Monogenic diabetes

🧬 Monogenic diabetes is diabetes caused by a pathogenic variant in a single gene. It is often misdiagnosed as type 1 or type 2 diabetes, but genetic diagnosis may change treatment, prognosis and family screening.

📌 Main Types

• MODY: usually young-onset diabetes caused by impaired pancreatic beta-cell function.
• Neonatal diabetes: diabetes presenting before 6 months of age.
• Syndromic diabetes: diabetes associated with renal, neurological, auditory or developmental abnormalities.
• Mitochondrial diabetes: maternally inherited diabetes, often associated with deafness.

🔎 When to Suspect Monogenic Diabetes

• Diabetes diagnosed before 6 months of age.
• Young-onset diabetes affecting several generations.
• Negative pancreatic autoantibodies.
• Persistent C-peptide several years after diagnosis.
• Low insulin requirements or absence of ketoacidosis.
• Mild stable fasting hyperglycaemia from childhood.
• Diabetes with renal cysts, deafness, optic atrophy or developmental abnormalities.

🧪 Diagnosis

• Take a three-generation family history.
• Measure GAD, IA-2 and, where available, ZnT8 antibodies.
• Measure C-peptide with a simultaneous glucose level.
• Assess for renal, auditory, neurological and pancreatic abnormalities.
• Confirm the diagnosis using molecular genetic testing.
• Refer to a diabetes specialist or regional monogenic diabetes service.

🩸 GCK Diabetes

GCK diabetes causes mild, stable fasting hyperglycaemia because the pancreatic glucose threshold for insulin release is increased. GCK means glucokinase, an enzyme that acts as the pancreatic beta cell’s glucose sensor. It phosphorylates glucose and helps determine the blood-glucose threshold at which insulin secretion begins. Fasting glucose is commonly approximately 5.5–8 mmol/L. Patients are usually asymptomatic. Hyperglycaemia shows little progression. Complication risk is low. Treatment is usually unnecessary outside pregnancy.

🩸 HNF1A and HNF4A Diabetes

These disorders cause progressive beta-cell dysfunction and usually follow autosomal-dominant inheritance.

• HNF means hepatocyte nuclear factor
• Diabetes often develops during adolescence or early adulthood.
• Patients may be lean and have negative autoantibodies.
• HNF1A diabetes may cause glycosuria at relatively modest glucose levels.
• Many patients respond well to low-dose sulfonylureas.
• Insulin may eventually be required as beta-cell function declines.
• HNF4A variants may be associated with macrosomia and neonatal hypoglycaemia.

🩺 HNF1B Diabetes

• Associated with renal cysts, renal impairment and hypomagnesaemia.
• May cause pancreatic hypoplasia, abnormal liver tests and genital-tract abnormalities.
• A family history may be absent because de novo variants are common.
• Insulin treatment is frequently required.

👶 Neonatal Diabetes

Diabetes presenting before 6 months of age is unlikely to be autoimmune type 1 diabetes and requires urgent genetic testing.

• Important genes include KCNJ11, ABCC8 and INS.
• KCNJ11 and ABCC8 variants affect pancreatic ATP-sensitive potassium channels.
• Many affected infants can transfer from insulin to high-dose sulfonylureas.
• Some variants are associated with developmental delay, epilepsy and muscle weakness.

👂 Mitochondrial Diabetes

• Usually inherited through the maternal line.
• Often associated with sensorineural deafness.
• May also cause cardiomyopathy, renal disease or neurological abnormalities.
• Affected men do not transmit mitochondrial variants to their children.

👁️ Wolfram Syndrome

Wolfram syndrome is an inherited disorder characterised by: Diabetes mellitus. Optic atrophy. Diabetes insipidus. Deafness.

💊 Treatment Principles

• GCK: usually no treatment outside pregnancy.
• HNF1A or HNF4A: low-dose sulfonylurea is often effective.
• HNF1B: insulin is frequently required.
• KCNJ11 or ABCC8: many patients respond to high-dose sulfonylureas.
• INS-related diabetes: usually requires insulin.
• Do not stop insulin solely because monogenic diabetes is suspected.
• Major treatment changes should follow genetic confirmation and specialist review.

👨‍👩‍👧 Family Screening

• Most common MODY forms are autosomal dominant.
• An affected person usually has a 50% chance of passing the variant to each child.
• Once a familial variant is identified, relatives can undergo targeted testing.
• Genetic counselling should include pregnancy and reproductive implications.

🩺 Example Case 1

A slim 20-year-old woman has an HbA1c of 44 mmol/mol and fasting glucose of 6.6 mmol/L. Similar mild fasting hyperglycaemia has been present since childhood, and her father has diet-controlled diabetes. This suggests GCK diabetes. Genetic confirmation may prevent unnecessary treatment.

🩺 Example Case 2

A 25-year-old man diagnosed with type 1 diabetes at 18 remains C-peptide positive, has negative autoantibodies and requires only a small insulin dose. His mother and grandfather developed young-onset diabetes. This suggests HNF1A or HNF4A diabetes. Following genetic confirmation, supervised transfer to a sulfonylurea may be possible.

🩺 Example Case 3

A 3-month-old infant develops severe hyperglycaemia and poor weight gain. This is likely to represent neonatal diabetes. Urgent genetic testing may identify a potassium-channel variant treatable with sulfonylureas.

💡 Clinical Clues

• Diabetes before 6 months is monogenic until proven otherwise.
• Negative antibodies and persistent C-peptide should prompt reconsideration of type 1 diabetes.
• Mild lifelong fasting hyperglycaemia suggests GCK diabetes.
• Young-onset diabetes across generations suggests MODY.
• Renal cysts and diabetes suggest HNF1B disease.
• Maternal inheritance with deafness suggests mitochondrial diabetes.