What are the symptoms and management of Maturity-Onset Diabetes of the Young (MODY) and Latent Autoimmune Diabetes in Adults (LADA)?

Symptoms and Clinical Features of MODY and LADA

MODY (Maturity-Onset Diabetes of the Young)

MODY typically presents with mild, often asymptomatic hyperglycemia in non-obese individuals diagnosed before age 25 years, with a strong multigenerational family history suggesting autosomal dominant inheritance. 1, 2

Key Clinical Presentations by MODY Subtype:

GCK-MODY (MODY 2):

• Stable, non-progressive mild fasting hyperglycemia (100-150 mg/dL) present from birth 1, 3
• Typically asymptomatic with no classic diabetes symptoms 1
• Small rise in 2-hour plasma glucose during OGTT (<54 mg/dL) 1
• Rare microvascular complications 1, 3
• HbA1C typically between 5.6-7.6% 1, 2

HNF1A-MODY (MODY 3) and HNF4A-MODY (MODY 1):

• Progressive insulin secretory defect leading to worsening hyperglycemia over time 1, 4
• May present with typical diabetes symptoms: polydipsia, polyuria, polyphagia 1
• Large rise in 2-hour plasma glucose during OGTT (>90 mg/dL) 1
• Lowered renal threshold for glucosuria in HNF1A-MODY 1
• HNF4A-MODY may have history of large birth weight and transient neonatal hypoglycemia 1
• Risk of microvascular complications similar to type 1 and type 2 diabetes 3, 4

HNF1B-MODY (MODY 5):

• Renal developmental disorders and genitourinary abnormalities 1, 3
• Pancreatic atrophy 1
• Hyperuricemia and gout 1
• Multi-organ involvement requiring specialized management 1, 3

Distinguishing Features from Type 1 and Type 2 Diabetes:

• Negative for β-cell autoantibodies (GAD, IA-2, insulin autoantibodies, ZnT8), though rare coexistence has been reported 1, 2
• BMI <25 kg/m² (non-obese presentation) 2
• Minimal or no insulin resistance with impaired insulin secretion 1, 2
• Stable mild hyperglycemia rather than progressive deterioration initially 1, 2
• No ketoacidosis at presentation in classic MODY 5

LADA (Latent Autoimmune Diabetes in Adults)

LADA initially presents as apparent type 2 diabetes in adults over age 35 years but progresses to insulin dependence within months to years, with positive β-cell autoantibodies distinguishing it from true type 2 diabetes. 5, 2

Key Clinical Features:

Initial Presentation:

• Diagnosed after age 35 years 2
• Initially appears clinically similar to type 2 diabetes with mild hyperglycemia 5, 6
• Often responsive to oral agents initially 5
• May be lean or have lower BMI than typical type 2 diabetes patients 5

Progressive Course:

• Slowly progressive β-cell destruction over months to years 5, 6
• C-peptide levels decrease over time, paralleling the curve for classical type 1 diabetes 6
• Most patients require insulin within three years of diagnosis 6
• Eventually develop more severe hyperglycemia requiring intensive insulin regimens 5

Laboratory Findings:

• Positive for β-cell autoantibodies, most commonly GAD antibodies 2, 6
• ICA (islet cell antibodies) is the second most frequently occurring autoantibody 6
• Progressive decline in C-peptide levels over time 6

Distinguishing Features from Type 2 Diabetes:

• Presence of pancreatic autoantibodies (especially anti-GAD) is the key distinguishing feature 5, 2
• Progressive insulin requirement despite initial response to oral agents 5, 6
• Lower BMI and less insulin resistance than typical type 2 diabetes 5
• Younger age at diagnosis within the adult population (<35 years suggests consideration) 2
• Personal or family history of autoimmune disease may be present 2

Management Implications

MODY Management:

GCK-MODY (MODY 2):

• Typically requires no pharmacological treatment except sometimes during pregnancy 1, 3
• Lifestyle modifications only 1

HNF1A-MODY (MODY 3) and HNF4A-MODY (MODY 1):

• Low-dose sulfonylureas as first-line therapy due to high sensitivity to these medications 5, 1, 3
• Insulin therapy may be required as the condition progresses 1

HNF1B-MODY (MODY 5):

• Insulin therapy required due to pancreatic atrophy 1, 3
• Multidisciplinary management for renal disease, hyperuricemia, and other organ involvement 1, 3

LADA Management:

• Earlier transition to insulin therapy is recommended to preserve remaining β-cell function 5, 2
• Measuring titers of islet-associated autoantibodies (e.g., anti-GAD) aids identification and encourages more rapid transition to insulin 5
• Most patients will require insulin within three years despite initial response to oral agents 6

Critical Diagnostic Approach

Test all adults diagnosed with diabetes who are non-obese, <35 years old, or have atypical features for β-cell autoantibodies to identify LADA. 2

Consider MODY genetic testing when:

• Diabetes diagnosed in first 6 months of life (immediate genetic testing mandatory) 1, 3
• Diagnosis before age 25 years with negative autoantibodies 1, 2
• Strong family history in successive generations (autosomal dominant pattern) 1, 2, 3

Common Pitfalls to Avoid:

• Do not assume autoantibody positivity rules out MODY, as rare coexistence has been reported 1, 2
• Do not delay genetic testing in suspected MODY, as this prevents years of inappropriate treatment 1
• Do not assume all lean adults with diabetes have type 1 diabetes—consider LADA and MODY 5, 2
• Do not rely solely on clinical features to distinguish diabetes types; autoantibody and genetic testing are essential 2, 6