What is Maturity-Onset Diabetes of the Young (MODY)?

Maturity-Onset Diabetes of the Young (MODY)

Maturity-Onset Diabetes of the Young (MODY) is a monogenic form of diabetes characterized by impaired insulin secretion with minimal or no defects in insulin action, autosomal dominant inheritance, and onset typically before age 25 years. 1

Definition and Characteristics

MODY is a rare genetic form of diabetes that accounts for approximately 1-5% of all diabetes cases. It is characterized by:

• Early onset (typically before age 25, though diagnosis may occur later)
• Autosomal dominant inheritance pattern (family history across multiple generations)
• Primary defect in pancreatic β-cell function
• Absence of pancreatic islet autoimmunity
• Generally non-insulin dependent at diagnosis
• Usually presents in lean individuals

Genetics and Classification

MODY is caused by mutations in at least 13 different genes on different chromosomes 1. The most common subtypes are:

1. GCK-MODY (MODY2)

   • Mutation in the glucokinase gene
   • Characterized by stable, mild fasting hyperglycemia
   • Rarely requires treatment
   • Low risk of microvascular complications
   • Small rise in 2-hour plasma glucose on OGTT (<54 mg/dL)

2. HNF1A-MODY (MODY3)

   • Mutation in hepatocyte nuclear factor 1-alpha
   • Progressive insulin secretory defect
   • Lowered renal threshold for glucosuria
   • Large rise in 2-hour plasma glucose on OGTT (>90 mg/dL)
   • Highly sensitive to sulfonylureas

3. HNF4A-MODY (MODY1)

   • Mutation in hepatocyte nuclear factor 4-alpha
   • Progressive insulin secretory defect
   • May have large birth weight and transient neonatal hypoglycemia
   • Responsive to sulfonylureas

4. HNF1B-MODY (MODY5)

   • Associated with developmental renal disease (typically cystic)
   • Genitourinary abnormalities
   • Pancreatic atrophy
   • Hyperuricemia and gout

Diagnostic Approach

Genetic testing for MODY should be performed in children and young adults who do not have typical characteristics of type 1 or type 2 diabetes and who often have a family history of diabetes in successive generations. 1

Key diagnostic indicators:

• Diabetes diagnosis before age 25-30 years
• Non-obese body habitus
• Family history of diabetes across multiple generations
• Absence of pancreatic autoantibodies
• Preserved C-peptide levels 3-5 years after diagnosis
• Lack of insulin resistance markers

Treatment Considerations

Treatment varies significantly based on the specific MODY subtype:

1. GCK-MODY (MODY2):

   • Generally requires no pharmacologic treatment
   • Stable, non-progressive hyperglycemia
   • Microvascular complications are rare
   • May require treatment during pregnancy

2. HNF1A-MODY (MODY3) and HNF4A-MODY (MODY1):

   • First-line therapy: low-dose sulfonylureas
   • Progressive insulin secretory defect may eventually require insulin
   • Risk of vascular complications similar to type 1 and type 2 diabetes

3. HNF1B-MODY (MODY5):

   • Often requires insulin therapy
   • Requires monitoring for associated renal, genital, and hepatic abnormalities

Clinical Implications

The correct diagnosis of MODY has significant treatment implications 1:

• Patients misdiagnosed with type 1 diabetes may be able to transition from insulin to oral agents
• Appropriate treatment reduces the risk of diabetic complications
• Enables predictive genetic testing for asymptomatic family members
• Guides pregnancy management, particularly for GCK-MODY

Pitfalls and Caveats

• MODY is frequently misdiagnosed as type 1 or type 2 diabetes
• Not all patients with early-onset diabetes have MODY; consider autoimmune markers
• Treatment response varies significantly between MODY subtypes
• Consultation with a center specializing in diabetes genetics is recommended to understand the significance of mutations and determine appropriate treatment 1
• Some MODY subtypes have extra-pancreatic manifestations requiring multisystem monitoring

Early identification and appropriate treatment of MODY are essential for reducing morbidity and mortality related to diabetic complications and improving quality of life for affected individuals.