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March 20, 2016

LADA and MODY

Question from Lapeer, Michigan, USA:

My son was diagnosed as type 1 in April 2015. We pushed for MODY testing, since the endocrine team did not feel that he was at a strong risk for it because there doesn't seem to be a strong genetic prevalence. Fast forward to today, March 2016, and after requesting MODY and getting the paperwork signed by his endocrinologist, we just received the results. It says that he is negative for MODY 1-4, but "VUS - variant unknown significance for MODY 5". His specialist needed to look it up and then get back to us, but with an A1c of 11, he needed to get on Lantus (right now he's just on a correction factor and counting carbohydrates/insulin at each meal - Humalog). What your opinion about long-term treatment? I've read that MODY 3 responds to pills, but not anything about MODY 5. We are also wondering if it's possible for his body to become resistant to insulin, much like a type 2 patient. Before starting on Lantus, we need to know if it's just going to cause his body to need more and more. Already we keep increasing his Humalog and now they are saying it's crucial that he be put on Lantus. We are fighting this because we don't yet know all of the treatment protocol for MODY 5 and it sounds like few do.

Answer:

It was our group in Chicago that discovered many of the MODY genes in the 1990s, including MODY5 and we currently maintain an NIH-funded research program in MODY and the larger group of monogenic diabetes. You can find a lot of information on all the forms of monogenic diabetes at The University of Chicago Medicine Kovler Diabetes Institute website.

MODY is present in only about 2% of young people with diabetes, and most people have MODY 1-3. MODY 5 is less common but not zero; we have quite a few cases in our registry and more are added regularly. MODY 5 is caused by a mutation in the HNF1B gene. It is something to consider in people who have elevated blood sugars, are under 25, are non-obese and have negative antibodies with type 1 diabetes. Some have kidney disease. The antibody tests are really critical. These include anti-GAD anti-IA2, anti-Insulin and anti-ZNT8. There is often, but not always, a family history of diabetes, early onset and non-obese, and sometimes a history of kidney disease that looks like polycystic kidney disease. If the antibodies are positive, it virtually rules out MODY 5. Negative antibodies do not necessarily mean MODY as about 15% of everyone with Type 1 diabetes is antibody negative. Only about 10 to 15% of those people have been found to have a form of MODY.

A variant of unknown significance is common – it means there is a sequence change that has not yet been reported in the medical literature. I would not expect a general endocrinologist to be able to interpret this finding. It is usually accompanied in the report by a likelihood statement as some VUS are highly unlikely to be disease causing, while others look more interesting.

We need to see the exact report – from Athena? – to understand what they found and whether we can find it in our own database. We would then be able to contact our colleagues in the UK, for example, to see if they have found this particular sequence change if it looks like it could be disease causing.

If you would like our help, please send us, the Kovler Diabetes Institute, the antibody results and the actual genetics report. We can help with the interpretation and work with you and your doctor on next steps.

If it turns out it is MODY 5, we can help with some other suggestions and information on the implications. Lantus and mealtime insulin can be part of that approach.

For now, you are right that the pills that often work in MODY 3 do not help much in MODY 5. With an A1c of 11%, I do agree that he immediately needs Lantus insulin daily, and if I were the doctor, I would also continue meal time insulin and treat this as if it were type 1 diabetes for sure. The mealtime insulin does not last through the night and it is impossible to treat diabetes like this without Lantus. I don’t know why you are resistant to the Lantus for your son, but I can assure you it is the right thing to do. There are too many short term complications of high blood sugars, including dehydration, weight loss, infections, and even ketoacidosis, to wait a day longer with an A1c of 11%.

As far as insulin resistance, high blood sugars in poorly controlled diabetes causes resistance to insulin which is reversible when the sugars improve. That is another reason why it is important to start a long acting insulin like Lantus and get the sugars closer to the normal range.

LP