Skip to main content

The search for undiagnosed MODY patients: what is the next step?

When, more than two decades ago, I started working as a physician providing medical care to patients with diabetes, I was completely unaware of the diversity of its forms. At that time, I knew only that there was an insulin-dependent diabetes (renamed later as type 1) and a non-insulin-dependent diabetes (currently known as type 2). I am convinced that this was the predominant viewpoint at that time. Over the last 20 years, however, scientists—both basic researchers and clinicians—have discovered and characterised more than 20 forms of monogenic diabetes [13]. The term MODY attracted my attention in the early 1990s when discoveries of its molecular basis were emerging [4, 5] and my personal interest in the genetics of diabetes was growing. It should be noted that much earlier there were some bright physicians whose brilliant observations pointed to rare cases of patients with diabetes who have a very rich family history of this disease and whose symptoms did not fit into either of the two categories identified at that time [6, 7]. These patients shared some common features, such as an autosomal dominant inheritance and abnormalities of insulin secretion; they were also usually thin and non-insulin-dependent. We later learnt that MODY was not a uniform entity but, rather, constituted a heterogeneous group that included several forms of single gene diabetes [8, 9]. Clinically, patients with MODY exhibited different degrees of hyperglycaemia, rates of disease progression, responses to pharmacological treatment and concomitant extra-pancreatic features. Individuals involved in MODY research revealed the origin of these differences and learnt how to use them in medical practice [2, 1012]. Although the molecular aetiology of MODY has not yet been fully dissected, genetic testing is now available for the most prevalent subtypes.

To date, thousands of MODY patients have been diagnosed all over the world, most of them probably thanks to research projects. These individuals, along with their families, benefited from genetic testing. Many patients, mainly carriers of the HNF1A mutation, were able to switch from insulin to sulfonylurea [13, 14]. Not only did their glycaemic control improve [14], but it is likely this switch also enhanced their quality of life. Some other patients, mostly individuals with GCK mutations, were able to discontinue pharmacological treatment altogether and controlled their diabetes through diet alone [15]. The genetic diagnosis also defined the prognosis for the disease progression or, in predictive testing, the risk of diabetes development in the examined individuals and their relatives. One may assume, although this has yet to be objectively proven on a large patient population, that the cost of their medical care was reduced as a result of treatment optimisation and decreased use of glucometric strips and reduced number of referrals for laboratory tests (type 1 diabetes related auto-antibodies, insulin levels etc.) [15]. However, solid health economic analysis is lacking in this area; this is why we only have a ballpark cost for genetic testing in Europe. Nevertheless, there can be no doubt that all of us—patients, healthcare providers and entire societies—benefit from the changes in clinical practice that have resulted from genetic discoveries. We currently need to answer a few important questions: How many MODY patients are there estimated to be in European countries? How many of them have yet to be diagnosed? Once these questions have been answered, the next task will be to find a way of identifying most, if not all, MODY patients and to provide them with optimal medical care. In other words, we need to abandon the narrow perspective of local research centres and start perceiving MODY diagnosis as part of routine clinical practice. Obviously, we must not forget about the necessity of pursuing well-organised genomic research focused on the unelucidated MODY cases and finding new genes.

In this edition of Diabetologia, Shields at al. report on their efforts to answer the above-mentioned crucial questions concerning the prevalence of MODY [16]. There has been some earlier experience with other monogenic forms of diabetes, such as permanent neonatal diabetes (PNDM). For example, it has been reported that PNDM occurs at least once in 260,000 live births [17]. Unlike MODY, PNDM has a strict and simple definition: diabetes diagnosed before the end of the sixth month of life. In addition, the task of determining the incidence PNDM was facilitated by registries of juvenile diabetes, which are available in some countries [18]. With MODY, however, the challenge is much more difficult as we cannot give it a precise definition. The main reasons being that age at diabetes diagnosis spans a wide range and that the clinical picture frequently overlaps with more common forms of this disease. Based on the number of identified mutation carriers in the UK (1,177 individuals between 1996 and 2009) and their distribution throughout the country, British scientists estimated the minimum prevalence of MODY to be 108 cases per million population [16]. This means that, in the UK alone, there are at least 5,000 individuals with undiagnosed MODY. We may cautiously assume that the actual number is several times higher, probably reaching a rate of approximately 1% of all diabetes cases. This notion is supported by data from earlier, but much smaller, studies [19, 20]. If these figures are extrapolated to the entire population of Europe, the number of MODY patients waiting to be diagnosed may go into hundreds of thousands, and the number of genetic tests that need to be performed, taking into account the pick-up rate for the probands described in the commented paper, is several times larger and is expressed in millions! Thus, not only is there a job to do in the UK, but other European countries have an even longer way to go. For example, in Poland, a country with a population of 38 million, with several scientific groups committed to MODY research for over a decade, the number of identified patients is about 300 (M. T. Malecki, W. Mlynarski, unpublished data). How can we rise to the challenge of identifying the remaining as yet undiagnosed MODY patients?

The paper by Shields and colleagues provides some clues [16]. There is marked regional variation in the prevalence of identified MODY cases in the UK. Therefore, attention should be focused on the areas where the referral and diagnosis rates are the highest. South West England is one such area. The high number of diagnosed MODY cases in this area can certainly be explained by the influence of a world-leading research centre in the field of monogenic diabetes, based in the Peninsula Medical School. This centre, which also offers intensive education for physicians and nurses in the diagnosis of MODY, must have locally increased the awareness of MODY and the importance of the differential diagnosis of diabetes. Another region with a high number of confirmed cases is Scotland. Interestingly, this is the only area in the UK where central funding for genetic testing is provided. So it seems that to successfully identify MODY patients, an awareness among physicians and nurses is needed as well as available funds to perform screening. To maximise the medical and economic effectiveness of the screening, appropriate guidelines are required and these are already available [21]. Is there anything apart from education and money that may help the search for MODY patients? Two tools should be mentioned here. The first is new generation sequencing, which, when introduced to genetics labs, will substantially boost the efficacy of screening and will hopefully reduce its cost [22]. The second is the development of cheap, non-genetic biomarkers that are widely available and can be used as a more economical screening test to perform pre-diagnostic molecular testing [23]. Such testing could possibly be combined with phenotypic, clinical or other laboratory information. Over the last decade several such biomarkers were proposed, for example apolipoprotein M or 1,5-anhydroglucitol for HNF1A MODY [24, 25]. The enthusiasm concerning their clinical usefulness after the initial publications was, however, reduced [26], or even perished [27, 28], following the results of replication studies. Thus, we should not expect that any of these earlier candidate biomarkers will be used in clinical practice. Nevertheless, the search for new biomarkers is underway and has been facilitated by the European Union funding the international Collaborative European Effort to Develop Diabetes Diagnostics (CEED3; scientific consortium, which aims to identify these markers.

So, returning to the initial question asked by Shields et al.: How many MODY cases are we missing? We know that we are missing most of them but we are also aware of how to search for them and, even more importantly, what to do once they are found.



permanent neonatal diabetes


  1. McCarthy MI, Hattersley AT (2008) Learning from molecular genetics: novel insights arising from the definition of genes for monogenic and type 2 diabetes. Diabetes 57:2889–2898

    CAS  Article  PubMed  Google Scholar 

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

    CAS  Article  PubMed  Google Scholar 

  3. Vaxillaire M, Bonnefond A, Froguel P (2009) Breakthroughs in monogenic diabetes genetics: from pediatric forms to young adulthood diabetes. Pediatr Endocrinol Rev 6:405–417

    PubMed  Google Scholar 

  4. Froguel P, Zouali H, Vionnet N et al (1993) Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. N Engl J Med 328:697–702

    CAS  Article  PubMed  Google Scholar 

  5. Bell GI, Xiang KS, Newman MV et al (1991) Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q. Proc Natl Acad Sci U S A 88:1484–1488

    CAS  Article  PubMed  Google Scholar 

  6. Cammidge PJ (1928) Diabetes mellitus and heredity. BMJ 2:738–741

    Article  PubMed  Google Scholar 

  7. Tattersall RB, Fajans SS (1975) A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes 24:44–53

    CAS  Article  PubMed  Google Scholar 

  8. Tattersall RB, Mansell PI (1991) Maturity onset-type diabetes of the young (MODY): one condition or many? Diabet Med 8:402–410

    CAS  Article  PubMed  Google Scholar 

  9. Hattersley AT (1998) Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity. Diabet Med 15:15–24

    CAS  Article  PubMed  Google Scholar 

  10. Fajans SS, Bell GI, Polonsky KS (2001) Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med 345:971–980

    CAS  Article  PubMed  Google Scholar 

  11. Hattersley AT (2005) Molecular genetics goes to the diabetes clinic. Clin Med 5:476–481

    PubMed  Google Scholar 

  12. Malecki MT, Mlynarski W, Skupien J (2008) Can geneticists help clinicians to understand and treat non-autoimmune diabetes? Diabetes Res Clin Pract 82(Suppl 2):S83–S93

    Article  PubMed  Google Scholar 

  13. Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, Hattersley AT (2003) Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 362:1275–1281

    CAS  Article  PubMed  Google Scholar 

  14. Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT (2009) A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med 26:437–441

    CAS  Article  PubMed  Google Scholar 

  15. Schnyder S, Mullis PE, Ellard S, Hattersley AT, Flück CE (2005) Genetic testing for glucokinase mutations in clinically selected patients with MODY: a worthwhile investment. Swiss Med Wkly 135:352–356

    CAS  PubMed  Google Scholar 

  16. Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S (2010) Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia doi:10.1007/s00125-010-1799-4

    Google Scholar 

  17. Slingerland AS, Shields BM, Flanagan SE et al (2009) Referral rates for diagnostic testing support an incidence of permanent neonatal diabetes in three European countries of at least 1 in 260,000 live births. Diabetologia 52:1683–1685

    CAS  Article  PubMed  Google Scholar 

  18. Stanik J, Gasperikova D, Paskova M et al (2007) Prevalence of permanent neonatal diabetes in Slovakia and successful replacement of insulin with sulfonylurea therapy in KCNJ11 and ABCC8 mutation carriers. J Clin Endocrinol Metab 92:1276–1282

    CAS  Article  PubMed  Google Scholar 

  19. Schober E, Rami B, Grabert M et al (2009) 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 26:466–473

    CAS  Article  PubMed  Google Scholar 

  20. Eide SA, Raeder H, Johansson S et al (2008) Prevalence of HNF1A (MODY3) mutations in a Norwegian population (the HUNT2 Study). Diabet Med 25:775–781

    CAS  Article  PubMed  Google Scholar 

  21. Ellard S, Bellanné-Chantelot C, Hattersley AT; European Molecular Genetics Quality Network (EMQN) MODY group (2008) Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 51:546–553

    Article  Google Scholar 

  22. Hert DG, Fredlake CP, Barron AE (2008) Advantages and limitations of next-generation sequencing technologies: a comparison of electrophoresis and non-electrophoresis methods. Electrophoresis 29:4618–4626

    CAS  Article  PubMed  Google Scholar 

  23. Owen KR, Skupien J, Malecki MT; CEED3 Consortium (2009) The clinical application of non-genetic biomarkers for differential diagnosis of monogenic diabetes. Diabetes Res Clin Pract 86(Suppl 1):S15–S21

    Google Scholar 

  24. Richter S, Shih DQ, Pearson ER et al (2003) Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1α: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Diabetes 52:2989–2995

    CAS  Article  PubMed  Google Scholar 

  25. Skupien J, Gorczynska-Kosiorz S, Klupa T et al (2008) Clinical application of 1,5-anhydroglucitol measurements in patients with hepatocyte nuclear factor-1α maturity-onset diabetes of the young. Diabetes Care 31:1496–1501

    CAS  Article  PubMed  Google Scholar 

  26. Pal A, Farmer AJ, Dudley C et al (2010) Evaluation of serum 1,5-anhydroglucitol levels as a clinical test to differentiate subtypes of diabetes. Diabetes Care 33:252–257

    CAS  Article  PubMed  Google Scholar 

  27. Skupien J, Kepka G, Gorczynska-Kosiorz S et al (2007) Evaluation of apolipoprotein M serum concentration as a biomarker of HNF-1alpha MODY. Rev Diabet Stud 4:231–235

    Article  PubMed  Google Scholar 

  28. Cervin C, Axler O, Holmkvist J et al (2010) An investigation of serum concentration of apoM as a potential MODY3 marker using a novel ELISA. J Intern Med 267:316–321

    CAS  Article  PubMed  Google Scholar 

Download references


M. T. Malecki is supported by the EU Framework 7 CEED3 grant. The author is grateful to W. Mlynarski (Department of Pediatrics, Oncology, Haematology and Diabetology, Medical University of Łódź, Łódź, Poland) for sharing his unpublished results and to A. Malecka for her linguistic help in the preparation of this manuscript.

Duality of interest

The author declares that there is no duality of interest associated with this manuscript.

Author information

Authors and Affiliations


Corresponding author

Correspondence to M. T. Malecki.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Malecki, M.T. The search for undiagnosed MODY patients: what is the next step?. Diabetologia 53, 2465–2467 (2010).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • Diabetes
  • Differential diagnosis
  • MODY
  • Monogenic disease