When should screening for Maturity-Onset Diabetes of the Young (MODY) be considered?

When to Screen for Maturity-Onset Diabetes of the Young (MODY)

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 (suggestive of an autosomal dominant pattern of inheritance). 1

Key Clinical Scenarios Warranting MODY Screening

Primary Indications

• Age at diagnosis: Diabetes diagnosed at a young age (classically before age 25 years), although diagnosis may occur at older ages 1
• Family history: Autosomal dominant pattern of inheritance (diabetes occurring in successive generations) 1
• Atypical diabetes presentation: Clinical features not characteristic of either type 1 or type 2 diabetes 1

Specific Clinical Features Suggesting MODY

• Absence of typical type 1 diabetes features:

  • Negative diabetes-associated autoantibodies 1
  • Detectable C-peptide levels 3-5 years after diagnosis (indicating preserved β-cell function) 2

• Absence of typical type 2 diabetes features:

  • Non-obese patient 1, 2
  • Lacking other metabolic syndrome features 1
  • Minimal or no defects in insulin action 1

• Glycemic patterns suggestive of MODY:

  • Stable, mild fasting hyperglycemia (100–150 mg/dL [5.5–8.5 mmol/L]) 1
  • Stable A1C between 5.6% and 7.6% (38-60 mmol/mol), especially in non-obese individuals 1

Special Populations Requiring MODY Screening

Neonatal Diabetes

• All children diagnosed with diabetes in the first 6 months of life should have immediate genetic testing for neonatal diabetes 1
• This is critical as 80-85% of diabetes cases in this age group have an underlying monogenic cause 1

Pregnant Women

• Consider MODY testing in pregnant women with atypical diabetes presentation, as management differs significantly (especially for GCK-MODY) 3, 2

Importance of Correct Diagnosis

Treatment Implications

• GCK-MODY (MODY2): Typically requires no treatment except sometimes during pregnancy 1, 3
• HNF1A-MODY (MODY3) and HNF4A-MODY (MODY1): Usually respond well to low doses of sulfonylureas 1, 4
• HNF1B-MODY (MODY5): Associated with renal cysts and other organ malformations requiring specialized management 1

Avoiding Misdiagnosis

• MODY is frequently misdiagnosed as type 1 or type 2 diabetes, leading to inappropriate treatment 5, 6
• Correct diagnosis prevents unnecessary insulin therapy in many cases 6
• Enables early diagnosis of affected family members through genetic counseling 4

Recommended Approach to Testing

• Biomarker screening: Urinary C-peptide/creatinine ratio and antibody screening may help determine who should undergo genetic testing 1
• Genetic testing: Commercially available genetic testing is increasingly cost-effective and often covered by health insurance 1
• Specialist consultation: Consultation with a center specializing in diabetes genetics is recommended to understand the significance of mutations and guide further evaluation, treatment, and genetic counseling 1

Common Pitfalls to Avoid

• Overlooking MODY in obese patients: While MODY typically occurs in non-obese individuals, patients with MODY are increasingly becoming overweight/obese like the general population 3
• Assuming autoantibody positivity rules out MODY: While uncommon, the presence of autoantibodies has been reported in patients with monogenic diabetes 1
• Delaying testing: Early genetic diagnosis can prevent years of inappropriate treatment 1, 3

Remember that MODY accounts for approximately 1-2% of all diabetes cases, but making the correct diagnosis has significant implications for treatment approach, prognosis, and family screening 5, 3.