Maturity-onset diabetes of the young

Other Names: MODY; Mason type diabetes Maturity-onset diabetes of the young (MODY) is a form of diabetes that is characterized by an early onset diabetes. These forms of diabetes typically begin before age 30, although they can occur later in life. In MODY, elevated blood sugar arises from reduced production of insulin, which is a hormone produced in the pancreas that helps regulate blood sugar levels. Specifically, insulin controls how much glucose (a type of sugar) is passed from the blood into cells, where it is used as an energy source. MODY represents about 2% of all diabetes cases and is commonly misdiagnosed as type 1 or type 2 diabetes mellitus. It is due to a primary defect in pancreatic β-cell function.

Epidemiology

MODY is estimated to account for 1 to 3 percent of all cases of diabetes.

Types

The different types of MODY are distinguished by their genetic causes. The most common types are HNF1A-MODY (also known as MODY3), accounting for 50 to 70 percent of cases, and GCK-MODY (MODY2), accounting for 30 to 50 percent of cases. Less frequent types include HNF4A-MODY (MODY1) and renal cysts and diabetes (RCAD) syndrome (also known as HNF1B-MODY or MODY5), which each account for 5 to 10 percent of cases. At least ten other types have been identified, and these are very rare.

Cause

MODY can be caused by a mutation in one of several genes. HNF1A-MODY, GCK-MODY, HNF4A-MODY, and RCAD, are caused by mutations in the HNF1A, GCK, HNF4A, and HNF1B gene, respectively. All of these genes provide instructions for making proteins involved in the production of insulin to control blood sugar levels in the body. In particular, the proteins are important in specialized cells in the pancreas called beta cells, which secrete insulin.

The proteins produced from the HNF1A, HNF4A, and HNF1B genes all act as transcription factors, which means they control the activity of other genes. In particular, these proteins regulate genes that direct the development and function of beta cells. HNF1A, HNF4A, or HNF1B gene mutations result in production of an altered transcription factor that is unable to function normally. These changes alter gene activity in cells, impairing normal beta cell development and function. As a result, beta cells are less able than normal to produce insulin in response to sugar in the blood, which means the body cannot control blood sugar. Elevated blood sugar results in the signs and symptoms of MODY. Some of these MODY-related genes play roles in the development of other body systems, in addition to beta cells. Disrupted development of these systems underlies additional signs and symptoms in particular forms of MODY. For example, the HNF1B gene is involved in kidney development, which helps explain the kidney abnormalities in people with RCAD.

The protein produced from the GCK gene acts as a sensor that recognizes when the amount of glucose in the blood rises. In response, the protein helps stimulate the release of insulin from beta cells so sugar can be taken up and used by cells for energy. This protein also helps determine when excess sugar should be taken into liver cells and stored. Mutations in the GCK gene limit the protein's ability to sense a rise in blood sugar, so levels remain elevated.

Other genes involved in controlling blood sugar cause rare types of MODY. It is likely that additional genes that have not been identified are also involved in the condition.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

MODY is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In most cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Signs and symptoms

HNF1A-MODY and HNF4A-MODY have similar signs and symptoms that develop slowly over time. Early signs and symptoms in these types are caused by high blood sugar and may include frequent urination (polyuria), excessive thirst (polydipsia), fatigue, blurred vision, weight loss, and recurrent skin infections. Over time uncontrolled high blood sugar can damage small blood vessels in the eyes and kidneys. Damage to the light-sensitive tissue at the back of the eye (the retina) causes a condition known as diabetic retinopathy that can lead to vision loss and eventual blindness.

Kidney damage (diabetic nephropathy) can lead to kidney failure and end-stage renal disease (ESRD). While these two types of MODY are very similar, certain features are particular to each type. For example, babies with HNF4A-MODY tend to weigh more than average or have abnormally low blood sugar at birth, even though other signs of the condition do not occur until childhood or young adulthood. People with HNF1A-MODY have a higher-than-average risk of developing noncancerous (benign) liver tumors known as hepatocellular adenomas.

GCK-MODY is a very mild type of the condition. People with this type have slightly elevated blood sugar levels, particularly in the morning before eating (fasting blood sugar). However, affected individuals often have no symptoms related to the disorder, and diabetes-related complications are extremely rare.

RCAD is associated with a combination of diabetes and kidney or urinary tract abnormalities (unrelated to the elevated blood sugar), most commonly fluid-filled sacs (cysts) in the kidneys. However, the signs and symptoms are variable, even within families, and not everyone with RCAD has both features. Affected individuals may have other features unrelated to diabetes, such as abnormalities of the pancreas or liver or a form of arthritis called gout.

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. 30%-79% of people have these symptoms

• Abnormal C-peptide level
• Abnormal oral glucose tolerance
• Elevated hemoglobin A1c
• Glycosuria(Glucose in urine)
• Hyperglycemia(High blood sugar)
• Hypoinsulinemia

5%-29% of people have these symptoms

• Hyperinsulinemic hypoglycemia
• Intrauterine growth retardation(Prenatal growth deficiency)
• Large for gestational age(Birth weight > 90th percentile)
• Neonatal hypoglycemia(Low blood sugar in newborn)
• Nephropathy
• Overweight
• Retinopathy(Noninflammatory retina disease)
• Transient neonatal diabetes mellitus

1%-4% of people have these symptoms

• Exocrine pancreatic insufficiency(Inability to properly digest food due to lack of pancreatic digestive enzymes)
• Hepatocellular adenoma
• Obesity(Having too much body fat)
• Pancreatic hypoplasia(Underdeveloped pancreas)
• Renal cyst(Kidney cyst)

Diagnosis

The following characteristics suggest the possibility of a diagnosis of MODY in hyperglycemic and diabetic patients:

• Mild to moderate hyperglycemia (typically 130–250 mg/dl, or 7–14 mmol/l) discovered before 30 years of age. However, anyone under 50 can develop MODY.
• A first-degree relative with a similar degree of diabetes.
• Absence of positive antibodies or other autoimmunity (e.g., thyroiditis) in patient and family. However, Urbanova et al. found that about one quarter of Central European MODY patients are positive for islet cell autoantibodies (GADA and IA2A). Their expression is transient but highly prevalent. The autoantibodies were found in patients with delayed diabetes onset, and in times of insufficient diabetes control. The islet cell autoantibodies are absent in MODY in at least some populations (Japanese, Britons).
• Persistence of a low insulin requirement (e.g., less than 0.5 u/kg/day) past the usual "honeymoon" period.
• Absence of obesity (although overweight or obese people can get MODY) or other problems associated with type 2 diabetes or metabolic syndrome (e.g., hypertension, hyperlipidemia, polycystic ovary syndrome).
• Insulin resistance very rarely happens.
• Cystic kidney disease in patient or close relatives.
• Non-transient neonatal diabetes, or apparent type 1 diabetes with onset before six months of age.
• Liver adenoma or hepatocellular carcinoma in MODY type 3.
• Renal cysts, rudimentary or bicornuate uterus, vaginal aplasia, absence of the vas deferens, epidymal cysts in MODY type 5
• The diagnosis of MODY is confirmed by specific gene testing available through commercial laboratories.

Treatment

Treatment depends on the subtype and may include sulfonylureas, insulin or diet and exercise.

NIH genetic and rare disease info

• NIH info on Maturity-onset diabetes of the young

Maturity-onset diabetes of the young is a rare disease.

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