Three Factors Distinguish MODY, a Rare Diabetes, in Youth

Miriam E. Tucker

November 21, 2019

Among youth newly diagnosed with diabetes, a simple clinical approach — looking for moderate hyperglycemia (A1c < 7.5%), asking about parental history of diabetes, and checking for autoantibodies associated with type 1 diabetes — should help determine whether kids need to be genetically screened for maturity-onset diabetes of the young (MODY), new research suggests.

Results from a 5-year analysis of data from nearly 4000 individuals in Sweden diagnosed with diabetes at ages 1-18 years were published online November 8, 2019, in Diabetes Care by Annelie Carlsson, MD, PhD, of Skane University Hospital, Malmo, Sweden, and colleagues. The study was supported by the Swedish Child Diabetes Foundation, National Institutes of Health, National Institute for Health Research (UK), and Wellcome Trust.

MODY is a monogenic, dominantly inherited form of diabetes that typically arises in adolescence or young adulthood, and accounts for 1-4% of cases of pediatric diabetes.

Recognizing MODY is important, as treatment and management are different from type 1 and type 2 diabetes. Depending on the specific genetic subtype, MODY can be managed with sulfonylureas, diet, or no treatment — a key point is that there is no need for insulin.

Misdiagnosis results in many young people being treated unnecessarily with insulin, with many years' delay from initial diabetes diagnosis to correct genetic diagnosis.

The new research suggests screening for at least three autoantibodies and A1c testing takes place in all youth at the time of diabetes diagnosis, along with inquiry as to whether either parent has diabetes.

If all antibodies are negative and the patient has an A1c < 7.5% and/or a parental history of diabetes, then MODY genetic screening should be performed, senior author Andrew T. Hattersley, MD, told Medscape Medical News.  

"We think this research leads to a simple clinical approach which will ensure the vast majority of MODY patients are rapidly and efficiently diagnosed and their insulin treatment replaced," he said.

"We show that there are excellent outcomes achieved off insulin in patients diagnosed with MODY," emphasized Hattersley, of the University of Exeter Medical School, UK. Hattersley is a senior investigator for the Wellcome Trust and National Institute for Health Research.

Approach Captures Nearly All Patients With MODY

Carlsson and colleagues studied 3933 Swedish youth aged 1-18 years who were diagnosed with diabetes between May 2005 and December 2010.

At the time of diagnosis, all were screened for four islet autoantibodies associated with type 1 diabetes: GAD antibody (GADA), insulinoma antigen-2A (IA-2A), zinc transporter 8A (ZnT8A), and insulin autoantibody (IAA).

Overall, 88% (3471) were positive for at least one of the four autoantibodies. On sequencing, none of those individuals were found to carry the MODY genes — GCK, HNF1A, or HNF4A — via routine clinical or research testing.

When 303 of the autoantibody-negative patients were genetically tested, 15% (46) had MODY, resulting in a minimal prevalence of 1.2%.

The others had either antibody-negative type 1 diabetes, type 2 diabetes, or other types, such as cystic fibrosis-related diabetes, Hattersley explained.  

The strongest discriminatory clinical feature for having MODY, compared with those not known to have MODY, was being negative to all four islet autoantibodies (100% vs 11%; P = 2 x 10-44).

Other discriminatory features were lower A1c (7.0% vs 10.7%; 53 vs 93 mmol/mol; P = 1 x 10-20), lower random plasma glucose (mean 11.7 vs 26.7 mmol/L; P = 3 x 10-19), parental diabetes (63% vs 12%; P = 1 x 10-15), and not having diabetic ketoacidosis (0 of 46 vs 601 of 3887 patients; P = .001). 

In an adjusted analysis, only plasma glucose (P = 6 x 10-5) and parental history of diabetes (P = .02) remained significant predictors of MODY.   

Limiting MODY testing to just the 73 individuals who were both autoantibody negative and had an A1c < 7.5% improved the detection rate to 49% (36 out of 73) and identified 78% (36 out of 46) of those who had MODY.

If MODY genetic testing were limited to the 96 patients who were both autoantibody negative and had a parental family history of diabetes, the MODY detection rate would be 30% (29 out of 96), and 63% (29 out of 46).

And if testing were done for the 131 patients who were autoantibody negative and had either A1c < 7.5% or an affected parent, those rates would be 33% (44 out of 131) and 96% (44 out of 46), respectively.

The researchers add that "Both glycemia at diagnosis and family history have a role in selecting which autoantibody-negative patients to test, but if selecting on a single clinical criteria only," then modest hyperglycemia (A1c < 7.5%; < 58 mmol/mol) would be both more sensitive and more specific than family history.

The major strengths of the study, say researchers, is that it is a large, consecutive series recruiting 87% of cases with newly diagnosed diabetes in the pediatric population, allowing assessment of both clinical features and autoantibodies at diagnosis. Another strength is that all autoantibody tests were conducted at a central laboratory.

All With MODY Had Excellent Glycemic Control; Most Off Insulin

At an average of about 6 years following initial diabetes diagnosis, all 46 patients identified as having MODY had achieved excellent glycemic control, (mean A1c 6.4%) and 42 out of 46 (91%) patients were not on insulin treatment. Instead, they were taking the recommended treatments by MODY subtype: no treatment for GCK MODY (29 of 29), and diet or sulfonylurea for HNF1A MODY (9 out of 10), and HNF4A MODY (4 of 7).

Of 18 patients who had been started on insulin at diabetes diagnosis, 14 discontinued it following the positive MODY genetic test.

Clinically, the authors note that although there is a clear benefit for testing three of the islet autoantibodies — GADA, IA-2A, and ZnT8A — adding IAA may be less helpful.

IAA is technically difficult to measure and only reduces the proportion of antibody-negative patients from 13% to 12%, so "it may not be considered necessary clinically."

Asked to what extent these results might apply to adults, Hattersley told Medscape Medical News that MODY typically occurs between ages 10 and 30 years, but in [older] adults there will be more cases of type 2 diabetes who are also antibody negative, so screening will be less effective at detecting MODY cases.

However, he advised, "any young adult who is normal weight who is negative for three islet autoantibodies and has an A1c < 7.5% should be tested for MODY as it is still highly likely."

Diabetes Care. Published online November 8, 2019. Abstract

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