Characteristics of maturity onset diabetes of the young in a large diabetes center

Maturity onset diabetes of the young (MODY) is a monogenic form of diabetes caused by a mutation in at least one of the genes known to affect insulin production or secretion. There are at least 13 genes whose mutations have been associated with specific subtypes of MODY. The most commonly occurring MODY subtypes are caused by mutations in glucokinase (GCK) (MODY2) and in hepatocyte nuclear factor 1A (HNF1A) (MODY3) 1. GCK‐ and HNF1A‐MODY each account for approximately 20–50% of all MODY cases. Approximately 10% of MODY cases are from mutations in hepatocyte nuclear factor 4A (HNF4A) (MODY1) and hepatocyte nuclear factor 1B (HNF1B) (MODY5). An additional 20% of MODY cases are because of newly discovered or as yet unknown gene mutations for which testing is not yet commercially available 2. Typically, GCK‐MODY presents clinically as stable, asymptomatic, mild hyperglycemia 3 while HNF1A‐MODY and HNF4A‐MODY present with hyperglycemia and the typical symptoms of diabetes such as polyuria/polydipsia, weight loss, and rarely diabetic ketoacidosis (DKA) 4, 5. In addition to hyperglycemia, patients with HNF1B‐MODY may have renal abnormalities 6, 7. The clinical diagnosis of MODY has been based upon the following criteria: family history of diabetes, insulin independence, and onset by age 25 yr. However, there can be significant clinical overlap of the MODY subtypes with both type 1 and type 2 diabetes mellitus (T1DM and T2DM) 1. Recently, some studies have attempted to determine clinical and biochemical markers that are specific and sensitive for subtypes of MODY in children. Gandica et al. found HNF1A and GCK mutations in 5 of 10 (50%) subjects who met a clinical diagnosis of T1DM and at least 2 of the following 3 criteria: negative autoantibodies to at least 1 of either GAD65, IAA, or ICA, hemoglobin A1c level (HbA1c) <7% with an insulin requirement of <0.5 U/kg/day, or at least 3 consecutive generations of family members with diabetes 8. Pihoker et al. evaluated 586 subjects with diabetes, not selected for by referral type or family history, and found that the MODY‐positive group had fewer T2DM features such as lower body mass index (BMI) z‐score, lower prevalence of acanthosis nigricans, and a higher insulin sensitivity, but no significant differences in parental history of diabetes or symptoms at presentation 9. As genetic testing for MODY can be cost prohibitive for many patients, it is necessary to determine which clinical and biochemical characteristics would be more predictive of a positive MODY diagnosis in a given patient 10. It is important that the diagnosis of MODY be established in affected patients, as there can be significant treatment and hereditary implications depending on the subtype. HNF1A‐MODY and HNF4A‐MODY can be successfully treated with oral sulfonylurea medications as opposed to injected insulin 11, 12, 13, 14, 15 and GCK‐MODY, caused by an altered set point for glucose sensing, may not require any treatment or alterations in diet 16. However, during pregnancy, insulin therapy may be recommended to prevent obstetric complications caused by maternal hyperglycemia 17. Furthermore, clinicians should be aware of the complications associated with the specific subtype of MODY a patient has in order to implement appropriate monitoring and subsequent treatments. Once a mutation is identified in an index case, affected family members should be tested to guide their treatment and clinical monitoring. The goal of this study was to estimate the frequency of MODY at the Barbara Davis Center (BDC), University of Colorado, among antibody‐negative subjects with diabetes onset less than age 25 and conserved C‐peptide, as well as to assess the clinical characteristics that could distinguish those with genetic mutations for MODY from those without pathologic MODY mutations.