Searching for Maturity-Onset Diabetes of the Young (MODY): When and What for?

Maturity-onset diabetes of the young (MODY) is a group of monogenic diseases that results in primary defects in insulin secretion and dominantly inherited forms of nonautoimmune diabetes. Although many genes may be associated with monogenic diabetes, heterozygous mutations in 6 of them are responsible for the majority of cases of MODY. Glucokinase (GCK)-MODY is due to mutations in the glucokinase gene, 3 MODY subtypes are associated with mutations in the hepatocyte nuclear factor (HNF) transcription factors, and 2 others with mutations in ABCC8 and KCNJ11, which encode the subunits of the ATP-dependent potassium channel in pancreatic beta cells. GCK-MODY and HNF1A-MODY are the most common subtypes. The clinical presentation of MODY subtypes has been reported to differ according to the gene involved, and the diagnosis of MODY may be considered in various clinical circumstances. However, except in patients with GCK-MODY whose phenotype is very homogeneous, in most cases the penetrance and expressivity of a given molecular abnormality vary greatly among patients and, conversely, alterations in various genes may lead to similar phenotypes. Moreover, differential diagnosis among more common forms of diabetes may be difficult, particularly with type 2 diabetes. Thus, careful assessment of the personal and family histories of patients with diabetes is mandatory to select those in whom genetic screening is worthwhile. The diagnosis of monogenic diabetes has many consequences in terms of prognosis, therapeutics and family screening.