What is MODY (Maturity-Onset Diabetes of the Young)?
MODY is a rare monogenic form of diabetes caused by autosomal dominant genetic mutations that impair insulin secretion, classically presenting before age 25 years with a strong multigenerational family history, and accounting for less than 5% of all diabetes cases. 1
Core Pathophysiology
MODY fundamentally differs from type 1 and type 2 diabetes because it results from single-gene mutations inherited in an autosomal dominant pattern, meaning each affected parent has a 50% chance of passing the mutation to their children. 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 characteristic of type 2 diabetes and the autoimmune β-cell destruction seen in type 1 diabetes. 1
At least 13 different genes have been identified that cause MODY, with abnormalities on different chromosomes leading to clinically heterogeneous presentations. 1 The most commonly reported forms are:
- GCK-MODY (MODY 2): Mutations in the glucokinase gene on chromosome 7p 1
- HNF1A-MODY (MODY 3): Mutations in hepatocyte nuclear factor-1α on chromosome 12 1
- HNF4A-MODY (MODY 1): Mutations in hepatocyte nuclear factor-4α 1
Clinical Recognition Features
Key Diagnostic Red Flags
The American Diabetes Association recommends genetic testing for MODY in children and young adults who do not have typical characteristics of type 1 or type 2 diabetes. 2 Specific features include:
- Age at diagnosis: Classically before age 25 years, though diagnosis may occur at older ages 1
- Family history: Diabetes in successive generations indicating autosomal dominant inheritance 2
- Absence of type 1 diabetes features: Negative pancreatic autoantibodies (GAD65, IA-2, insulin autoantibodies, ZnT8) 2
- Absence of type 2 diabetes features: Non-obese, lacking metabolic syndrome features 2
- Preserved β-cell function: Detectable C-peptide levels 2
Subtype-Specific Clinical Presentations
GCK-MODY (MODY 2) presents with stable, non-progressive elevated fasting blood glucose (typically 100-150 mg/dL), mild hyperglycemia from birth, and a small rise in 2-hour plasma glucose on oral glucose tolerance testing (<54 mg/dL or <3 mmol/L). 1, 2 Patients are typically asymptomatic with rare microvascular complications. 1
HNF1A-MODY (MODY 3) demonstrates a progressive insulin secretory defect with presentation in adolescence or early adulthood, lowered renal threshold for glucosuria (glycosuria at normal blood glucose levels), and a large rise in 2-hour plasma glucose on oral glucose tolerance testing (>90 mg/dL or >5 mmol/L). 1, 2 Patients may develop typical diabetes symptoms including polydipsia, polyuria, and polyphagia. 2
HNF4A-MODY (MODY 1) shows a progressive insulin secretory defect with possible history of large birth weight and transient neonatal hypoglycemia. 1, 2
HNF1B-MODY (MODY 5) is associated with developmental renal disease (typically cystic), genitourinary abnormalities, pancreatic atrophy, hyperuricemia, and gout. 1, 2
Diagnostic Approach
Genetic testing is the gold standard for MODY diagnosis and is increasingly cost-effective and often covered by health insurance. 2 Biomarker screening including urinary C-peptide/creatinine ratio and antibody screening may help identify candidates for genetic testing. 1, 2
Oral glucose tolerance testing patterns can help differentiate MODY subtypes before genetic confirmation: GCK-MODY shows a small rise (<54 mg/dL) in 2-hour glucose, while HNF1A-MODY shows a large rise (>90 mg/dL). 1, 2
Critical Diagnostic Pitfall
The presence of autoantibodies does NOT rule out MODY, as autoantibodies have been reported in patients with monogenic diabetes. 1, 2 Do not assume autoantibody positivity excludes MODY from the differential diagnosis.
Treatment Implications by Subtype
The treatment approach differs dramatically based on MODY subtype, making genetic diagnosis clinically essential rather than academic. 3
GCK-MODY (MODY 2)
No pharmacological treatment is required except commonly during pregnancy. 1, 2 Lifestyle modifications only are recommended. 2 Microvascular complications are rare due to stable, mild hyperglycemia. 1
HNF1A-MODY and HNF4A-MODY (MODY 3 and 1)
Low-dose sulfonylureas are first-line therapy due to high sensitivity to these medications. 1, 2 These patients respond well to sulfonylureas by acting on ATP-sensitive potassium channels. 4 Insulin therapy may be required later in life as the condition progresses or if sulfonylurea resistance develops. 1, 5
HNF1B-MODY (MODY 5)
A multidisciplinary approach is necessary due to multi-organ involvement, including management of renal disease, treatment of hyperuricemia and gout, and possible insulin therapy. 2 Pancreatic atrophy often necessitates insulin treatment. 2
Prevalence and Misdiagnosis
MODY represents approximately 1% of all diabetes cases but is frequently misdiagnosed as type 1 or type 2 diabetes, resulting in years of inappropriate treatment. 3, 4, 5 Correct diagnosis is crucial because GCK-MODY patients may be unnecessarily treated with insulin or oral agents, while HNF1A-MODY and HNF4A-MODY patients may achieve superior glycemic control with low-dose sulfonylureas compared to insulin or metformin. 1
Special Populations
All children diagnosed with diabetes in the first 6 months of life should have immediate genetic testing for neonatal diabetes, as 80-85% of diabetes cases in this age group have an underlying monogenic cause. 1, 2 Neonatal diabetes is distinct from MODY but represents another form of monogenic diabetes requiring genetic diagnosis.
Genetic Counseling Considerations
Most mutations causing MODY are dominantly inherited, making genetic counseling essential for affected families. 1 Consultation with a center specializing in diabetes genetics is recommended to interpret mutations and guide treatment, evaluation, and genetic counseling for family members. 2