Maturity Onset Diabetes in the Young

Etiology

MODY is caused by defects in pancreatic islet cell development that impairs insulin secretion. It is usually inherited in an autosomal dominant fashion, and patients generally have heterozygous mutations. Penetrance and expressivity can vary immensely, even among family members, and the phenotype is largely dependent on the gene involved.[3] MODY genes affect insulin secretion via impairment of insulin sensing, glucose metabolism in beta cells, or activation of adenosine triphosphate (ATP)-dependent potassium channels.[4]

Epidemiology

MODY accounts for less than 5.0% of all patients with diabetes mellitus (DM). It is now thought that 6.5%[5][6] 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 and type 2 diabetes and are often misdiagnosed as having either 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.[7]

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 1-6). 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 the 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) accounts for less than 5% of the cases of MODY.

The difference in the 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 by inhibiting the key steps of glucose transport and metabolism as well as mitochondrial metabolism in pancreatic beta cells. HNF1A is found in the 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.[8][9] 

HNF1A is very responsive to sulfonylureas and meglitinides, even though beta cells do not respond well to hyperglycemia with insulin production and release.[10] 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.[11] The use of sulfonylureas can frequently delay the need for insulin replacement for many years.

GCK (MODY 2)

Glucokinase is an enzyme that 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 a higher fasting glucose level. Oral glucose tolerance testing reveals a mild increase in glucose concentration. Patients with a GCK mutation typically display 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.[12][8]

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.[13]

Note: HNF1A and HNF4A are both genes that regulate the expression of numerous genes encoding serum proteins, such as clotting factors and apolipoproteins.[14]

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, kidneys, 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.[15]

 Patients with HNF1B generally are not responsive to oral medications and will require treatment with insulin. 

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 affects pancreatic development and insulin gene expression.

NEUROD1 (MODY 6)

NEUROD1 is a mutation in a basic-loop-helix transcription factor that affects pancreatic and neuronal development. Most patients will require treatment with insulin.[16]

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 in life. Neonatal diabetes has been associated with mutations in the potassium-ATP channel genes or mutations in the insulin gene.[5] Additionally, these mutations have been linked to neonatal hypoglycemia due to elevated insulin levels; this is usually transient, but the patient may develop diabetes later in life. In these cases, monitoring of fetal growth during pregnancy and blood glucose levels in neonates can be crucial. The patients who develop 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

History should first include a thorough personal medical history. The diabetes diagnosis characteristic of MODY occurs in adolescence or early adulthood. Therefore details surrounding their diabetes diagnosis become of utmost importance. Also, birth history can provide some helpful information if known. Intrauterine growth retardation (IUGR) is seen in those with HNF1B (MODY 5) in addition to some congenital abnormalities such as renal and urogenital tract anomalies as well as pancreatic hypoplasia. Those with the HNF4A (MODY 1) subtype may have a history of a birth weight generally more than 800gr above normal, as well as transient neonatal hyperinsulinemic hypoglycemia. GCK (MODY 2) patients may have had a history of mild fasting hyperglycemia at birth. Finally, some of those with HFN1A (MODY 3) may have had transient neonatal hyperinsulinemic hypoglycemia.[17] A further personal medical history should include a full review of systems and enquire about known medical problems involving other organ systems as some forms of MODY can be associated with extra-beta cell manifestations, including renal, hepatic, genitourinary, exocrine pancreatic, or intestinal effects.

Family history is vital and provides some of the most useful information. Patients with MODY have a strong family history of diabetes spanning at least 3 generations. Details surrounding the diabetes diagnosis for each family member should include the age of onset, their body habitus at diagnosis, and history of insulin use. Information on prior genetic testing in the family can be very helpful. [17]

Physical examination does not provide any specific information guiding one to the diagnosis of MODY or a specific subtype. Even though those with MODY are characteristically of normal weight, obesity in these patients can coexist. [17] The physical examination, in general, should also include the basics as for any patient with diabetes, as some forms of MODY do develop complications; therefore, testing for retinopathy and neuropathy should always be included in addition to urine microalbumin and a lipid panel.

Evaluation

In 2008, diagnostic criteria were created in the Practice Guidelines for MODY. The criteria include the age of onset in a family member of 25 years of age, at least two consecutive generations of patients with diabetes in the family, no beta-cell autoantibodies, persistent endogenous insulin production in addition to preservation of pancreatic beta-cell function as evidenced by c-peptide levels >200pmol/L in addition to lack of necessity for insulin therapy even years after diagnosis.[18]

The evaluation of patients should first start at diagnosis by ruling out DM1 by testing for pancreatic autoantibodies. 

Particularly in GCK MODY, checking hemoglobin A1C (HbA1C) and fasting plasma glucose levels can be helpful as they typically fall within specific ranges. Fasting plasma glucose generally falls between 99-144mg/dL[18], and the typical range for HbA1C is 5.6-7.3% if less than 40 years of age and 5.9-7.6% if older than that.[19]

High sensitive CRP (hsCRP) is another surrogate test that can help distinguish HFN1A MODY from other types of diabetes. This value will be lower in HNF1A MODY (MODY 3), usually less than 0.75mg/L, when compared to other forms of diabetes.[20]

Additionally, one can assess for residual beta-cell function. Patients with MODY generally have elevated C-peptide levels when there is hyperglycemia, usually 0.6mg/dL or higher.[21]

 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 have 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

Molecular genetic testing helps to identify which mutation is involved. The type of testing performed depends on the clinician's pretest probability of knowing which particular gene is involved. Should a patient have particular characteristics of a specific subtype, such as typical associated extra-pancreatic features, single-gene testing or serial single-gene testing can be performed. If a patient's phenotype cannot be differentiated from other subtypes, one may opt to perform a MODY multigene panel which tests for 14 known genes to be associated with MODY. Finally, if the patient has clinically suggestive features, but the mutation cannot be found utilizing conventional testing, one can consider comprehensive genomic testing.[17]

Treatment / Management

The optimal treatment for diabetes associated with MODY varies on the gene mutation. Thus knowing the genetic subtype is important in understanding the treatment and prognosis in these patients.

In MODY 2 (GCK), patients tend to have elevated fasting blood glucose but do not usually develop postprandial hyperglycemia as they have sufficient insulin secretion in response to elevated glucose. These patients generally need lifestyle and dietary modification alone.[22]

For MODY 3 (HNF1A) and MODY 1 (HNF4A), patients can generally be managed with dietary changes alone in the beginning. These patients do experience postprandial hyperglycemia after carbohydrate-rich food.[23] Progressively over time, they may get deterioration of their beta cells and may require treatment. These patients tend to respond well to sulfonylureas. An alternative treatment option is a glucagon-like peptide 1 agonist (GLP-1RA). A randomized control trial that compared GLP1RA to glimepiride in the treatment of MODY 3 patients found that these drugs were comparable in lowering blood glucose (although glimepiride had a slightly greater glucose-lowering effect but in conjunction with an increased risk of hypoglycemia).[24](A1)

Patients with MODY 5 (HNF1B) generally do not respond well to sulfonylureas. This may in part be explained by concurrent pancreatic hypoplasia in addition to a degree of hepatic insulin resistance.[25] Thus these patients will usually require insulin to control their hyperglycemia. This subset of MODY patients has been described as having a propensity for microvascular complications. In particular, their renal function needs to be monitored closely as most of these patients will develop renal dysfunction by age 45 and can progress to end-stage kidney disease.[26]

In general, guidelines do not exist for many of the subtypes due to the paucity of cases and how rare they are.

Management of MODY in the Youth

In most countries, metformin and insulin are approved for use in the youth. Certain countries have approved the use of sulfonylureas in the adolescent population. Otherwise, no other category of oral antidiabetic agents has been approved in those less than 18 years of age.[27](B3)

Management in Pregnancy[28]

As mentioned above, GCK MODY generally does not require treatment except during pregnancy. Determining which GCK MODY patients need treatment is determined by the fetal genotype. This is not genetically determined but assessed by the abdominal circumference of the fetus measured during the second trimester. Should this value exceed 75%, this infers that the fetus does not carry the GCK mutation, and thus these mothers should be treated with insulin during pregnancy to help prevent macrosomia. If the fetus has an abdominal circumference less than 75%, this infers the fetus does not carry the gene as they will have the same glucose setpoint as the mother, which is increased, and thus maternal hyperglycemia will be sensed by the fetus as normal and therefore growth will be normal and maternal treatment with insulin is not indicated, and it can even result in growth restriction.[28]

Differential Diagnosis

• Type 1 diabetes mellitus
• Type 2 diabetes mellitus
• Chronic pancreatitis
• Cystic fibrosis
• Diabetic ketoacidosis (DKA)
• Diabetic nephropathy
• Disorders of target tissues
• Endocrine disorders
• Glucocorticoids
• Insulin resistance
• Lead nephropathy
• Nondiabetic glycosuria
• Renal glycosuria
• Secondary hyperglycemia

Prognosis

MODY 2 (GCK) patients generally have a good prognosis as a result of the relatively mild hyperglycemia and low complication rates.[29]

MODY 3 (HNF1A) patients have similar complication rates and prognosis to type 1 and type 2 diabetes mellitus. This is the case with most subtypes of MODY, with the exception of MODY 2, which has the best prognosis.[29]

MODY 5 (HNF1B) patients have a propensity of developing end-stage kidney disease requiring renal replacement therapy independent of diabetic nephropathy. This is because the affected gene is involved in the organogenesis of multiple organs, including the kidneys.[29]

Complications

Complications are dependent on the genetic subtype of MODY.

MODY 1 (HNF4A): These patients can have vascular complications. In addition, given the fact that HNF4A is also expressed in the liver, the elevation of serum lipids and metabolic syndrome can occur.[30]

MODY 2 (GCK): This subtype is rarely associated with diabetes-associated complications such as microvascular and macrovascular complications.[31]

MODY 3 (HNF1A): It carries a high risk of microvascular and macrovascular complications, similar to DM1 and DM2.[9] 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. This is despite the fact that these patients have high HDL-C and low hsCRP levels; they are particularly prone to cardiovascular disease. Thus it is imperative to start a statin in these patients by the time they are 40 years old. Pancreatic exocrine dysfunction has also been reported in this genetic subtype.[32]

MODY 4 (PDX1): This rare defect has been associated with pancreatic agenesis, neonatal DM, and pancreatic exocrine dysfunction.[33]

MODY 5 (HNF1B): These patients, in addition to MODY, develop congenital urogenital anomalies.[34] 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, these patients may demonstrate insulin resistance in some cases, and microvascular complications can also be common.

MODY 6 (NEUROD1): Heterozygotes cause diabetes in children, neurological abnormalities, and learning disabilities.[16]