Abstract
MODY2 is the most prevalent monogenic form of diabetes in Italy with an estimated prevalence of about 0.5–1.5%. MODY2 is potentially indistinguishable from other forms of diabetes, however, its identification impacts on patients' quality of life and healthcare resources. Unfortunately, DNA direct sequencing as diagnostic test is not readily accessible and expensive. In addition current guidelines, aiming to establish when the test should be performed, proved a poor detection rate. Aim of this study is to propose a reliable and easy-to-use tool to identify candidate patients for MODY2 genetic testing. We designed and validated a diagnostic flowchart in the attempt to improve the detection rate and to increase the number of properly requested tests. The flowchart, called 7-iF, consists of 7 binary “yes or no” questions and its unequivocal output is an indication for whether testing or not. We tested the 7-iF to estimate its clinical utility in comparison to the clinical suspicion alone. The 7-iF, in a prospective 2-year study (921 diabetic children) showed a precision of about the 76%. Using retrospective data, the 7-iF showed a precision in identifying MODY2 patients of about 80% compared to the 40% of the clinical suspicion. On the other hand, despite a relatively high number of missing MODY2 patients, the 7-iF would not suggest the test for 90% of the non-MODY2 patients, demonstrating that a wide application of this method might 1) help less experienced clinicians in suspecting MODY2 patients and 2) reducing the number of unnecessary tests. With the 7-iF, a clinician can feel confident of identifying a potential case of MODY2 and suggest the molecular test without fear of wasting time and money. A Qaly-type analysis estimated an increase in the patients' quality of life and savings for the health care system of about 9 million euros per year.
Highlights
Maturity-onset diabetes of the young type 2 (MODY2) is a monogenic form of diabetes with autosomic dominant transmission caused by heterozygous, inactivating mutation in the glucokinase gene (GCK)
7-item flowchart We defined the seven clinical, biochemical and anamnestic criteria that best characterize a typical MODY2 patient: 1) negative test for pancreatic autoimmune markers; 2) insulin therapy naive; 3) HbA1c levels above or equal to 42 mmol/mol (HbA1c = 6%) on at least one occasion; 4) diabetes/hyperglycemia-onset ranging between 6 months and 25 years; 5) one parent affected by diabetes of any type or impaired fasting glucose (IFG) with or without impaired glucose tolerance (IGT); 6) no signs or symptoms suggestive of different types of diabetes; and 7) without concurring severe diseases, and not undergoing therapy that could impair glucose homeostasis (Table S1)
Prospective evaluation of the 7-iF To assess the clinical utility of the 7-iF, we evaluated clinical records of the 921 patients followed in the Diabetic Outpatient Clinic of the Department of Pediatrics of the Second University of Naples with biochemical data of the autoimmune markers for type 1 diabetes (GAD, islet cell antibodies (ICA), insulin auto-antibodies (IAA), IA2 and the zinc transporter 8 (ZnT8))
Summary
Maturity-onset diabetes of the young type 2 (MODY2) is a monogenic form of diabetes with autosomic dominant transmission caused by heterozygous, inactivating mutation in the glucokinase gene (GCK). Loss-of-function GCK mutations impair glucose-sensing of the pancreatic beta cells (and liver) that in turn increase the threshold of pancreatic glucose-stimulated insulin secretion [1,2,3]. MODY2 patients have a moderate, not-progressive increase in fasting glucose and HbA1c levels and impaired glucose tolerance at the oral glucose tolerance test. It is clearly established that MODY2 patients under treatment with insulin or oral anti-diabetic drugs can discontinue therapy without deterioration of their metabolic control. The typical MODY2 patient requires less frequent clinical surveillance than patients with other forms of diabetes. To diagnose MODY 2, especially in the pediatric age, is of paramount importance to ensure the appropriate clinical management and save healthcare resources [7]
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