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.

Gilliam LK, Pihoker C, Ellard S, Hattersley AT, Dabelea D, Davis C, Dolan LM, Greenbaum CJ, Imperatore G, Lawrence JM, Marcovina SM, Mayer-Davis E, Rodriguez BL, Steck AK, Williams DE; for the SEARCH for Diabetes in Youth Study Group.

Source

Departments of Medicine (L.K.G., S.M.M.) and Pediatrics (C.P.), University of Washington, Seattle, WA; the Institute of Biomedical and Clinical Science, Peninsula Medical School, University of Exeter, Exeter, U.K. (S.E., A.T.H.); the Department of Epidemiology, CO School of Public Health (D.D.), and the Barbara Davis Center for Childhood Diabetes (A.K.S.), University of Colorado Denver, Aurora, CO; the Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC (C.D.); the Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH (L.M.D.); Diabetes Research Program, Benaroya Research Institute, Seattle, WA (C.J.G.); the Division of Diabetes Translation, Centers for Disease Control and Prevention, Atlanta, GA (G.I., D.E.W.); the Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA (J.M.L.); Department of Nutrition, UNC Gillings School of Global Public Health, Chapel Hill, NC (E.M.-D.); and Kuakini Medical Center, Honolulu, HI (B.L.R.).

Abstract

Aims:Our study aims were to determine the frequency of MODY mutations (HNF1A, HNF4A, Glucokinase) in a diverse population of youth with diabetes and to assess how well clinical features identify youth with MODY.Methods:The SEARCH for Diabetes in Youth study is a US multicenter, population-based study of youth with diabetes diagnosed at < 20 years. We sequenced genomic DNA for mutations in the HNF1A, HNF4A, and glucokinase genes in 586 participants enrolled in SEARCH between 2001 and 2006. Selection criteria included diabetes autoantibody negativity and fasting C-peptide levels ≥ 0.8 ng/ml.Results:We identified a mutation in one of three MODY genes in 47 participants, or 8.0% of the tested sample, for a prevalence of at least 1.2% in the pediatric diabetes population. Of these, only three had a clinical diagnosis of MODY, and the majority was treated with insulin. Compared with the MODY-negative group, MODY-positive participants had lower FCP levels (2.2±1.4 ng/ml vs. 3.2±2.1 ng/ml, p< 0.01) and fewer type 2 diabetes-like metabolic features. Parental history of diabetes did not significantly differ between the two groups.Conclusions/Interpretation:In this systematic study of MODY in a large pediatric US diabetes cohort, unselected by referral pattern or family history, MODY was usually misdiagnosed and incorrectly treated with insulin. While many type 2 diabetes-like metabolic features were less common in the mutation-positive group, no single characteristic identified all patients with mutations. Clinicians should be alert to the possibility of MODY diagnosis, particularly in antibody negative youth with diabetes.