Diabetes, Maturity Onset in the Young (MODY)

Article Author:
Laura Hoffman
Article Editor:
Ishwarlal Jialal
Updated:
10/29/2018 8:47:06 AM
PubMed Link:
Diabetes, Maturity Onset in the Young (MODY)

Introduction

In the 1990s endocrinologists recognized a subgroup of patients with diabetes who manifested features both type 1 and type 2 diabetes mellitus (DM1 and DM2). These patients were referred to as having "diabetes type 1.5." Type 1 diabetes is an autoimmune disorder while type 2 diabetes is a polygenic disorder influenced by both genetics and environment.  Professionals now understand that there are more than just 2 forms of diabetes; although, hybrid forms occur much less frequently. These include monogenic forms of diabetes. Maturity-onset diabetes (MODY) is a subgroup if this form. 

In a 1954[1] study, 19% of 152 relatives of patients with known diabetes were also found to have diabetes through oral glucose tolerance testing (OGTT). Some of these subjects were diagnosed as young as 10 years old. A 1960 study reported the observation of a “mild, asymptomatic form of diabetes” in some non-obese children, adolescents, and young adults.  Improvement with sulfonylureas in OGTT testing and fasting blood sugars was seen in these patients. In 1974, Tattersall and Fajans coined the term mature onset diabetes of the young (MODY). Since 1974, and with the explosion of genetic technology, many genes linked to MODY have been sequenced and described.

Etiology

MODY is caused by defects in pancreatic islet cell development and insulin secretion. It is usually inherited in an autosomal dominant fashion, patients generally have heterozygote mutations. Penetrance and expressivity can vary immensely, even among family members. MODY genes affect insulin secretion via impairment of insulin sensing, glucose metabolism in beta cells or activation of adenosine triphosphate (ATP)-dependent potassium channels.

Epidemiology

MODY accounts for less than 5.0% of all patients with diabetes. It is now thought that 6.5%[2][3] of children with antibody-negative diabetes have a form of MODY. The onset of MODY is typically between the ages of 10 to 40 years old. Patients with MODY share genotypic features of both type 1 diabetes and type 2 diabetes and are often misdiagnosed as having type 1 diabetes or type 2 diabetes. Therefore, as the frequency of MODY diagnoses increases, the prevalence may prove to be higher. While MODY has been described predominantly in Caucasian populations, it has also been reported in other races such as Asian Indians in South Africa by Jialal et al .[4]

Pathophysiology

Whereas DM1 and DM2 are polygenic, MODY is caused by a single gene mutation that leads to a defect in beta cell insulin secretion in response to glucose stimulation. Most genetic versions of MODY have autosomal dominant transmission although, less frequently, autosomal recessive versions may also exist and could account for neonatal diabetes. Initially, different types of MODY were described numerically (“MODY 1 through 6”). However, they are now classified by their genetic defect.

There are now at least 14 different known MODY mutations. They include GCK, HNF1A, HNF4A, HNF1B, INS,  NEURO1, PDX1, PAX4, ABCC8, KCNJ11, KLF11, CEL, BLK and APPL1. The different genes vary with respect to age of onset, response to treatment, and the presence of extra-pancreatic manifestations. The most common gene mutations are the following:

  1. Gene mutation in the hepatocyte nuclear factor 1 alpha (HNF1A) accounts for 30% to 60% of MODY.
  2. Gene mutation in the hepatocyte nuclear factor 4 alpha (HNF4A), accounts for 5% to 10% of MODY cases.
  3. Gene mutations in glucokinase (GCK) account for 30% to 60% of the cases of MODY.
  4. Gene mutation in hepatocyte nuclear factor 1 beta (HNF1B), which accounts for less than 5% of the cases of MODY.

The difference in prevalence of the MODY genes varies from country to country which may be, in part, due to differences in reporting.

HNF1A (MODY 3)

The gene mutation in Hepatocyte nuclear factor 1-alpha-HNF1A (MODY 3) acts to inhibit the key steps of glucose transport and metabolism as well as mitochondrial metabolism in pancreatic beta cells. HNF1A is found in liver, kidney, and intestine as well as pancreatic tissue. There is progressive beta cell dysfunction. These patients have a decreased renal threshold for glycosuria. The diagnosis of HNF1A is typically made between the ages of 21 to 26. The gene defect has high penetrance; 63% of carriers develop DM by age 25 years old; 79% by 35 years old and 96% by age 35 years old.[5][6] It carries a high risk of microvascular and macrovascular complications, similar to DM1 and DM2.[6] The HDL-C is typically elevated, which can help distinguish it from DM2. Additionally, hsCRP levels are typically lower in HNF1A than in other forms of DM, thereby making it a potential biomarker.

HNF1A is very responsive to sulfonylureas and meglitinides even though beta cells do not respond well to hyperglycemia with insulin production and release.[7] The mechanism of action involves the binding of the medication to sulfonylurea receptors on beta cell membranes. This triggers the influx of calcium, which leads to the fusion of vesicles containing stored insulin.[8] The use of sulfonylureas can frequently delay the need for insulin replacement for many years.

GCK (MODY 2)

Glucokinase is an enzyme, which enables the pancreatic beta cells and hepatocytes to respond to glucose levels. In the GCK gene mutation (MODY 2), the glucose threshold for insulin secretion is reset, leading to higher fasting glucose level. Oral glucose tolerance testing reveal a mild increase in glucose concentration. Patients with a GCK mutation display typically mild and nonprogressive hyperglycemia, which is generally not symptomatic. The HBA1C in these patients is usually less than 8%, and the risk of microvascular (and possibly macrovascular) complications is low.[9][5]

Treatment of the hyperglycemia in GCK is generally unnecessary[10] except during pregnancy when insulin may be required to prevent excess fetal growth.  This is specifically important if the fetus does not carry the MODY gene because increased fetal insulin levels in response to maternal hyperglycemia may result in macrosomia.[11] Glucokinase activator drugs may prove to be useful in the future.

HNF4A (MODY 1)

The HNF4A mutation (MODY 1) is less common than HNF1A or GCK.  Its presentation is similar to HNF1A. It should be considered when the patient has features similar to HNF4A, but genetic testing is negative.  Patients with HNF4A mutation may have decreased HDL-C levels and are therefore more similar to DM2. Additionally, these patients have a higher birth weight and a higher level of macrosomia. They may display transient neonatal hypoglycemia.[9] Patients with diabetes and a strong family history of neonatal hypoglycemia should be suspected for HNF4A. Sulfonylureas work well for the treatment of hyperglycemia.[12]

These patients are prone to microvascular complications.

Note: HNF1A and HNF4A are both genes that regulate the expression of numerous genes encoding serum proteins such as clotting factors and apolipoproteins.[13]

HNF1B (MODY 5)

The HNF1B mutation (MODY 5) accounts for less than 5% of MODY. It is associated with a wide variation in presentations. Half of these patients present with early onset DM. This mutation can affect gene regulation in the liver, kidney, intestines, lungs, or ovaries. Patients can present with abnormalities such as renal cysts, dysplasia, renal tract malformations, or hypoplastic glomerulocystic kidney disease. HNF1B MODY is sometimes referred to as RCAD (renal cysts and diabetes syndrome). There can be a progressive loss of renal function independent of diabetic nephropathy.[14]

The HNF1B mutation has also been associated with genital abnormalities including a bicornate uterus, Rokitanski syndrome, agenesis of the vas deferens and hypospadias.[9] Additionally, it has been associated with hypomagnesemia due to renal wasting, hyperuricemic nephropathy with gout, and primary hyperparathyroidism.[9] These patients can also develop pancreatic atrophy, genital tract abnormalities, abnormal liver enzyme levels and neuropsychiatric abnormalities including intellectual disability and autism. Patients with HNFIB can have low birth rates due to decreased insulin secretion in utero. Interestingly, patients may demonstrate insulin resistance in some cases. Patients with HNF1B generally are not responsive to oral medications and require treatment with insulin. Microvascular complications are common.

PDX1 (MODY 4)

A defect in IPF1 (insulin gene promoter factor 1) causes another form of MODY. PDX1 is a homeobox-containing transcription factor that effects pancreatic development and insulin gene expression. This rare defect has been associated with pancreatic agenesis, neonatal DM, and pancreatic exocrine dysfunction.[7]

NEUROD1 (MODY 6)

NEURODI is a mutation in a basic-loop-helix transcription factor which effects pancreatic and neuronal development. Heterozygotes cause diabetes in children, neurological abnormalities, and learning disabilities. Most patients require treatment with insulin.[7]

ABCC8 (MODY 12) and KCNJ11 (MODY 13)

The ABCC8 and KCNJ1 mutations have been associated with a spectrum of disorders including neonatal diabetes.[9] Neonatal diabetes can be permanent or transient, in which case, it often recurs later on in life. Neonatal diabetes has been associated with mutations in the potassium-ATP channel genes or mutations in the insulin gene.[2] Additionally, these mutations have been linked to neonatal hypoglycemia due to elevated insulin levels. It is usually transient, but the patient may develop diabetes later on in life. In these cases, monitoring of fetal growth during pregnancy and blood glucose levels in neonates can be crucial. Patients with diabetes generally respond well to sulfonylureas.

MODY Genes Associated with Syndromes not Involving DM

MODY mutations have also been noted in several other syndromes.

  1. Wolfram Syndrome, also known as DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness)
  2. Thiamine-responsive megaloblastic anemia syndrome
  3. Maternity-inherited diabetes with deafness

History and Physical

Patients with MODY have strong family histories of diabetes spanning at least 3 generations. In general, patients with MODY are not obese and do not have elevated anti-insulin or islet cell autoantibody levels.  Ketosis is rare. They are generally not insulin-resistant and are not, at least initially, insulin-dependent. Depending on the type of gene defect present, their course may be slowly or rapidly progressive, eventually resulting in very low C-peptide and insulin levels.[15] Some forms of MODY can be associated with extra-beta cell manifestations including renal, hepatic, genitourinary, exocrine pancreatic or intestinal effects. A clinical examination for retinopathy and neuropathy and assessment of albuminuria and the lipid profile is essential since some forms develop complications.

Evaluation

Who Should be Genetically Tested for MODY?

Genetic testing for MODY should be done in cases where there is a high index of suspicion that the patient does not have DM1 or DM2. A diagnosis of MODY may change the understanding of the course of the disease and the optimal treatment (or if treatment is needed at all). Genetic counseling may be beneficial to family members of MODY patients. 

However, given the time and expense of genetic testing, criteria for narrowing down the patients appropriate for testing has been sought. Indications for genetic testing include:

  • Patients with a strong family history of DM presenting in the second to fifth decade of life
  • Leanness
  • Autoantibody negative
  • Features inconsistent with DM1 or DM2 such as:
    • Low renal threshold
    • A large increase in blood sugar in OGTT
    • Lower than expected CRP levels
  • Lower than expected HDL-C
  • High insulin sensitivity; although, as noted above insulin resistance has been observed in a small number of MODY gene defects
  • Children diagnosed with DM1 who are antibody-negative and exhibit
  • Elevated C peptide levels

Until recently, genetic testing was performed with “Sanger” sequencing and was usually restricted to a small subset of genes. More recently, new generation sequencing (NGS) has been developed and can assess for multiple genes resulting in a higher pick-up rate of mutations in a single test. Most recent discoveries of monogenic diabetes have been forms of neonatal diabetes.

Treatment / Management

As mentioned above, the optimal treatment for diabetes associated with MODY varies on the gene mutation. For example, in some cases, no treatment at all is necessary due to the slow progression of the disease and lack of complications (such as in GCK). In other cases, insulin replacement therapy is eventually required due to a progression of disease (as in HNF1A and HNF1B). 

In some forms of MODY, patients respond to sulfonylureas (such as in HNF4A, ABCC8, and KCNJ11) even though the mutation causes an impairment of insulin secretion in response to hyperglycemia.

Pearls and Other Issues

Recent MODY literature has proposed that there is “no longer” a strict genetic delineation between monogenic diabetes and DM2. Variations in gene mutations are associated with “a spectrum of glycemic phenotypes.”

Healthcare professionals will likely discover more patients who have been incorrectly diagnosed with DM1 or DM2 diabetes, resulting in changes in their treatment. Both DM1 and DM2 can be difficult and frustrating to manage because they don’t always respond well to treatment despite our best efforts. Our growing awareness and exploration of MODY may be an indication that we have only just begun to understand diabetes in general. Until healthcare professionals can understand it further, they may not treat it optimally.