What is Maturity Onset Diabetes of the Young (MODY)

Posted on November 23, 2009

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Maturity onset diabetes of the young (MODY) refers to any of several rare hereditary forms of diabetes mellitus due to dominantly inherited defects of insulin secretion. As of 2004, six types have been enumerated, but more are likely to be added. 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. It is not type 2 diabetes in a young person, as might erroneously be inferred from the name.

In 1992, Graeme Bell, the Louis Block Professor in Biochemistry & Molecular Biology, Medicine and Human Genetics,  led a team that discovered that glucokinase mutations were one cause of a sub-type of diabetes called maturity onset diabetes of the young, or MODY. According to Bell, that defect appears to be relatively common and underdiagnosed.

MODY is a type of diabetes that has six basic sub classifications depending upon the gene that contributed onset (there may be more, but so far, only six genes have been identified in MODY).  Only 1-2% of type 1 diabetics have this form of diabetes but it often goes unrecognized.  MODY is an autosomal dominantly inherited disease, which means that it is inherited by a single (auto) gene which can come from either parent.  When a parent has MODY their children have a 50% chance of also developing MODY.

The three main identifying characteristics of MODY are:

  • May or may not require insulin and can sometimes be treated by diet or medication.
  • Onset is usually before age 25.
  • A family history of diabetes can be traced from one generation to the next.

Identifying which form of MODY a person has is key to ensuring proper treatment.  Hepatic Nuclear Factor 1 Alpha (HNF1-a) accounts for approximately 70% of all diagnosed cases of MODY.  Other genes currently known to be involved are HNF4-a,  IPF1, and Neuro D1.  Two other forms of MODY affect the genes Glucokinase, and RCAD (Renal Cysts And Diabetes), a newly described familial cystic kidney syndrome associated with mutations in the hepatocyte nuclear factor-1  gene.

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 by either (1) accident, when a high glucose is discovered during testing for other reasons, or (2) 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, the two primary advantages of confirming a diagnosis of MODY are that (1) 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, and (2) it may prompt screening of relatives and discovery of 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. In some forms of MODY, standard treatment is appropriate, though exceptions occur. For example, in MODY2, oral agents are relatively ineffective and insulin is unnecessary, while in MODY1 and MODY3, insulin may be more effective than drugs to increase insulin sensitivity. Sulfonylureas are effective in the KATP channel forms of MODYX.

The following characteristics should warrant consideration of a diagnosis of MODY in hyperglycemic and diabetic patients:

  • Mild to moderate hyperglycemia (typically 130-250 mg/dl, or 7-14 mM) discovered before 30 years of age.
  • 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 (though obese people can get MODY), or other problems associated with type 2 diabetes or metabolic syndrome (e.g. hypertension, hyperlipidemia, polycystic ovary syndrome).
  • Cystic kidney disease in patient or close relatives.

The diagnosis of MODY is confirmed by specific gene testing, now available through several commercial laboratories.

Pathophysiology

The 6 recognised forms of MODY are all due to ineffective insulin production or release by pancreatic β-cells. Five of the 6 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 & Subtypes of MODY

They are 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%).

What are the different types of MODY?

There are 5 genes which have been identified as causing MODY. The type of MODY inherited will depend on the gene responsible and are labelled as MODY 1 to MODY 5.

The 5 genes identified are:

  • HNF1-a
  • Glucokinase
  • HNF1-b
  • HNF4-a
  • IPF1

http://www.isletsofhope.com/diabetes/symptoms/maturity_onset_diabetes_mody_1.html