A spotlight on MODY

Dr Louise Johnson, a diabetes specialist, clarifies what Maturity Onset Diabetes in the Young (MODY) is.

---

MODY was first recognised in 1974 as mild familial diabetes with a dominant inheritance. This form of diabetes can be confused with either Type 1 or Type 2 diabetes.

 The criteria for suspecting MODY are:

• Diabetes before the onset of 25 years of age
• Absence of autoantibodies against the Beta cells (also called GAD antibodies and are present in Type 1 diabetes and Latent Autoimmune Diabetes in Adult (LADA))
• Presence of diabetes in two consecutive generations of your family.
• C-peptide of more than 200 pmol/L (this indicates the presence of beta-cell function of the pancreas) even after three years of insulin treatment.¹

To date, 14 different gene mutations are recognised in MODY. MODY is a rare condition accounting for 1-5% of all cases of diabetes and 1-6% of paediatric cases of diabetes.

Approximately 80% of patients with MODY may be misdiagnosed with Type 1 or Type 2 diabetes at diagnosis and current calculations indicate a delay of approximately 15 years from diagnosis of diabetes to the genetic diagnosis of MODY.²

Diagnosis of MODY

At diagnosis, MODY can’t be distinguished easily from Type 1 or Type 2 diabetes based on clinical characteristics. Rather, Type 1 diabetes mostly differs from MODY in terms of disease aetiology. In Type 1 diabetes, the cause is autoantibodies, called GAD antibodies, against the beta cell of the pancreas.

Patients with MODY usually maintain beta-cell function. This can be demonstrated by doing a blood sample and measuring C-peptide. In MODY this value is above 200 pmol/L. Their diabetes is well-controlled with no or low dose insulin for at least five years after diagnosis.

The clinical manifestation of Youth Onset Type 2 diabetes clinically resembles MODY but Type 2 diabetes patients are obese. Patients with MODY may become obese due to poor diet habits and lack of exercise but are usually lean. Both Type 2 diabetes and MODY patients have a strong family history. To detect MODY, genetic testing should be done.

Candidates for genetic testing

• Non-obese person with abnormal glucose.
• No autoantibodies against the beta-cell of the pancreas.
• Preservation of beta-cell function as shown by a C-peptide of more than 200pmol/L.
• Strong history of the same type of diabetes in first-degree relative (mother or father).

However genetic testing remains expensive and is limited to cases of strong suspicion of MODY.

MODY subtypes

There are at least 14 different MODY subtypes reported. However, there are six major subtypes, as discussed below. MODY subtype determination is important as the subtypes differ in terms of age of onset of diabetes, clinical course and progression, and response to treatment.

• MODY 1(HNF 4 alpha MODY)

This group has a progressive decline of beta-cell function. They present in adolescence. These patients also have increased triglycerides (blood fat content).

• MODY 2 (GCK -MODY)

This mutation increases the glucose threshold for insulin secretion and thus results in increased fasting glucose values. These patients are asymptomatic, and the majority are discovered during pregnancy through a routine glucose evaluation. MODY is present in 2-6% of gestational diabetes. The clinical course of this subtype may be mild and non-progressive, and complications are rare.

• MODY 3 (HNF1 Alpha MODY)

This mutation causes a progressive insulin deficiency that manifest as mild hyperglycaemia in childhood and early adulthood. In this group, the risk of complications is similar to Type 1 or Type 2 diabetes.

• MODY 4 (PDX-MODY)

These patients have neonatal diabetes. This is very rare.

• MODY 5 (HNF 1 beta MODY)

This presents in children with abnormal glucose and abnormality of the kidney and urinary tract to the bladder. These patients will develop kidney failure by 45 years of age. This should be suspected in diabetes with non-diabetic kidney disease. They develop insulin deficiency early in their disease progression.

• MODY 6 (NEURODI-MODY)

This can cause neonatal diabetes or childhood diabetes with associated neurological manifestations and learning difficulties.

How can MODY be diagnosed correctly?

The clinical characteristics of:

• Diagnosed before 25 years of age.
• Presence of diabetes in two consecutive family generations.
• Absence of beta-cell autoantibodies.
• Preserved insulin secretion as demonstrated by a C-peptide of more than 200 pmol/L.
• Not obese.
• Not prone to ketones.

Treatment of MODY

Children and adolescent diagnosed with diabetes will initially be treated with insulin. After glucose is stabilised, an evaluation can be done to exclude MODY by applying the above-mentioned criteria.

MODY 2 can be treated by diet and oral antidiabetic tablets.

MODY 3 needs to be treated with oral diabetic tablets, such as gliclazide or glimepiride. The newer class drug GLP1 agonists (liraglutide) have also been approved.

MODY 5 patients need intensive insulin treatment to control glucose.

Remember MODY should be suspected in the presence of mild to moderate hyperglycaemia without ketones in the presence of a non-obese individual with a strong family history of diabetes.

---

References

1. Ellard S, Ballane-Chantelot C et. al. Best practice guidelines for the molecular genetic diagnosis of maturity onset diabetes of the young. Diabetologia.2008; 51:546-553

 

2. Shields BM, Hicks S et. al.Maturity onset diabetes of the young (MODY): how many cases are we missing? Diabetologia.2010;53:2504-2508

Header image by Adobe Stock