March 10, 2008
5 min read

MODY: an underdiagnosed and underappreciated condition

MODY cases often misdiagnosed as type 1 diabetes in younger patients or type 2 in patients in their late 20s and early 30s.

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The term MODY — maturity onset diabetes of youth — is used to designate a group of conditions characterized by onset of diabetes before age 35 years, autosomal dominant inheritance in at least two and preferably three generations, and generally milder clinical features than typical type 1 diabetes.

Affected people are predominately lean and generally white. Patients with MODY rarely have diabetic ketoacidosis and lack markers of autoimmunity such as ICA, GAD, IA-2 or high-risk HLA alleles associated with type 1 diabetes. They differ from patients with type 2 diabetes by retaining normal insulin sensitivity, remaining lean, and having measurements of insulin that show diminished but not absent concentrations in serum.

Cem Demirci, MD
Cem Demirci

Mark A. Sperling, MD
Mark A. Sperling

Gene mutations

At least six well-characterized single gene mutations are associated with MODY; candidate genes for MODY 7, 8 and 9 have been proposed, and yet to be identified genes are also considered to exist for entities believed to be clinically consistent with MODY (see chart).

It has been proposed that MODY may represent as much as 1% to 2% of all young patients with diabetes, but even if only half as frequent, MODY cases are likely to be misdiagnosed as either insulin dependent type 1 in younger patients or type 2 in patients in their late 20s and early 30s. This may be deleterious for affected younger patients as simple exercise and diet regimens are effective in MODY 2 and oral hypoglycemic agents suffice to achieve near-normal glucose values in several of the MODY forms, particularly in MODY 3.

Between them, MODY 3 (50% to 55%) and MODY 2 (20% to 25%) constitute some 75% of all cases of MODY, although regional differences of MODY types exist. For example, MODY 2 (glucokinase deficiency) is more frequent in southern Europe and Mediterranean populations, whereas MODY 3 (mutations in hepatic nuclear factor 1 alpha-aka— TCF-1) is more prevalent in northern European populations and their descendants.

Recent experience in our medical center suggest that these entities are underdiagnosed, leading to potentially inappropriate treatment. Over the past two years, we have identified three extensive pedigrees of patients previously considered to have type 1 or type 2 diabetes.

We briefly describe below two families with the two most common forms of MODY, namely MODY 3 and MODY 2; a third family with MODY 5 is currently being evaluated.

Case histories

Family A was clinically recognized when the middle of three siblings presented with mild, asymptomatic hyperglycemia discovered on routine physical examination; an older and younger sibling were classified as type 1 diabetes eight and five years previously, each treated with insulin and maintained a HbA1c of 11% and 8%, respectively.

Baseline C-peptide of 3.5 ng/mL and insulin of 29 µU/mL in our index case suggested “mild” diabetes, and review of the family history revealed multiple affected members, some on insulin and some on oral hypoglycemic agents.

Notably, the father had diabetes since the age of 32 and had excellent control with a HbA1c of 6.5% and now, some 30 years since diagnosis, he is completely free of microvascular or macrovascular complications. His two sisters had been diagnosed with diabetes in their late teens and early 20s and had been treated with insulin and/or oral agents; they also had no complications.

The paternal grandfather had diabetes diagnosed during a terminal illness with acute lymphatic leukemia while he was in his early 40s; little else is known of his diabetes. Molecular diagnostics (Athena Diagnostics) in the index case revealed a mutation in exon 4 of the TCF-1 gene ( HNF-1α) 779 C>T leading to a Thr 260 Met change in sequence.

Later, the other two siblings were shown to have the identical mutation; all are now being treated with oral agents with improved metabolic control as a result of compliance and the production of endogenous insulin. In addition, the father and his two sisters also had molecular diagnostic tests demonstrating the same mutation in the TCF-1 gene which causes the most common form of MODY, namely MODY 3.

In family B, glucokinase mutation was confirmed as the cause of MODY 2 in our index case and his cousin by detection of novel variant T206P in exon 6 of the GCK gene (Athena Diagnostics). The remaining four family members likely have the same mutation, but this remains to be determined.

In family C, deteriorating glycemic control, increasing weight, increasing insulin requirement and early albuminuria led to reassessment and to a likely diagnosis of MODY 5 due to HNF-1β.

Glucokinase inactivating heterozygous mutations cause MODY, whereas homozygous inactivating mutations have been described in permanent neonatal diabetes mellitus. Activating mutations in glucokinase cause hyperinsulinemic hypoglycemia. IPF1-Insulin promoter factor-1 aka PDX-1, pancreas duodenal homeobox causes permanent neonatal diabetes when homozygous and has been associated with type 2 diabetes in adults.


It is clear from our experience that monogenic forms of diabetes are overlooked; they mimic mild type 1a diabetes (autoimmune), type 1b diabetes with similar clinical features but without evidence of autoimmunity and type 2 diabetes clinically. Molecular diagnostics clearly permits confirmation of a suspected diagnosis and is of significant value when the family history reveals two to three generations of affected members with “mild” diabetes.

The correct diagnosis in both families allowed appropriate treatment and genetic counseling. Additional benefits were a sense of relief with less fear of future complications as has been the case with a father and two aunts in family A.

Generally, with defects in the various transcription factors as causing MODY, about one-third may progress to require insulin and develop complications and so they need ongoing monitoring and evaluation. In family B, some of our patients have been labeled as having type 2 diabetes and are treated with oral agents, when generally diet and exercise suffice and complications are rare, though not impossible.

Our experience has led us to recommend that physicians caring for families with multiple affected members with young onset and mild features consider MODY forms in their differential diagnosis for which appropriate confirmatory diagnostic tools are now available.

Cem Demirci, MD, is a Pediatric Endocrinology Fellow in the Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh.

Mark A. Sperling, MD, is a Professor of Pediatrics in the Department of Pediatrics, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, and a member of Endocrine Today’s Editorial Board.

From the authors: We thank our colleagues in the Division of Pediatric Endocrinology for referral of some of the patients listed. We gratefully acknowledge the assistance of Athena Diagnostics, which performed molecular typing of the three adult members of family A for research purposes at no charge.

For more information:

  • Fajans SS, Bell GI, Polonsky KS. Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med. 2001;345:971-980.
  • Ledermann HM. Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed? Lancet. 1995;345:648.
  • Johansen A, Ek J, Mortensen HB, et al. Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF-4A, GCK, and TCF-1. J Clin Endocrinol Metab. 2005;90:4607-4614.
  • Sagen JV, Bjørkhaug L, Molnes J, et al. Diagnostic screening of MODY2/GCK mutations in the Norwegian MODY Registry. Pediatric Diabetes. 2008;In press.