What is Maturity-Onset Diabetes of the Young (MODY)?
MODY is a monogenic form of diabetes caused by autosomal dominant genetic mutations affecting insulin secretion, classically presenting before age 25 years with a strong multigenerational family history, and representing less than 5% of all diabetes cases. 1
Core Definition and Pathophysiology
MODY is fundamentally different from type 1 and type 2 diabetes because it results from single-gene mutations inherited in an autosomal dominant pattern, meaning it passes through successive generations with a 50% transmission risk. 1 The primary defect involves impaired insulin secretion with minimal or no defects in insulin action (in the absence of obesity), distinguishing it from the insulin resistance seen in type 2 diabetes and the autoimmune destruction in type 1 diabetes. 1
At least 13 different genes have been identified as causing MODY, though three subtypes account for approximately 80-95% of all cases. 1, 2
The Three Most Common MODY Subtypes
GCK-MODY (MODY 2)
- Stable, non-progressive mild fasting hyperglycemia (typically 100-150 mg/dL) present from birth 1
- Small rise in 2-hour plasma glucose on oral glucose tolerance test (<54 mg/dL) 1
- Microvascular complications are rare 1
- Typically requires no pharmacological treatment except sometimes during pregnancy 1
- This represents a "reset" glucostat rather than progressive diabetes 2
HNF1A-MODY (MODY 3)
- Progressive insulin secretory defect with presentation in adolescence or early adulthood 1
- Large rise in 2-hour plasma glucose on oral glucose tolerance test (>90 mg/dL) 1
- Lowered renal threshold for glucosuria (glucose appears in urine at lower blood glucose levels) 1
- Highly sensitive to low-dose sulfonylureas, which are first-line therapy 1
- Vascular complication rates similar to type 1 and type 2 diabetes if untreated 3
HNF4A-MODY (MODY 1)
- Progressive insulin secretory defect similar to HNF1A-MODY 1
- May present with large birth weight and transient neonatal hypoglycemia 1
- Responds well to low-dose sulfonylureas as first-line therapy 1
- Requires similar monitoring for complications as HNF1A-MODY 3
HNF1B-MODY (MODY 5)
- Associated with developmental renal disease (typically cystic kidneys) 1
- Genitourinary abnormalities and pancreatic atrophy 1
- Hyperuricemia and gout 1
- Requires multidisciplinary management and often insulin therapy 4
Clinical Recognition: When to Suspect MODY
Genetic testing should be pursued in children and young adults with diabetes not characteristic of type 1 or type 2 diabetes that occurs in successive generations. 1
Key Clinical Red Flags:
- Diabetes diagnosed before age 25 years (though diagnosis can occur later) 1
- Strong multigenerational family history suggesting autosomal dominant inheritance (affected parent and grandparent) 1
- Non-obese patient without metabolic syndrome features 4
- Negative diabetes-associated autoantibodies (GAD, IA-2, ZnT8) 4
- Preserved C-peptide levels 3-5 years after diagnosis (unlike type 1 diabetes) 3
- Stable mild hyperglycemia with A1C between 5.6-7.6% 4
Critical Pitfall to Avoid:
The presence of autoantibodies does NOT rule out MODY, as autoantibodies have been reported in patients with monogenic diabetes. 4, 5 Do not dismiss MODY based solely on positive antibodies if other clinical features are suggestive.
Diagnostic Approach
All children diagnosed with diabetes in the first 6 months of life should have immediate genetic testing for neonatal diabetes, as 80-85% have an underlying monogenic cause. 1
For suspected MODY beyond infancy:
- Biomarker screening with urinary C-peptide/creatinine ratio and antibody testing can help identify candidates for genetic testing 4
- Genetic testing is the gold standard and is increasingly cost-effective and often covered by insurance 4
- Consultation with a center specializing in diabetes genetics is recommended to interpret results and guide treatment and genetic counseling 1
Treatment Implications: Why Correct Diagnosis Matters
The treatment approach differs dramatically based on MODY subtype, making genetic diagnosis clinically essential rather than academic:
GCK-MODY (MODY 2):
- No treatment required in most cases 1
- Lifestyle modifications only 4
- Treatment may be needed during pregnancy 1
HNF1A-MODY and HNF4A-MODY (MODY 3 and 1):
- Low-dose sulfonylureas are first-line therapy due to high sensitivity 1
- Patients respond to doses much lower than typically used for type 2 diabetes 6
- Insulin may be required as disease progresses 4
- Lifestyle modification including low-carbohydrate diet should accompany pharmacotherapy 3
HNF1B-MODY (MODY 5):
- Often requires insulin therapy due to pancreatic atrophy 4
- Multidisciplinary management for renal disease, hyperuricemia, and other organ involvement 4
Prevalence and Misdiagnosis
MODY represents less than 5% of all diabetes cases but is frequently misdiagnosed as type 1 or type 2 diabetes. 1, 2 This misdiagnosis can lead to years of inappropriate treatment—patients may be unnecessarily placed on insulin when sulfonylureas would be more effective, or conversely, may receive no treatment when monitoring is appropriate. 4