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

Diagnosis of Maturity-Onset Diabetes of the Young (MODY)

Genetic testing should be performed in children and young adults with diabetes not characteristic of type 1 or type 2 diabetes, particularly those with a family history of diabetes across multiple generations in an autosomal dominant pattern. 1

Clinical Features Suggesting MODY

MODY should be considered in patients with the following characteristics:

• Diabetes diagnosed at a young age (typically before 25-30 years) 1, 2
• Absence of obesity or other features of metabolic syndrome 1
• Strong family history of diabetes across multiple generations (autosomal dominant pattern) 1
• Absence of pancreatic autoantibodies (negative for GAD, IA-2, IAA, ZnT8) 1, 2
• Preserved C-peptide levels 3-5 years after diagnosis 2, 3
• Stable, mild fasting hyperglycemia (100-150 mg/dL) 1
• A1C between 5.6-7.6% (38-60 mmol/mol), especially in non-obese individuals 1

Diagnostic Algorithm

1. Initial Screening:

   • Test for pancreatic autoantibodies (to rule out type 1 diabetes)
   • Measure C-peptide levels (should be detectable with glucose >144 mg/dL)
   • Assess for features of metabolic syndrome (to differentiate from type 2 diabetes)

2. Biomarker Screening:

   • Consider urinary C-peptide/creatinine ratio 1
   • Low hs-CRP can help identify HNF1A-MODY specifically 1

3. Genetic Testing:

   • Next-generation sequencing panel targeting known MODY genes 1, 2
   • Focus on the most common mutations:
     • GCK (MODY2)
     • HNF1A (MODY3)
     • HNF4A (MODY1)
     • HNF1B (MODY5)

4. Specialist Consultation:

   • Refer to a center specializing in diabetes genetics for result interpretation and management guidance 1

Common MODY Subtypes and Their Clinical Characteristics

GCK-MODY (MODY2)

• Stable, nonprogressive elevated fasting blood glucose
• Small rise in 2-h plasma glucose on OGTT (<54 mg/dL [<3 mmol/L])
• Typically does not require treatment
• Microvascular complications are rare 1

HNF1A-MODY (MODY3)

• Progressive insulin secretory defect
• Lowered renal threshold for glucosuria
• Large rise in 2-h plasma glucose on OGTT (>90 mg/dL [>5 mmol/L])
• Highly responsive to sulfonylureas 1

HNF4A-MODY (MODY1)

• Progressive insulin secretory defect
• May have large birth weight and transient neonatal hypoglycemia
• Responsive to sulfonylureas 1

HNF1B-MODY (MODY5)

• Developmental renal disease (typically cystic)
• Genitourinary abnormalities
• Atrophy of the pancreas
• Hyperuricemia and gout 1

Clinical Pitfalls to Avoid

1. Misdiagnosis as Type 1 or Type 2 Diabetes:

   • MODY accounts for 1-5% of all diabetes cases but is frequently misdiagnosed 2, 4
   • Misdiagnosis can lead to inappropriate treatment (unnecessary insulin in some cases) 4, 5

2. Overlooking Atypical Presentations:

   • Some MODY patients may present with diabetic ketoacidosis, which can lead to misdiagnosis as type 1 diabetes 6
   • Always consider family history even in patients with acute presentations 6

3. Assuming All MODY Types Are Treated Similarly:

   • Treatment varies significantly based on the specific genetic defect 2
   • GCK-MODY generally requires no treatment
   • HNF1A/HNF4A-MODY respond well to sulfonylureas
   • HNF1B-MODY often requires insulin therapy 2

4. Failing to Screen Family Members:

   • Due to autosomal dominant inheritance, first-degree relatives have a 50% chance of carrying the mutation 2
   • Genetic counseling and testing of family members is recommended 1, 2

Benefits of Accurate Diagnosis

• Allows for appropriate treatment selection (e.g., sulfonylureas instead of insulin for HNF1A/HNF4A-MODY)
• Prevents unnecessary treatment in GCK-MODY
• Enables early identification and appropriate monitoring of affected family members
• Guides monitoring for specific complications (e.g., renal abnormalities in HNF1B-MODY) 2

Accurate diagnosis of MODY through genetic testing is cost-effective and often cost-saving in the long term, with increasing support from health insurance providers 1.