What is Maturity-Onset Diabetes of the Young (MODY) and how is it managed?

Maturity-Onset Diabetes of the Young (MODY): Diagnosis and Management

MODY is a group of monogenic diabetes disorders characterized by autosomal dominant inheritance, early onset (typically before age 25), and impaired insulin secretion with minimal or no defects in insulin action. 1 This form of diabetes accounts for approximately 1-5% of all diabetes cases but is frequently misdiagnosed as type 1 or type 2 diabetes, leading to suboptimal treatment.

Definition and Characteristics

MODY is characterized by:

• Autosomal dominant inheritance pattern
• Early onset of hyperglycemia (usually before age 25)
• Impaired insulin secretion with preserved insulin sensitivity
• Absence of pancreatic islet autoimmunity
• Non-insulin dependent at diagnosis
• Absence of obesity (in most cases)

MODY Subtypes

At least 13 genetic subtypes have been identified 1, with the most common being:

GCK-MODY (MODY2)

• Pathophysiology: Mutations in glucokinase gene (chromosome 7) affecting the glucose sensor of β-cells
• Clinical features:
  • Stable, mild fasting hyperglycemia (100-150 mg/dL)
  • Non-progressive
  • Small rise in 2-hour glucose during OGTT (<54 mg/dL)
  • Rarely causes microvascular complications
• Treatment:
  • Generally requires no pharmacological treatment
  • Lifestyle modifications only
  • May require treatment during pregnancy 1

HNF1A-MODY (MODY3)

• Pathophysiology: Mutations in hepatocyte nuclear factor-1α
• Clinical features:
  • Progressive insulin secretory defect
  • Presentation in adolescence or early adulthood
  • Lowered renal threshold for glucosuria
  • Large rise in 2-hour glucose during OGTT (>90 mg/dL)
  • Risk of microvascular complications similar to type 1 and type 2 diabetes
• Treatment:
  • Highly sensitive to sulfonylureas (first-line therapy)
  • May eventually require insulin 1

HNF4A-MODY (MODY1)

• Pathophysiology: Mutations in hepatocyte nuclear factor-4α
• Clinical features:
  • Progressive insulin secretory defect
  • May have large birth weight and transient neonatal hypoglycemia
  • Similar clinical course to HNF1A-MODY
• Treatment:
  • Sulfonylureas are effective (first-line therapy)
  • May eventually require insulin 1

HNF1B-MODY (MODY5)

• Pathophysiology: Mutations in hepatocyte nuclear factor-1β
• Clinical features:
  • Developmental renal disease (typically cystic)
  • Genitourinary abnormalities
  • Pancreatic atrophy
  • Hyperuricemia and gout
• Treatment:
  • Often requires insulin due to pancreatic atrophy 1

Diagnostic Approach

MODY should be suspected in patients with:

1. Diabetes diagnosed at young age (typically <25 years)
2. Strong family history of diabetes in multiple generations (autosomal dominant pattern)
3. Absence of obesity or other features of insulin resistance
4. Absence of islet autoantibodies
5. Preserved β-cell function (detectable C-peptide)
6. Mild fasting hyperglycemia (100-150 mg/dL), especially if stable

Diagnostic Testing

• Genetic testing is the gold standard for diagnosis 1
• Testing should include the most common MODY genes (GCK, HNF1A, HNF4A)
• Consultation with a center specializing in diabetes genetics is recommended 1

Treatment Approach

Treatment should be tailored to the specific MODY subtype:

1. GCK-MODY (MODY2):

   • No pharmacological treatment required in most cases
   • Stable hyperglycemia rarely leads to complications
   • Monitoring only

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

   • First-line: Low-dose sulfonylureas (highly effective)
   • Monitor for progressive β-cell failure
   • May eventually require insulin therapy
   • Regular screening for microvascular complications

3. HNF1B-MODY (MODY5):

   • Often requires insulin therapy due to pancreatic atrophy
   • Monitor for renal dysfunction and other associated abnormalities

Clinical Implications of Correct Diagnosis

Making the correct diagnosis of MODY has significant implications:

1. Appropriate treatment: Many patients misdiagnosed as type 1 diabetes can discontinue insulin and be effectively managed with oral sulfonylureas
2. Prognosis: Different MODY subtypes have different risks for complications
3. Family screening: Allows early identification of affected family members
4. Genetic counseling: Important for family planning

Common Pitfalls to Avoid

1. Misdiagnosis as type 1 diabetes: Leading to unnecessary insulin therapy
2. Misdiagnosis as type 2 diabetes: Leading to inappropriate metformin therapy
3. Failure to consider MODY in lean young patients with diabetes
4. Overlooking family history: MODY has an autosomal dominant inheritance pattern
5. Assuming all MODY subtypes are the same: Treatment varies significantly by subtype

Genetic testing is essential for accurate diagnosis and should be considered in any young, non-obese patient with diabetes who has a strong family history and preserved β-cell function, as correct identification significantly impacts treatment decisions and quality of life 1, 2.