Features to Look For

forpatientsLanding

There are dozens of gene causes of monogenic diabetes, and often they can present differently than the classical types. Thankfully many of the gene causes give clinical clues. Typical patterns include:


1. Diabetes in babies or Neonatal diabetes

Diabetes diagnosed less than 6 months of age usually has an identifiable monogenic cause (around 75-80%). Those diagnosed between 6-12 months have a much smaller chance of having a monogenic cause (around 5%). We suggest all those diagnosed under 6 months of age be tested and encourage families to contact us if they were diagnosed under 1 year.

slide1

2. Chronic mild fasting high sugars

One form of monogenic diabetes (MODY2 or GCK-MODY) has a distinctive glucose pattern. Family members affected have chronically raised morning blood sugars throughout their lives. Some may be described as having type 2 diabetes, pre-diabetes or impaired fasting glucose. Multiple members and generations of a family with this pattern alert us to the possibility of this form of diabetes. The features are:

  • Fasting sugars of 100-140mg/dl (5.6- 7.5mmol/l) for many years
  • 2 or 3 generations of diabetes diagnosed at a young age
  • A HbA1c that does not go over 7.8%
  • Blood sugars rarely ever go above 250mg/dl (14mmol/l)
  • Negative antibody testing
  • Persistently detectable C-Peptide
  • No history of diabetic ketoacidosis

3. Diabetes in adolescence / early adulthood

There are a group of gene causes (MODY1 and MODY3) that typically manifest before 30 years of age and are often misdiagnosed as type 1 diabetes mellitus or called unusual forms of type 2 diabetes. These can be hard to distinguish from the more common types. The following features suggest these forms:

  • Negative antibody testing
  • Persistently detectable C-Peptide
  • 2 or 3 generations of diabetes diagnosed at a young age
  • High sensitivity to sulfonylurea medications
  • No history of diabetic ketoacidosis

4. Diabetes and renal (kidney) cysts

One form of monogenic diabetes (MODY 5) often results in diabetes in combination with a structural kidney or kidney tract problem. Features that distinguishing MODY 5 from other forms of diabetes include

  • A 2 or 3 generation family history of renal cysts
  • A family history of structural problems of the uterus or kidneys
  • Diabetes in multiple family members with renal cysts
  • No history of diabetic ketoacidosis

Clinical scenarios

Distinguishing monogenic diabetes from the more common forms of diabetes can be difficult. Some common clinical scenarios are listed below. Follow the links to learn more about each scenario:

I was initially diagnosed as Type 1 diabetes but I don’t fit the usual pattern
I was initially diagnosed as Type 2 diabetes but I don’t fit the usual pattern
My morning sugars are constantly mildly elevated
I was diagnosed with diabetes under 1 year of age

Questions?

Contact us at The National Center for Monogenic Diabetes at the University of Chicago Monogenic Diabetes Registry

 

I was initially diagnosed as Type 1 diabetes but I don’t fit the usual pattern

Distinguishing MODY from Type 1 diabetes can be difficult. Type 1 diabetes is usually caused by autoimmune destruction of the body’s insulin-producing cells (beta cells). It can manifest at almost any age. There are a few features that suggest a genetic cause rather than an autoimmune one:

Diabetes diagnosis at a very young age

Type 1 diabetes is extraordinarily rare under 6 months of age. If diabetes develops in children under 6 months then a genetic cause should be investigated. A genetic cause is less likely if diagnosed after 6 months of age.

Age of diabetes diagnosis

Genetic forms of diabetes present at a young age. Those with MODY are often diagnosed under 25 years of age or have another affected family member diagnosed under 25.

Absence of diabetes antibodies

Antibodies associated with diabetes are usually seen in the first few years after diagnosis with Type 1. The absence of antibodies can suggest a non-autoimmune cause for diabetes. The antibodies associated with type 1 include GAD, IAA, IA2, ZnT8.

Family history of diabetes

MODY typically runs in families. The pattern of inheritance is described as linear, a mutation is passed from parent to child. Families affected by MODY usually have multiple generations affected. While type 1 diabetes can also be seen in multiple family members, the inheritance pattern is not as dramatic.

Positive C-peptide test many years after diagnosis

Most patients with type 1 diabetes will stop producing their own insulin within a few months or years after their diagnosis. It is difficult to distinguish insulin given by injection from any insulin made by the pancreas. C-peptide is made by beta cells and it is rare to find c-peptide detectable in patients 3-5 years after diagnosis.

Other suggestive features

Some patients will report no history of having significant ketones at any stage or will report significant hypoglycemia in response to some oral medicines (sulfonylureas).

 

I was initially diagnosed as Type 2 diabetes but I don’t fit the usual pattern

Distinguishing MODY from Type 2 diabetes can be difficult. Type 2 diabetes is usually caused by a combination of factors

• Increased insulin demands (high insulin resistance)
• Abnormal production of glucose from the liver
• Decreased insulin production

Type 2 diabetes often runs in families. Being overweight or obese dramatically increases the risk of developing type 2 diabetes. There are a few features that suggest a genetic cause rather than type 2 diabetes:

Age of diabetes diagnosis

Genetic forms of diabetes present at a young age. Those with MODY are often diagnosed under 25 years of age or have another affected family member diagnosed under 25.

Family history of diabetes

MODY typically runs in families. The pattern of inheritance is described as linear, a mutation is passed from parent to child. Families affected by MODY usually have multiple generations affected.

Chronic mildly raised fasting glucose

One form of MODY (MODY2 or GCK-MODY) has a distinctive glucose pattern. Family members affected have chronically raised morning blood sugars throughout their lives. Some may be described as having type 2 diabetes, pre-diabetes or impaired fasting glucose. Multiple members and generations of a family with this pattern alert us to the possibility of this form of diabetes.

Response to treatment

Some patients with particular types of MODY (MODY1/HNF4A-MODY or MODY3/HNF1A-MODY) will be very sensitive to oral sulfonylurea and glinide medications. These medications can cause hypoglycemia in all patients but an exaggerated response is seen in MODY 1 and MODY 3 patients.

 

My morning sugars are constantly mildly elevated

One form of MODY (MODY2 or GCK-MODY) has a distinctive glucose pattern. Family members affected have chronically raised morning blood sugars throughout their lives.

Some may be described as having type 2 diabetes, pre-diabetes or impaired fasting glucose. Multiple members and generations of a family with this pattern alert us to the possibility of this form of diabetes.

Often this mild blood glucose rise is picked up incidentally.

 

Diagnosed with diabetes under 1 year

Diabetes diagnosed under one year of age may be monogenic. The age of diabetes diagnosis is important when determining the likelihood of a monogenic origin. Over 80% of children diagnosed in the first months of life are almost certain to have an underlying gene cause. While less than 5% of children diagnosed after 6 months (but before one year of age) are found to have monogenic diabetes.

There are over 20 genes reported to cause neonatal diabetes. The list of genes affected is growing and each causes diabetes in a different way. The neonatal diabetes genes are important for:

• Insulin production
• Insulin release/secretion
• Entire pancreatic organ development
• Beta cell development

The insulin gene (INS gene), if mutated, results in the production of an abnormal insulin protein. This protein damages the beta cell and results in diabetes at a young age. Treatment is similar to type 1 diabetes with lifelong insulin therapy required.

If the KCNJ11 gene is mutated, abnormal insulin secretion results. This can usually be corrected with the use of a tablet (sulfonylurea) rather than insulin therapy.