(6608):458–60

  3. ^ Yamagata, K., N. Oda, P.J. Kaisaki, et al. Mutations in the hepatic nuclear factor 1 alpha gene in maturity-onset diabetes of the young (MODY3). Nature 1996;384(6608):455–8

  4. ^ Horikawa Y, Iwasaki N, Hara M et al. Mutation in hepatocyte nuclear factor-1b gene (TCF2) associated with MODY. Nat Genet 1997;17(4):384–5

  5. ^ Stoffers DA, Zinkin NT, Stanojevic V, et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet 1997; 15(1):106–10.

  6. ^ Malecki MT, Jhala US, Antonellis A, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet 1999;23(3):323–8

  7. ^ Raeder H, Johansson S, Holm PI, et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet 2006;38(1):54–62

  8. ^ Flanagan SE, Patch AM, Mackay DJ, et al. Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes 2007;56(7):1930–7

  9. ^ Molven A, Ringdal M, Nordbo AM, et al. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes 2008;57(4):1131–5

  10. ^ Lehto M, Wipemo C, Ivarsson S-A, et al. High frequency of mutations in MODY and mitochondrial genes in Scandinavian patients with familial early-onset diabetes. Diabetologia 1999;42(9):1131–7

  11. ^ Lindner T, Cockburn BN, Bell GI et al. Molecular genetics of MODY in Germany. Diabetologia 1999; 42(1):121–3

  12. ^ Bjorkhaug L, Sagen JV, Thorsby P, et al. Hepatocyte nuclear factor-1 alpha gene mutations and diabetes in Norway. J Clin Endocrinol Metab 2003;88(2):920–31

  13. ^ Massa O, Meschi F, Cuesta-Munoz A, et al. High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetes (SIEDP). Diabetologia 2001;44(7):898–905

  14. ^ Estalella I, Rica I, Perez de Nanclares G, et al. Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. Clin Endocrinol (Oxf) 2007;67(4):538–46

  15. ^ Chèvre JC, Hani EH, Boutin P, et al. Mutation screening in 18 Caucasian families suggest the existence of other MODY genes. Diabetologia 1998;41(9):1017–23.

  16. ^ 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):2504-8

  17. ^ Ledermann HM. Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed? [letter] [see comments]. Lancet 1995;345(8950):648

  18. ^ Eide SA, Raeder H, Johansson S, et al. Prevalence of HNF1A (MODY3) mutations in a Norwegian population (the HUNT2 Study). Diabet Med 2008;25(7):775–81

  19. ^ Kropff J, Selwood MP, McCarthy MI, et al. Prevalence of monogenic diabetes in young a community-based, cross-sectional study in Oxfordshire, UK. Diabetologia 2011;54(5):1261–3


  1. Gauranga Dhar
    Gauranga Dhar added a compliment on 22 February 2015 at 01:32PM
    Well written.
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