Maturity onset diabetes of the young

Maturity onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes caused by mutations in an autosomal dominant gene (sex independent, i.e. inherited from any of the parents) disrupting insulin production. MODY is often referred to as "monogenic diabetes" to distinguish it from the more common types of diabetes (especially type 1 and type 2), which involve more complex combinations of causes involving multiple genes (i.e., "polygenic") and environmental factors. MODY 2 and MODY 3 are the most common forms. The severity of the different types varies considerably, but most commonly MODY acts like a very mild version of type 1 diabetes, with continued partial insulin production and normal insulin sensitivity. MODY is not type 2 diabetes in a young person, as might erroneously be inferred from the name.

History of the concept and treatment of MODY
The term MODY dates back to 1964, when diabetes mellitus was considered to have two main forms: juvenile-onset and maturity-onset, which roughly corresponded to what we now call type 1 and type 2. MODY was originally applied to any child or young adult who had persistent, asymptomatic hyperglycemia without progression to diabetic ketosis or ketoacidosis. In retrospect we can now recognize that this category covered a heterogeneous collection of disorders which included cases of dominantly inherited diabetes (the topic of this article, still called MODY today), as well as cases of what we would now call type 2 diabetes occurring in childhood or adolescence, and a few even rarer types of hyperglycemia (e.g., mitochondrial diabetes or mutant insulin). Many of these patients were treated with sulfonylureas with varying degrees of success.

By the 1990s, as the understanding of the pathophysiology of diabetes has improved, the concept and usage of "MODY" have become refined and narrower. It is now used as a synonym for dominantly inherited, monogenic defects of insulin secretion occurring at any age, and no longer includes any forms of type 2 diabetes.

Signs, symptoms and differential diagnosis
There are two general types of clinical presentation.
 * Some forms of MODY produce significant hyperglycemia and the typical signs and symptoms of diabetes: increased thirst and urination (polydipsia and polyuria).
 * In contrast, however, many people with MODY have no signs or symptoms and are diagnosed either by accident, when a high glucose is discovered during testing for other reasons, or screening of relatives of a person discovered to have diabetes. Discovery of mild hyperglycemia during a routine glucose tolerance test for pregnancy is particularly characteristic.

MODY cases may make up as many as 5% of presumed type 1 and type 2 diabetes cases in a large clinic population. While the goals of diabetes management are the same no matter what type, there are two primary advantages of confirming a diagnosis of MODY.
 * Firstly, insulin may not be necessary and it may be possible to switch a person from insulin injections to oral agents without loss of glycemic control.
 * Secondly, it may prompt screening of relatives and so help identify other cases in family members.

As it occurs infrequently, many cases of MODY are initially assumed to be more common forms of diabetes: type 1 if the patient is young and not overweight, type 2 if the patient is overweight, or gestational diabetes if the patient is pregnant. Standard diabetes treatments (insulin for type 1 and gestational diabetes, and oral hypoglycemic agents for type 2) are often initiated before the doctor suspects a more unusual form of diabetes.

Treatment
In some forms of MODY, standard treatment is appropriate, though exceptions occur:


 * In MODY2, oral agents are relatively ineffective and insulin is unnecessary.
 * In MODY1 and MODY3, insulin may be more effective than drugs to increase insulin sensitivity.
 * Sulfonylureas are effective in the KATP channel forms of neonatal-onset diabetes.

Presentation of MODY
The following characteristics suggest the possibility of a diagnosis of MODY in hyperglycemic and diabetic patients: The diagnosis of MODY is confirmed by specific gene testing, now available through several commercial laboratories.
 * Mild to moderate hyperglycemia (typically 130–250 mg/dl, or 7-14 mM/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.
 * 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 6 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

Pathophysiology
The recognised forms of MODY are all due to ineffective insulin production or release by pancreatic &beta;-cells. Several of the defects are mutations of transcription factor genes. One form is due to mutations of the glucokinase gene. For each form of MODY, multiple specific mutations involving different amino acid substitutions have been discovered. In some cases, there are significant differences in the activity of the mutant gene product that contribute to variations in the clinical features of the diabetes (such as degree of insulin deficiency or age of onset).

Genetics
Some sources make a distinction between two different forms of monogenetic diabetes: MODY and neonatal diabetes. However, they have much in common, and are often studied together.

Heterozygous
MODY is inherited in an autosomal dominant fashion, and most patients therefore have other members of the family with diabetes; penetrance differs between the types (from 40% to 90%).

Homozygous
By definition, the forms of MODY are autosomal dominant, requiring only one abnormal gene to produce the disease; the severity of the disease is moderated by the presence of a second, normal allele which presumably functions normally. However, conditions involving people carrying two abnormal alleles have been identified. Unsurprisingly, combined (homozygous) defects of these genes are both much rarer and much more severe in their effects.


 * MODY2: Homozygous glucokinase deficiency causes severe congenital insulin deficiency resulting in persistent neonatal diabetes mellitus. About 6 cases have been reported worldwide. All have required insulin treatment from shortly after birth. The condition does not seem to improve with age.


 * MODY4: Homozygous IPF1 results in failure of the pancreas to form. Congenital absence of the pancreas, termed pancreatic agenesis, involves deficiency of both endocrine and exocrine functions of the pancreas.

Homozygous mutations in the other forms have not yet been described. Those mutations for which a homozygous form has not been described may be extremely rare, or may result in clinical problems not yet recognized as connected to the monogenic disorder, or may be lethal for a fetus and not result in a viable child.

Management
Unfortunately, chronic hyperglycemia of any cause can eventually cause blood vessel damage and the microvascular complications of diabetes. The principal treatment goals for people with MODY &mdash; keeping the blood sugars as close to normal as possible ("good glycemic control"), while minimizing other vascular risk factors &mdash; are the same for all known forms of diabetes.

Tools available for management are also those available for all forms of diabetes: blood testing, changes in diet, physical exercise, oral hypoglycemic agents, and insulin injections. In many cases these goals can be achieved more easily with MODY than with ordinary types 1 and 2 diabetes. Some people with MODY may require insulin injections to achieve the same glycemic control that another person may attain with careful eating or an oral medication.

When oral hypoglycemic agents are used in MODY, the sulfonylureas remain the oral medication of first resort. When compared to patients with type 2 diabetes, MODY patients are often more sensitive to sulphonylureas, such that a lower dose should be used to initiate treatment to avoid hypoglycaemia. Patients with MODY less often suffer from obesity and insulin resistance than those with ordinary type 2 diabetes (for whom insulin sensitizers like metformin or the thiazolidinediones are often preferred over the sulfonylureas).

Incidence
According to data from Saxony, Germany, MODY was responsible for 2.4% of diabetes incidence in children aged less than 15 years.