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

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

MODY is a group of monogenic disorders causing autosomal dominant inherited diabetes, characterized by onset of hyperglycemia typically before age 25 years, impaired insulin secretion with minimal insulin resistance, and strong family history across successive generations. 1

Core Defining Features

MODY represents approximately 1% of all diabetes cases and is frequently misdiagnosed as type 1 or type 2 diabetes. 2, 3 The condition differs fundamentally from these common forms:

• Genetic inheritance: Autosomal dominant pattern, meaning affected individuals have a 50% chance of passing the mutation to offspring 1, 4
• Age of onset: Classically diagnosed before age 25 years, though diagnosis can occur at older ages 1, 4
• Insulin secretion defect: Primary problem is impaired insulin secretion from pancreatic β-cells, not insulin resistance 1
• Preserved β-cell function: Unlike type 1 diabetes, patients maintain detectable C-peptide levels years after diagnosis 5
• Absence of autoimmunity: No diabetes-associated autoantibodies present (though rare exceptions exist) 4, 6

Major MODY Subtypes

At least 13 genetic mutations have been identified, but three subtypes account for approximately 80-95% of all MODY cases. 1, 3

GCK-MODY (MODY 2)

• Clinical presentation: Mild, stable, non-progressive fasting hyperglycemia (100-150 mg/dL) present from birth 1, 4
• OGTT pattern: Small rise in 2-hour plasma glucose (<54 mg/dL or <3 mmol/L) 1
• Treatment: Typically requires no pharmacological therapy except commonly during pregnancy 1, 7
• Complications: Microvascular complications are rare 1, 6
• Mechanism: Defective glucokinase enzyme raises the glucose "set point" for insulin secretion 1

HNF1A-MODY (MODY 3)

• Clinical presentation: Progressive insulin secretory defect presenting in adolescence or early adulthood 1, 6
• Distinctive features: Lowered renal threshold for glucosuria; large rise in 2-hour plasma glucose on OGTT (>90 mg/dL or >5 mmol/L) 1
• Treatment: Highly sensitive to low-dose sulfonylureas, which are first-line therapy 1, 7
• Complications: Vascular complication rates similar to type 1 and type 2 diabetes 7, 5

HNF4A-MODY (MODY 1)

• Clinical presentation: Progressive insulin secretory defect similar to HNF1A-MODY 1, 6
• Distinctive features: May have large birth weight and history of transient neonatal hypoglycemia 1, 4
• Treatment: Sensitive to low-dose sulfonylureas as first-line therapy 1, 7

HNF1B-MODY (MODY 5)

• Clinical presentation: Multi-organ involvement beyond diabetes 1, 4
• Associated features: Developmental renal disease (typically cystic), genitourinary abnormalities, pancreatic atrophy, hyperuricemia, and gout 1, 2
• Treatment: Often requires insulin therapy due to pancreatic atrophy; multidisciplinary management needed 7

When to Suspect MODY

The American Diabetes Association recommends considering MODY in specific clinical scenarios: 4, 6

• Young age at diagnosis: Diabetes diagnosed before age 25-30 years in non-obese individuals 4, 5
• Strong family history: Diabetes in successive generations suggesting autosomal dominant inheritance 4, 7
• Atypical presentation: Clinical features not characteristic of type 1 or type 2 diabetes 4
• Negative autoantibodies: Absence of GAD, IA-2, or other diabetes-associated autoantibodies 6
• Preserved C-peptide: Detectable C-peptide levels 3-5 years after diagnosis with glucose >144 mg/dL 5
• Non-obese phenotype: Absence of obesity and metabolic syndrome features 6
• Stable mild hyperglycemia: HbA1c between 5.6% and 7.6% with stable fasting glucose 4, 6

Critical Importance of Correct Diagnosis

Making the correct genetic diagnosis has profound treatment implications that directly impact patient outcomes and quality of life. 1, 4

Treatment Differences by Subtype

• GCK-MODY patients can avoid unnecessary lifelong medication, as they typically need no treatment except during pregnancy 1, 7
• HNF1A/HNF4A-MODY patients respond dramatically to low-dose sulfonylureas and can often discontinue insulin if misdiagnosed with type 1 diabetes 1, 8
• Misdiagnosis consequences: Patients are frequently inappropriately managed with insulin when oral sulfonylureas would be more effective 8

Genetic Counseling Benefits

• Allows identification of other affected family members through predictive genetic testing 6, 3
• Provides accurate recurrence risk information (50% for autosomal dominant inheritance) 1
• Enables early diagnosis and treatment of asymptomatic relatives 2, 3

Diagnostic Approach

Genetic testing is the gold standard for definitive MODY diagnosis and is increasingly cost-effective and covered by insurance. 4, 6

Recommended Testing Strategy

• Biomarker screening first: Urinary C-peptide/creatinine ratio and antibody screening help identify candidates for genetic testing 4
• OGTT patterns: Can help differentiate MODY subtypes (small rise <54 mg/dL suggests GCK-MODY; large rise >90 mg/dL suggests HNF1A-MODY) 1, 4
• Specialist consultation: Referral to centers specializing in diabetes genetics is recommended for interpretation of mutations and management guidance 4

Special Population: Neonatal Diabetes

All infants diagnosed with diabetes in the first 6 months of life require immediate genetic testing, as 80-85% have an underlying monogenic cause. 1, 7 This is distinct from MODY but represents another critical monogenic diabetes scenario where genetic diagnosis changes management.

Common Diagnostic Pitfalls

• Assuming autoantibody positivity rules out MODY: Rare cases of autoantibody-positive monogenic diabetes have been reported 1, 4
• Delaying genetic testing: Years of inappropriate treatment can be prevented by early genetic diagnosis 4
• Missing family history: Always obtain detailed three-generation family history looking for autosomal dominant pattern 4
• Age cutoff rigidity: While classically diagnosed before age 25, MODY can be diagnosed at older ages 1