Monogenic diabetes mellitus
Monogenic diabetes (maturity-onset diabetes of the young, MODY) is an autosomal dominant single-gene defect in beta-cell insulin secretion, presenting before age 25 years with a strong family history of atypical diabetes and no autoantibodies. Diagnosis rests on genetic testing, and treatment is guided by the specific gene mutation, with metformin, sulfonylurea, or insulin used empirically while confirmatory genetic results are pending.
- Topic reviewThe full article, organized the way the exam asks it.
- ABIM-format MCQsVignettes with an explanation for every wrong answer.
- Key factsThe numbers and thresholds worth memorizing, up front.
- AI tutorMedBrain answers the question you're stuck on.
What this article covers
- Overview
A single-gene cause of diabetes, distinct from type 1 and type 2 disease: monogenic diabetes results from an autosomal dominant mutation impairing beta-cell insulin secretion, with at least 14 known causative gene mutations identified.
- Epidemiology
An uncommon but under-recognized cause of diabetes, frequently misclassified as type 1 or type 2 diabetes at initial presentation because standard glucose criteria do not distinguish it.
- Risk factors
A first-degree relative with diabetes diagnosed at a young age, especially across multiple generations, is the dominant risk indicator.
- Pathophysiology
An autosomal dominant monogenetic defect on one of several chromosomal loci impairs a specific step in beta-cell function, most often glucose sensing or insulin secretion, while insulin action at target tissues remains normal.
- Clinical features
Diabetes onset before age 25 years in a person without obesity.
- Differential diagnosis
Type 1 diabetes mellitus: positive GAD65 or IA-2 autoantibodies with a tendency toward ketosis, unlike the antibody-negative, non-ketotic course of monogenic diabetes.
- Diagnosis
The clinching basis is targeted genetic testing confirming a causative mutation, pursued after standard diabetes glucose criteria are met (A1c 6.5% or higher, fasting glucose 126 mg/dL or higher, or…
- Management
First, confirm the diagnosis with genetic testing and genetic counseling, since treatment varies by the specific causative gene mutation and should not default to a standard type 1 or type 2 diabetes regimen without this step.
- Complications
Microvascular complications (retinopathy, nephropathy, neuropathy) can occur with sustained hyperglycemia in the subtypes that progress to clinically significant diabetes, similar to type 1 and type 2 diabetes.
- Prognosis
Highly variable by the specific causative gene mutation, ranging from mild, stable, lifelong hyperglycemia that may not require pharmacologic treatment, to progressive beta-cell failure resembling the course of type 2 diabetes.
- Prevention
No primary prevention exists for the inherited gene mutation itself, since monogenic diabetes is a fixed autosomal dominant trait.
Read the whole article
Subscribing to Internal Medicine opens every article, the full question bank and MedBrain, on the web, iPhone and Android.
Related articles
- Type 1 diabetes mellitus
Type 1 diabetes mellitus is an insulin-deficient state from autoimmune (type 1A) or idiopathic (type 1B) destruction of pancreatic beta cells, presenting with hyperglycemia that can range from mild to life-threatening diabetic ketoacidosis. Diagnosis combines standard glycemic criteria with autoantibody testing (GAD65, IA-2), and lifelong insulin therapy, generally as a basal-bolus regimen, is required from diagnosis, with self-monitoring or continuous glucose monitoring to guide dosing.
- Type 2 diabetes mellitus
Type 2 diabetes is hyperglycemia from insulin resistance with progressive relative insulin deficiency, diagnosed by a hemoglobin A1c of 6.5% or higher, a fasting glucose of 126 mg/dL or higher, or a 2-hour oral glucose tolerance test value of 200 mg/dL or higher. First-line treatment is lifestyle modification plus metformin, with an SGLT2 inhibitor or GLP-1 receptor agonist added early for patients with atherosclerotic disease, kidney disease, or heart failure.
- Latent autoimmune diabetes in adults
Latent autoimmune diabetes in adults (LADA) is a slowly progressive autoimmune beta-cell destruction that presents in adulthood without an initial insulin requirement, so it is frequently misclassified as type 2 diabetes until positive islet autoantibodies are identified. First-line management follows a standard stepwise diabetes approach, but basal insulin should be started proactively as beta-cell failure progresses, since earlier insulin reduces stress on the remaining beta cells.