CHICAGO – About 5% of antibody-negative/C-peptide-positive children and adolescents diagnosed with diabetes in the United States may have Maturity-Onset Diabetes of the Young rather than type 2 diabetes, Dr. Lisa Gilliam reported at the annual scientific sessions of the American Diabetes Association.
Maturity-Onset Diabetes of the Young (MODY) is a clinically heterogeneous group of disorders characterized by nonketotic diabetes, an autosomal dominant pattern of inheritance, and typical onset below the age of 25 years. It can arise from mutations in any one of at least six different genes associated with beta-cell function. The most common form, MODY3, arises from a mutation in the HNF [hepatocyte nuclear factor]-1[α] gene (N. Engl. J. Med. 2001;345:971-80).
New findings suggest that MODY is underrecognized and often inappropriately treated. Physicians “need to maintain a high level of suspicion for MODY in antibody-negative children who have residual beta-cell function, and certainly consider screening in individuals who meet the classic criteria for MODY,” said Dr. Gilliam, of the division of metabolism, endocrinology and nutrition at the University of Washington, Seattle, in an interview.
The data come from SEARCH, a federally funded study of physician-diagnosed diabetes in individuals under 20 years of age in six U.S. centers located in Southern California, Colorado, Ohio, Washington state, South Carolina, and North Carolina. Of 3,993 participants in whom diabetes-associated autoantibodies and fasting C-peptide were measured, 438 were autoantibody-negative. Direct sequencing for the HNF-1[α] gene was performed in a subset of 266 patients who were autoantibody-negative and who had fasting C-peptide levels greater than 0.8 ng/mL. Of those, 13 patients had 14 gene mutations, including 7 that had not previously been described.
Only 1 of the 13 patients had been clinically diagnosed with MODY, whereas 5 had been misdiagnosed with type 1 diabetes, and 7 with type 2 diabetes. Seven were currently being treated with insulin, and none was taking sulfonylureas, which is the recommended pharmacologic treatment for MODY3. MODY patients are sensitive to sulfonylureas, which are cheaper and easier to take than multiple daily insulin injections, Dr. Gilliam explained.
Several clinical characteristics helped distinguish MODY3 from type 1 diabetes. Compared with those 3,484 individuals with type 1 diabetes in this study, the 13 MODY3 patients were less likely to have had weight loss (46% vs. 74%) or polyuria (54% vs. 93%) at diagnosis. The MODY group also tended to be older, heavier, much more likely to have a parent with diabetes (62% vs. 14%), and much less likely to have medium- to high-risk HLA types (46% vs. 85%). Just 3 of the 13 were non-Hispanic white (23%), compared with 69% of the type 1 group.
In contrast, virtually no clinical or biochemical characteristic was identified that could help in distinguishing MODY3 from type 2 diabetes on an individual basis. Although the MODY group was somewhat younger and less obese than the type 2 patients, there was a great deal of overlap between the two groups. The type 2 patients were as likely as the MODY group to have a positive family history for diabetes–including an autosomal dominant three-generation family history–and fasting C-peptide levels were similar.
“With the prevalence of obesity and type 2 diabetes increasing in the pediatric population, it's becoming more challenging to distinguish MODY from type 2 diabetes,” she noted. Genetic screening is very expensive, at this point it's not feasible to recommend it in every antibody-negative child or adolescent with residual fasting C-peptide.