What is Mody (Maturity-Onset Diabetes of the Young)?

Maturity-Onset Diabetes of the Young (MODY)

MODY is a monogenic form of diabetes characterized by autosomal dominant inheritance, early onset (typically before age 25), impaired insulin secretion with minimal insulin resistance, and absence of obesity, affecting approximately 1% of all diabetes cases.1, 2

Definition and General Characteristics

• MODY is a heterogeneous group of monogenic disorders with at least 13 identified genetic subtypes, each caused by mutations in different genes on different chromosomes 1
• It is characterized by autosomal dominant inheritance pattern, with diabetes occurring in successive generations of a family 1, 3
• MODY presents with hyperglycemia at an early age, classically before 25 years, although diagnosis may occur later 1
• Unlike type 1 diabetes, MODY patients have preserved pancreatic beta-cell function and no autoimmunity 2, 4
• Unlike type 2 diabetes, MODY patients typically have no insulin resistance and are not obese 3, 5

Most Common MODY Subtypes

GCK-MODY (MODY2)

• Most frequent subtype characterized by mild, stable fasting hyperglycemia (100-150 mg/dL) 3, 6
• Caused by mutations in the glucokinase (GCK) gene, resulting in a higher glucose threshold for insulin secretion 1
• Non-progressive condition with small rise in 2-hour plasma glucose during OGTT (<54 mg/dL) 1
• Typically does not require treatment except sometimes during pregnancy 1, 4
• Very low risk of microvascular complications 1, 7

HNF1A-MODY (MODY3)

• Second most common subtype, caused by mutations in hepatocyte nuclear factor 1-alpha (HNF1A) gene 3, 8
• Progressive insulin secretory defect with presentation typically in adolescence or early adulthood 1
• Features include lowered renal threshold for glucosuria and large rise in 2-hour plasma glucose during OGTT (>90 mg/dL) 1
• Responds well to low-dose sulfonylureas, which are considered first-line therapy 1, 2
• May eventually require insulin as the condition progresses 1, 9
• Risk of microvascular complications similar to type 1 and type 2 diabetes 4, 6

HNF4A-MODY (MODY1)

• Third most common subtype, caused by mutations in hepatocyte nuclear factor 4-alpha (HNF4A) gene 1, 3
• Also presents with progressive insulin secretory defect 1
• May be associated with large birth weight and transient neonatal hypoglycemia 1
• Like HNF1A-MODY, responds well to low-dose sulfonylureas 1, 2
• May eventually require insulin therapy 1, 7

HNF1B-MODY (MODY5)

• Less common subtype with multi-organ involvement 3, 7
• Associated with developmental renal disease (typically cystic), genitourinary abnormalities, pancreatic atrophy, and hyperuricemia/gout 1
• Often requires insulin therapy due to pancreatic atrophy 2, 6
• Requires multidisciplinary management approach 2, 5

Diagnosis

• Consider MODY in non-obese patients diagnosed with diabetes at young age (<25 years) with family history of diabetes in successive generations 2, 4
• Absence of pancreatic autoantibodies helps distinguish from type 1 diabetes 2, 3
• Preserved C-peptide levels (>3 years after diagnosis) unlike type 1 diabetes 4, 9
• Genetic testing is the gold standard for diagnosis and is crucial for appropriate treatment selection 1, 2
• Consultation with a center specializing in diabetes genetics is recommended for interpretation of genetic results 1, 2

Treatment Approach Based on MODY Subtype

• GCK-MODY (MODY2): Generally requires no pharmacological treatment; only lifestyle modifications 2, 4
• HNF1A-MODY (MODY3) and HNF4A-MODY (MODY1): First-line treatment with low-dose sulfonylureas due to high sensitivity 1, 5
• HNF1B-MODY (MODY5): Often requires insulin therapy and management of associated renal disease and other organ involvement 2, 7
• Pregnancy in MODY patients may require special management, with GCK-MODY often needing treatment during pregnancy 1, 4

Clinical Implications

• Correct diagnosis has significant treatment implications and can prevent years of inappropriate therapy 2, 9
• Family screening is important due to autosomal dominant inheritance pattern 3, 8
• Regular monitoring for complications is essential, especially for HNF1A and HNF4A mutations which carry risk of microvascular complications 6, 7
• Genetic counseling should be offered to affected individuals and their families 2, 3

Common Pitfalls in Diagnosis

• MODY is frequently misdiagnosed as type 1 or type 2 diabetes 4, 8
• Presence of autoantibodies does not completely rule out MODY, as autoantibodies have been reported in some monogenic diabetes cases 2, 9
• Not all patients have a clear family history due to variable penetrance or expression of the disease 6, 7
• Delayed diagnosis can lead to years of inappropriate treatment 2, 9