Table 3.
Clinical phenotypes and genetic etiology of MODY syndromes*
| Subtype | Gene (function) | Extra-pancreatic involvement | Distinguishing clinical features | Medical management |
|---|---|---|---|---|
| MODY 1 | HNF-4α (transcription factor) | Neonatal HYPOglycemia | As in type 2 diabetes | |
| MODY 2 | Glucokinase (glucose sensing) | Hepatic glucose sensing | Mild hyperglycemia, low risk of secondary complications | Diet and exercise usually sufficient |
| MODY 3 | HNF-1α (transcription factor) | Subtle renal tubular defects | Presents between ages 10-40 | Especially responsive to sulfonylureas |
| MODY 4 | IPF-1 (transcription factor) | Pancreatic agenesis in homozygotes | As in type 2 diabetes | |
| MODY 5 | HNF-1β (transcription factor) | Renal cysts; female genital malformations | Renal cysts and diabetes syndrome | As in type 2 diabetes |
| MODY 6 | NeuroD1 (transcription factor) | Very rare | As in type 2 diabetes |
The clinical definition of MODY requires: autosomal dominant inheritance across 3 or more generations; a non-ketotic presentation or significant C-peptide levels 5 years after diagnosis; and hyperglycemia in 1-2 family members age < 25 years old. As type 2 diabetes becomes more prevalent at younger ages, the absence of obesity also helps to distinguish MODY from adolescent type 2 diabetes.