Symptoms and Management of Maturity-Onset Diabetes of the Young (MODY)
MODY is characterized by autosomal dominant inheritance, young-onset diabetes (typically before age 25), absence of pancreatic islet autoimmunity, and specific clinical features that vary by subtype, with treatment approaches differing significantly from type 1 and type 2 diabetes. 1, 2
Clinical Presentation and Symptoms
General Features
- Young age at diagnosis, typically before 25 years 2, 3
- Family history of diabetes in successive generations (autosomal dominant inheritance pattern) 2, 3
- Absence of typical features of type 1 diabetes (negative autoantibodies) 2
- Absence of typical features of type 2 diabetes (non-obesity, lack of metabolic syndrome) 2, 3
- Minimal or no defects in insulin action 2
Subtype-Specific Symptoms
GCK-MODY (MODY 2)
- Stable, non-progressive elevated fasting blood glucose 1
- Typically asymptomatic 4
- Mild hyperglycemia (100-150 mg/dL) 1, 3
- Small rise in 2-hour plasma glucose during OGTT (<54 mg/dL) 1
- Rare microvascular complications 1
HNF1A-MODY (MODY 3)
- Progressive insulin secretory defect presenting in adolescence or early adulthood 1
- Lowered renal threshold for glucosuria (glycosuria at relatively normal blood glucose levels) 1
- Large rise in 2-hour plasma glucose during OGTT (>90 mg/dL) 1
- May present with typical diabetes symptoms (polydipsia, polyuria, polyphagia) 1
HNF4A-MODY (MODY 1)
- Progressive insulin secretory defect with presentation in adolescence or early adulthood 1
- May have history of large birth weight 1
- May have history of transient neonatal hypoglycemia 1
HNF1B-MODY (MODY 5)
- Renal developmental disorders (typically cystic) 1
- Genitourinary abnormalities 1
- Pancreatic atrophy 1
- Hyperuricemia and gout 1
Diagnosis
When to Suspect MODY
- Diabetes diagnosed at young age (typically before 25 years) 2, 3
- Family history of diabetes across multiple generations 2
- Atypical presentation not consistent with type 1 or type 2 diabetes 2, 3
- Stable HbA1c between 5.6% and 7.6% 2
Diagnostic Approach
- Genetic testing is the gold standard for diagnosis 1, 2
- Biomarker screening (urinary C-peptide/creatinine ratio and antibody screening) may help determine candidates for genetic testing 1, 2
- Absence of autoantibodies associated with type 1 diabetes supports MODY diagnosis 2, 3
- OGTT patterns can help differentiate MODY subtypes 1
Management
GCK-MODY (MODY 2)
- Typically requires no pharmacological treatment 1, 3, 4
- Lifestyle modifications only 5
- May require treatment during pregnancy 3
HNF1A-MODY (MODY 3) and HNF4A-MODY (MODY 1)
- First-line therapy: low-dose sulfonylureas 1, 3, 4
- High sensitivity to sulfonylureas 1
- May eventually require insulin therapy as the condition progresses 6, 7
- Regular monitoring for microvascular complications 4
HNF1B-MODY (MODY 5)
- Requires multidisciplinary approach due to multi-organ involvement 1, 3
- Management of renal disease 1
- Treatment of hyperuricemia and gout 1
- May require insulin therapy 4
Important Clinical Considerations
Common Pitfalls to Avoid
- Misdiagnosing MODY as type 1 or type 2 diabetes, leading to inappropriate treatment 2, 7
- Assuming autoantibody positivity rules out MODY (autoantibodies can occasionally be present in monogenic diabetes) 1, 2
- Delaying genetic testing, which can lead to years of suboptimal treatment 2
Benefits of Correct Diagnosis
- Appropriate treatment selection (avoiding unnecessary insulin in many cases) 2, 7
- Identification of affected family members through genetic testing 1, 3
- Better prognostication and complication prevention 7
- Improved quality of life through optimized treatment 7
Screening Recommendations
- Consider genetic testing in patients with diabetes diagnosed before age 25 years 2, 3
- Test patients with strong family history of diabetes in successive generations 2
- Screen patients with atypical features not consistent with type 1 or type 2 diabetes 2, 3
- Immediate genetic testing for all infants diagnosed with diabetes in the first 6 months of life 2