Maturity Onset Diabetes of the Young
Maturity Onset Diabetes of the Young (MODY) is an autosomal dominant disorder that causes pancreatic beta cell dysfunction and the onset of mild diabetes during adolescence or early adulthood. MODY is the most common form of monogenic diabetes, accounting for 2 to 5% of cases. Most types of MODY cause isolated hyperglycemia rather than a syndrome.
Mutations in at least 13 genes have been associated with distinct forms of MODY. However, 3 mutations account for most cases: GCK, which encodes glucokinase, and HNF1A and HNF4A, which encode hepatocyte nuclear factors 1A and 4A, respectively. Mutations in GCK gene account for 50-65% of MODY cases, HNF1A 15-30% and HNF4a 10%.
More than a dozen mutations in the GCK gene have been reported. Glucokinase is an enzyme in pancreatic beta cells that phosphorylates glucose to glucose-6-phosphate and regulates the rate of glucose entry into the glycolytic pathway. GCK mutations decrease glucose sensing and insulin secretion resulting in an upward shift in fasting blood glucose levels to 100 to 145 mg/dL and increased postprandial blood glucose levels. The resulting hyperglycemia is stable and does not predispose to vascular complications. GCK-MODY is present at birth and is not altered by treatment.
HNF1A is a weak transactivator of the insulin gene in pancreatic beta cells. Mutations of HNF1A can lead to abnormal insulin secretion and a low renal threshold for glucose. These patients often display glucosuria. HNF4A is expressed by hepatocytes and pancreatic beta cells. One of its functions is to regulate positively the activity of HNF1A. The exact mechanism by which HNF4A mutations cause hyperglycemia is not clear, but they are associated with reduced insulin secretion in response to glucose.
MODY associated with HNF1A and HNF4A are characterized by the development of diabetes in early teen years or young adulthood, that is initially mild and then progresses to insulin dependence. These patients are at risk for microvascular and macrovascular complications of type 1 and type 2 diabetes mellitus as well as an increased risk of cardiovascular mortality. They can be successfully treated with sulfonylureas.
Patients may have type 1 or type 2 diabetes in addition to MODY, so affected patients should be screened for diabetes according to recommendations for the general population. Patients with GCK-MODY usually have HbA1c levels below 7.5% Higher values may indicate concomitant diabetes from another cause, which would.
Patients with MODY due to HNF1A or HNF4A mutations are frequently misdiagnosed as having insulin requiring type 1 diabetes because they present at an early age and are not obese. It is important to distinguish MODY from type 1 and 2 diabetes is important because treatment differs.
The diagnosis of MODY is made by performing gene sequencing in patients with a high index of suspicion. Risk factors include familial diabetes with autosomal dominant pattern of inheritance, onset before 25 years of age, nonobese, and absence of islet cell autoantibodies.
Reference
Udler MS et al. Case 6-2020: A 34-year-old woman with hyperglycemia. N Engl J Med 2020; 382:745-753
