Mutated gene causes rare form of diabetes

BALTIMORE » Sophia Baratta thought she was in the best shape of her life until a doctor diagnosed her with prediabetes after tests showed elevated levels of glucose in her blood.

At the time, she year-old spent grueling hours in the gym preparing for amateur kickboxing competitions. The doctor ordered the Baltimore kindergarten teacher to watch what she ate after the diagnosis, but Baratta already followed a strict diet as part of her training regimen that focused on lean proteins, vegetables and no sugar.

“It just didn’t make any sense,” said Baratta, 29, who was first told she had higher sugar levels in college.

A simple genetic test eventually explained what was happening.

University of Maryland School of Medicine geneticists found that Baratta has from a rare form of diabetes. It’s not brought on by the immune system problems that destroy insulin-producing cells as in Type 1 diabetes or by the bad health habits typical for Type 2 diabetes — the two most common forms of the disease.

Baratta’s diabetes is caused by a mutation in a single gene that runs in families. Scientists have discovered more than 20 genes where mutations can occur that can lead to what is called monogenic diabetes, according to the University of Chicago, which has conducted extensive research on the topic. The disease appears, and should be treated, in different ways depending on which gene is mutated.

Baratta’s prediabetes caused her blood-sugar levels to naturally hover at slightly elevated levels. No amount of healthy eating or exercise would bring the levels down. The elevated blood sugar posed no risk to Baratta’s health despite her doctor’s warnings to get it under control.

Researchers at the University of Maryland believe that many others like Baratta are misdiagnosed, leading to unnecessary treatment — and in some cases the wrong treatment. They are using a $3.7 million grant from the National Institutes of Health to work on correctly diagnosing more people. They are using the money to identify more people with monogenic diabetes through genetic testing, and to track which characteristics are common in these patients. They hope to create guidelines to help doctors better identify and treat those patients.

Nobody knows how many people have monogenic diabetes, but estimates have put it at 1 percent to 2 percent of all diabetes cases, and some researchers familiar with it believe the figure could be higher. One study found that monogenic diabetes is diagnosed correctly in only about 6 percent of cases.

University of Maryland researchers believe that many physicians don’t know enough about monogenic diabetes to correctly diagnose it and may pursue traditional treatments for Type 1 or 2 diabetes.

“When you see someone with high glucose, even though it’s mild, then the normal medical impulse is to treat that because you don’t want the person to develop complications,” said Toni Pollin, the lead researcher on the University of Maryland study.

The school’s researchers aim to develop an approach to make identifying its different symptoms easier, she said.

“If we can come up with an approach to help come up with a way to identify patients that are candidates for genetic testing, then it will be available in a much more widespread way,” she said.

It is important to find the correct diagnosis so that the best treatment is prescribed, Pollin and others said.

While the variation of monogenic diabetes Baratta has did not require medical intervention, others need immediate medical attention. But the treatment is different from that for Types 1 and 2.

Patients with Type 1 diabetes require treatment with insulin for survival. Those with Type 2 diabetes typically receive the drug metformin, which helps the body respond properly to the insulin it naturally produces and decreases the amount of sugar made by the liver and absorbed by the stomach and intestines.

Certain forms of the monogenic diabetes respond better to oral medications called sulfonylureas, which enable the patient to release their own insulin. These drugs can be more effective and less invasive than insulin injections, Pollin said. Some types of neonatal diabetes, a form of monogenic diabetes in babies, also can be better treated this way.

“If someone thinks they have regular Type 2, a lot of doctors will treat them with diet and exercise and they may not put them on medication right away, in hopes that it will get better,” said Kristin A. Maloney, a genetic counselor involved with the University of Maryland study. In some cases, she said, “the patient needs to be on some sort of medication because it is going to get progressively worse.”

There are signs that doctors can look for to identify patients who may have a monogenic diabetes. Patients who come in with high blood sugar levels but have no other typical signs of diabetes should be further evaluated, said Dr. Elizabeth Streeten, an endocrinologist and co-investigator on the University of Maryland study.

People with the more common Type 1 and 2 diabetes generally are lethargic, drink a lot and urinate often. Type 2 diabetes also is associated with lifestyle indicators, such as obesity and poor eating habits.

“Once you are sensitive of what to look for, it’s not that hard to spot,” Streeten said. “We are looking for anybody with diabetes where it seems unusual or atypical.”

Doctors can do blood tests to check for antibodies related to certain types of diabetes and to check if the body is producing insulin, before looking for a precise mutation.

“There are other tests before you get to genetic testing that can give you clues,” Pollin said.

Sharon Stewart, another patient in the University of Maryland study, had been diagnosed with Type 1 diabetes for many years after a blood test showed elevated sugar levels but no other symptoms. But it wasn’t until her 16-year-old daughter was told that she too had elevated levels, and was in danger of needing insulin, that the proper diagnosis began to emerge.

Stewart’s daughter was referred to Dr. Rana Malek, an endocrinologist with the University of Maryland Center for Diabetes and Endocrinology, about three years ago. Malek immediately became suspicious of the diagnosis because Stewart’s daughter was young and very thin.

A blood test found no antibodies associated with Type 1 diabetes. Another test found she was still making insulin, a second sign that she didn’t have Type 1 diabetes.

Rather than put her on medication, Malek tracked Stewart’s daughter’s blood-sugar level over several weeks. Although it remained slightly high, it never fluctuated. Type 1 diabetes would have risen rapidly, Malek said.

The young girl didn’t have insurance coverage to pay for genetic testing, but Malek deduced that she had a form of monogenic diabetes that wasn’t harmful and saw no need to treat her with medication.

Malek then became suspicious of Stewart’s Type 1 diabetes diagnosis as well. She looked at Stewart’s medical records for the previous eight years and found that her blood-sugar levels were the same each year. Once again, she suspected a genetic mutation. Stewart’s insurance partially covered genetic testing, but it still would cost her more than $300 out of pocket, more than the administrative worker could afford to pay.

A few years later, she was able to join the University of Maryland study, and Malek’s speculation was confirmed.

Stewart no longer takes medicine to treat her disease and said her life is a lot less complicated.

“It’s normal for me,” she said of her high blood-sugar levels.

The University of Maryland researchers hope their data eventually will help treat more patients. When doctors do suspect monogenic diabetes, they often have to write letters proving that the expensive genetic test is medically necessary. A test from one drug company costs about $3,000, Streeten said.

A correct diagnosis of monogenic diabetes can save significantly on medical costs, particularly for those forms where no treatment is needed, Pollin said.

The researchers said initial genetic testing would have to be done on only one family member. Once the genetic mutation is determined, other family members could get tested for just that marker, which is less expensive.

The researchers also hope to raise general awareness about monogenic diabetes.

“Part of it is also letting patients know,” Malek said. “Patients are sometimes their own advocates and doctors are so far from perfect and don’t look up from their charts. If a patient is aware, they can bring it up and help raise the red flag to their physician.”

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