Monogenic Diabetes

Monogenic diabetes is a rare form of diabetes caused by a change in a single gene, making it fundamentally different from the more common type 1 and type 2 diabetes that involve multiple genes and environmental factors.

Table of contents

• What is monogenic diabetes?
• How common is monogenic diabetes?
• Main forms of monogenic diabetes
• What causes monogenic diabetes?
• Symptoms
• Diagnosis and genetic testing
• Health problems and complications
• Treatment and management
• Inheritance and family implications

What is monogenic diabetes?

Monogenic diabetes is a group of uncommon forms of diabetes mellitus (a condition where blood sugar levels become too high) that are caused by a variant, or change, in a single gene^[1]. This makes it very different from type 1 and type 2 diabetes, which are caused by changes in multiple genes, and in the case of type 2 diabetes, also by lifestyle factors such as obesity^[2].

Monogenic forms of diabetes are part of the group of atypical diabetes—diabetes types where people have symptoms and signs that are different from those of type 1 or type 2 diabetes^[1]. People with monogenic diabetes often have a single gene abnormality that is sufficient by itself to cause diabetes^[3].

If you have monogenic diabetes, you may have high levels of blood glucose (also called blood sugar). Over time, diabetes may raise your risk of damage to the eyes, kidneys, nerves, and heart. Diabetes is also linked to some types of cancer. However, you may be able to prevent or delay diabetes health problems by managing your blood glucose level^[1].

How common is monogenic diabetes?

Monogenic diabetes accounts for approximately 1% to 5% of all diabetes cases^[2][5]. Despite being rare, experts believe that monogenic diabetes is significantly underdiagnosed. Up to 80% of cases may be misdiagnosed as type 1 or type 2 diabetes^[16]. The overwhelming majority of people with diabetes—about 98%—have either type 1 or type 2 diabetes^[3].

Main forms of monogenic diabetes

There are two main forms of monogenic diabetes: maturity-onset diabetes of the young (MODY) and neonatal diabetes mellitus (NDM)^[1].

Maturity-onset diabetes of the young (MODY)

MODY is the most common form of monogenic diabetes and may account for 0.5% to 5% of patients diagnosed with non-autoimmune diabetes^[8]. This form of diabetes usually develops in teens or young adults, typically before the age of 30 years^[1]. MODY often runs in families from one generation to the next^[3].

People with some forms of MODY have blood glucose levels that are only a little higher than normal and do not change much during their lives. The levels of blood glucose are typically not high enough to damage their organs, so they may not need treatment. However, people with other forms of MODY have higher blood glucose levels and need treatment^[1].

Researchers have identified several subtypes of MODY. The most common gene changes causing MODY are in the hepatocyte nuclear factor-1-alpha (HNF1A) gene and the glucokinase (GCK) gene. These account for 50% to 60% and 15% to 30% of people with monogenic diabetes, respectively^[2].

Neonatal diabetes mellitus (NDM)

NDM forms of diabetes develop in the first 6 to 12 months of life^[1]. The condition has a prevalence of 1 in 90,000 to 1 in 250,000 births^[10]. Babies with forms of NDM do not produce enough insulin, which allows their blood glucose levels to go up more than normal. Babies who develop diabetes in the first 6 months of life almost always have a form of NDM^[1].

NDM may be permanent, meaning babies will have lifelong diabetes, or it may be temporary, called transient neonatal diabetes. In transient cases, the diabetes remits in early infancy but may relapse in late childhood or early adulthood^[7].

What causes monogenic diabetes?

Monogenic diabetes is caused by changes or mutations in a single gene. Researchers have found variants in more than 20 genes that cause monogenic diabetes^[1]. More than 40 subtypes have been identified to date^[8].

A gene is a strand of DNA (deoxyribonucleic acid) that contains the code or blueprint for proteins that do all the work in all the cells of the body. Genes contain information to pass traits from parents to their children. If a genetic error occurs, it causes a change in the protein sequence. This is known as a mutation^[3].

These genetic mutations can be:

• Spontaneous: occurring during fetal development in a person whose parents do not appear to carry the mutation. Spontaneous mutations can then be passed along in future generations^[3].
• Hereditary: mutations that are passed along from parent to child^[3].

The genes involved in monogenic diabetes control the development, function, and regulation of the insulin-producing cells (also called islet cells or beta cells) of the pancreas^[2]. Your genes provide instructions for making proteins that help your body produce insulin and regulate blood sugar. When these genes change, it makes cells in your pancreas less effective at producing enough insulin to manage your blood sugar^[21].

Symptoms

Symptoms of monogenic diabetes are similar to those of other types of diabetes^[9]. Common symptoms include:

• Being very thirsty
• Needing to urinate more often (frequent urination)
• Losing weight unexpectedly
• Blurred vision
• Fatigue
• Recurrent skin infections
• Recurrent yeast infections
• Rapid breathing
• Dehydration

Your exact symptoms can vary depending on what gene change causes the condition. Most of the time, the symptoms start slowly^[21]. Some people with certain forms of MODY have blood glucose levels that are only mildly elevated and may not experience any symptoms at all^[1].

Diagnosis and genetic testing

Blood sugar tests and genetic testing are used to diagnose monogenic diabetes. Genetic testing is performed on blood or saliva samples. The DNA from the samples is examined for changes in the genes that cause monogenic diabetes^[9].

MODY should be considered in people who do not have obesity and who have diabetes that was diagnosed at a young age (younger than 30 years), a strong family history of diabetes, preserved pancreatic beta-cell function (as evidenced by detectable levels of a substance called C-peptide), and no laboratory evidence of pancreatic beta-cell autoimmunity^[16].

Unlike people with type 1 diabetes, patients with MODY have preserved pancreatic beta-cell function three to five years after diagnosis. This can be demonstrated by detectable serum C-peptide levels when blood glucose is elevated. Additionally, people with MODY do not have diabetes-related autoantibodies (substances the immune system produces to attack the body’s own cells) that are typically found in type 1 diabetes^[16].

Genetic testing is recommended if:

• Diabetes is diagnosed within the first six months of age
• Diabetes is diagnosed in children and young adults, especially individuals with a strong family history of diabetes, who do not display typical features of type 1 or type 2 diabetes
• A person exhibits stable, mild fasting high blood sugar, especially if they do not have obesity^[9]

A genetic diagnosis is made in 80% of patients with neonatal diabetes and in around 25% of patients with young-onset diabetes^[7]. The timely and accurate genetic diagnosis of monogenic diabetes provides an opportunity to target therapy to the underlying gene cause, refine management, and identify affected and at-risk relatives^[10].

Health problems and complications

If you don’t get the right treatment, there can be complications. Having high blood sugar can damage your:

• Kidneys
• Heart and arteries
• Nerves
• Eyes
• Joints

Patients with certain forms of MODY, such as those with HNF1A-MODY (MODY3) and HNF4A-MODY (MODY1), have progressive high blood sugar and vascular complication rates similar to patients with types 1 and 2 diabetes^[16].

However, some forms, like GCK-MODY (MODY2), usually don’t lead to complications because they’re mild forms. People with MODY2 have mild stable fasting high blood sugar with low risk of diabetes-related complications^[21][16].

Some forms of monogenic diabetes may be associated with additional health problems beyond blood sugar control. For example, HNF1B-MODY (MODY5) can cause other problems like kidney disease, an abnormally small pancreas, and genital abnormalities^[21]. Children with monogenic diabetes may also require treatment for other health problems, such as digestive enzyme deficiencies, kidney cysts, low magnesium levels, or autism^[6].

Treatment and management

Treatment for monogenic diabetes depends on the specific genetic mutation that is the cause of the condition^[9]. Knowing the subtype you have can help guide your treatment plan and predict how the disease may progress^[21].

GCK-MODY (MODY2)

People with MODY2 have asymptomatic, stable mild fasting high blood sugar and low risk of diabetes-related vascular complications. They generally do not require treatment, except in pregnancy^[16][7].

HNF1A-MODY (MODY3) and HNF4A-MODY (MODY1)

For these forms of MODY, lifestyle modification including a low-carbohydrate diet should be the first-line treatment^[16]. When medication is needed, sulfonylureas (oral diabetes medicines that help the body release more insulin into the blood) are the preferred pharmacologic therapy. People with HNF1A-MODY and HNF4A-MODY are particularly sensitive to sulfonylureas^[16][3].

Other oral medications that may be considered include meglitinide and glucagon-like peptide 1 agonist^[16]. Some individuals may eventually need insulin as the condition progresses^[21].

Neonatal diabetes

Individuals who have certain forms of neonatal diabetes can be treated with sulfonylureas. Some babies and young children with NDM caused by changes in genes called KCNJ11 and ABCC8 can be best treated with high doses of sulfonylureas^[7]. Others may require insulin injections^[6].

Pregnancy considerations

Pregnant patients with MODY may require insulin therapy and additional fetal monitoring for macrosomia (larger than normal baby size)^[16]. For GCK-MODY, the use of insulin during pregnancy is determined by the mutation status of the mother and fetus and/or evidence of accelerated fetal growth on ultrasound^[16].

Understanding the correct type of monogenic diabetes is important because precision medicine approaches—including specific treatments for high blood sugar, monitoring associated extra-pancreatic features, and following up clinical trajectories, especially during pregnancy—are available for some forms and can increase patients’ quality of life^[8].

Inheritance and family implications

Because MODY is inherited, it often affects multiple generations of the same family^[21]. Most cases of monogenic diabetes are inherited from a parent who also has the disorder^[2]. MODY is most often an autosomal dominant disease, with 50% of offspring affected^[1][2].

In the most common subtype (HNF1A-MODY), more than 95% of people with the mutation will develop diabetes, most by 25 years of age^[16]. However, pathogenic variations that cause disease inherited in a dominant pattern commonly arise spontaneously (called de novo mutations) in the child, which means that there may be no family history^[7].

Defining the underlying genetic cause has implications not only for treatment and prognosis, but also helps identify affected and at-risk family members^[10]. If you or your child has been diagnosed with monogenic diabetes, genetic counseling may be helpful to understand the inheritance pattern and risks for other family members.