While it’s probably common knowledge that diabetes tends to run in some families, many people may not realize that multiple genes can increase the risk for developing Type 1 and Type 2 diabetes mellitus. As a result, doctors refer to Type 1 and Type 2 diabetes as polygenic because more than one — often several — genes likely contribute to a person’s risk for developing the condition, according to the National Institutes of Health (NIH).
But a mutation in a single gene also can cause diabetes. Known as monogenic diabetes, this form accounts for an estimated 1% to 5% of all cases of diabetes and, according to the American Diabetes Association (ADA), most commonly affects infants, children, and young adults. However, research suggests that at least 80% of all cases of monogenic diabetes go unnoticed.
Although monogenic diabetes tends to be fairly uncommon, it may cause serious health problems if left untreated. Quite often, the condition either goes undiagnosed or is misdiagnosed as Type 1 diabetes, which could be problematic if someone with the condition does not receive proper treatment.
The term monogenic diabetes doesn’t just describe a single form of diabetes or manifestation of insulin resistance. The phrase is used to describe a large variety of rare but potentially serious diabetic disorders caused by a single abnormality that can occur in a variety of genes. To date, researchers have identified nearly 30 different genes that can cause the disorder. Like Type 1, monogenic diabetes is found most commonly in younger people — according to diabetesgenes.org, most receive a diagnosis before their 25th birthday. However, unlike Type 1, some forms of monogenic diabetes either may not require treatment and/or can be treated with drugs other than insulin.
An individual’s type of monogenic diabetes depends on the specific gene that carries the mutation, and identifying the faulty gene often plays a key role in helping doctors determine the best treatment plan for that patient. The condition is divided into two major categories: neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young or maturity-onset monogenic diabetes (MODY).
Neonatal diabetes mellitus
As its name indicates, NDM appears in neonates, or babies, within the first six months of life. A rare condition, NDM accounts for one in every 100,000 to 500,000 live births, and about one in every 400,000 infants born are diagnosed with NDM within six months. This is another major difference between NDM and Type 1: While NDM and Type 1 both first appear in younger populations than Type 2, signs of Type 1 normally appear after a baby’s first six months of life.
Some forms of NDM are temporary, while others last a lifetime. NDM that either comes and goes or eventually completely disappears is called transient neonatal diabetes mellitus. According to the NIH Genetics Home Reference, NDM disappears by age 18 in nearly 50% of babies born with it. The rest have permanent NDM, or PNDM.
To date, scientists have identified more than 20 different genes that cause NDM, and some can cause both temporary (transient) or permanent NDM. For example, babies born with defective genes such as KCNJ11 or ABCC8 may have NDM throughout their adult lives, according to the ADA. In fact, mutations in either of these genes are among the most common causes of permanent NDM, since 30% of people with permanent neonatal diabetes mellitus have a KCNJ11 gene defect, while another 20% carry a mutation in the ABCC8 gene.
Challenges for children with NDM
NDM can affect the health and development of a child, beginning at conception and continuing through childhood. Fetuses carrying a genetic mutation for NDM may grow slowly in the uterus and have high blood sugar, dehydration, and trouble gaining weight after birth, according to the NIH. Parents may find their child develops more slowly than other children in the same age group. In more severe cases, NDM children also may battle epilepsy and developmental delays.
Permanent NDM (PNDM) can have long-term effects on digestion, mainly due to an underdeveloped pancreas, which may not release enough insulin to help regulate blood sugar. The pancreas also may lack special enzymes the body needs to digest fat and absorb certain nutrients. As a result, some people with PNDM also may have fatty stools and trouble absorbing fat-soluble vitamins (Vitamins A, D, K, and E).
Maturity-onset monogenic diabetes
MODY generally occurs later in childhood — usually as children approach puberty or young adulthood, according to diabetesgenes.org. Some people with MODY may not have any signs or symptoms at all. While scientists have identified at least 11 different genes responsible for different forms of MODY, the most commonly diagnosed forms of monogenic diabetes fall under the MODY category, and most people with MODY are diagnosed by age 25.
Each of the 11 different MODY-causing genes may have different signs and symptoms that demand different treatments. For example, people who have a defect in the GCK gene may have hyperglycemia (high blood sugar) and an HbA1c ranging from 5% to 7%. Yet, unlike Type 2 diabetes, people with GCK mutations may not find that diet and exercise modification have much impact on their blood sugar.
Genetic mutations in HFN1A and HNF4A commonly are mistaken for Type 1 and therefore are treated with insulin. As with Type 1, people with these mutations typically are not overweight. HFN1A mutations may cause tumors to develop in the liver, called hepatic adenomas, while HFN1B mutations may cause kidney problems, including congenital birth defects or cysts. People carrying an HFN1B mutation also may have abnormalities in their genitalia or urinary tracts. But unlike Type 1 diabetes, people diagnosed with MODY caused by either HFN1A and HNF4A genetic defects may fare better taking low doses of sulfonylureas such as glipizide or glyburide rather than the insulin they likely would be prescribed if they are diagnosed with Type 1. However, with age, some of these patients may find their bodies no longer respond to sulfonylureas, so their doctors might switch them to insulin.
Genetic testing can help determine treatment for monogenic diabetes
Because multiple genes can cause monogenic diabetes, genetic testing can help doctors identify which form a patient has and design a treatment plan. Unfortunately, genetic testing can be expensive, and insurance companies do not routinely cover this type of screening. According to one study, genetic testing for monogenic diabetes can cost about $1,000. But it could be worth it if the patient is found to have a form of monogenic diabetes that could be confused with Type 1.
Specialists in children’s health are more likely to test babies who routinely have high blood sugar. Still, nearly 50% of children who either may have or develop MODY will not be diagnosed, since only those babies who show the classic symptoms of the condition are tested.
As with other forms of diabetes, having a family member with the condition can increase risk. Every child born to a parent with MODY has a 50% chance of developing the condition. If you have some form of monogenic diabetes or a parent with it, talk to your doctor about having your children tested. Experts also recommend children and families who developed diabetes before age 25 and whose families have been affected by the condition for two or three generations should ask their doctors about being tested.