What are the types and genetic mutations associated with Maturity-Onset Diabetes of the Young (MODY)?

From the Guidelines

Maturity-Onset Diabetes of the Young (MODY) is caused by several distinct genetic mutations, with the most common types being MODY 1 (HNF4A gene), MODY 2 (GCK gene), and MODY 3 (HNF1A gene), as reported in the most recent study 1.

Types of MODY

The main types of MODY include:

• MODY 1 (HNF4A gene): characterized by progressive insulin secretory defect with presentation in adolescence or early adulthood, and sensitive to sulfonylureas 1
• MODY 2 (GCK gene): typically causes mild, stable hyperglycemia that rarely requires treatment beyond lifestyle modifications, with a higher glucose threshold for glucose-stimulated insulin secretion 1
• MODY 3 (HNF1A gene): characterized by progressive insulin secretory defect with presentation in adolescence or early adulthood, lowered renal threshold for glucosuria, and sensitive to sulfonylureas 1

Less Common Variants

Less common variants of MODY include:

• MODY 4 (PDX1 gene)
• MODY 5 (HNF1B gene, associated with renal abnormalities)
• MODY 6 (NEUROD1 gene)

Genetic Mutations

These mutations are inherited in an autosomal dominant pattern, meaning affected individuals have a 50% chance of passing the mutation to their children, as stated in 1.

Importance of Genetic Testing

Genetic testing is essential for accurate diagnosis, as MODY is often misdiagnosed as type 1 or type 2 diabetes, and proper identification of the specific MODY subtype is crucial for determining appropriate treatment strategies, genetic counseling, and screening family members who may carry the same mutation but remain undiagnosed, as highlighted in 1.

From the Research

Types of MODY

• There are 14 known subtypes of MODY, with mutations in three genes (HNF1A, HNF4A, GCK) accounting for about 95% of all MODY cases 2
• The most common forms of MODY are caused by mutations in glucokinase and hepatic nuclear factor 1 alpha or 4 alpha genes and account for almost 80% of cases of MODY 3
• MODY subtypes 1-6 are caused by mutations in genes encoding proteins such as hepatocyte nuclear factor (HNF) 4α, glucokinase (GCK), HNF1α, pancreatic and duodenal homeobox 1 (PDX1), HNF1β, and neurogenic differentiation 1 (NEUROD1) 4

Genetic Mutations in MODY

• Mutations in the GCK gene result in asymptomatic, stable fasting hyperglycemia, which does not require specific treatment 5
• Mutations in the HNF1A and HNF4A genes result in pancreatic β-cell dysfunction, which in turn causes hyperglycemia and often leads to diabetic angiopathy 5
• Identification of the MODY subtype is important, given the subtype-related differences in the age of onset, clinical course and progression, type of hyperglycemia, and response to treatment 4

Diagnosis and Treatment of MODY

• Making the right diagnosis is critical for effective treatment as well as for genetic counselling and patients' quality of life 3
• Diagnostic tools based on currently available genetic tests can facilitate the correct diagnosis and appropriate treatment of patients with MODY 4
• Treatment is usually unnecessary for patients with mutations in the GCK gene, while oral hypoglycemic agents (generally sulphonylureas) are recommended for patients with mutations in the HNF4A and HNF1A genes 2, 5