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Clin Biochem Rev. 2009 May; 30(2): 67–74.
PMCID: PMC2702215

Investigating Maturity Onset Diabetes of the Young

Abstract

Maturity Onset Diabetes of Young (MODY) is a monogenic and autosomal dominant form of diabetes mellitus with onset of the disease often before 25 years of age. It is due to dysfunction of pancreatic ß cells characterised by non-ketotic diabetes and absence of pancreatic auto-antibodies. It is frequently mistaken for type 1 or type 2 diabetes mellitus. Diagnosis of MODY is important as the GCK subtype has better prognosis and may not require any treatment. Subtypes HNF1A and HNF4A are sensitive to sulfonylureas, however diabetes complications are common if not treated early. Moreover, there is genetic implication for the patient and family. Rare MODY subtypes can be associated with pancreatic and renal anomalies as well as exocrine dysfunction of the pancreas. So far there are six widely accepted subtypes of MODY described but the list has grown to nine. Although the majority of diabetes mellitus in youth remains type 1 and the incidence of type 2 is rising, MODY should be considered in patients with non-ketotic diabetes at presentation, and in patients with a strong family history of diabetes mellitus without pancreatic auto-antibodies. Furthermore the diagnosis must be confirmed by molecular studies. With advancement in genomic technology, rapid screening for MODY mutations will become readily available in the future.

Introduction

MODY was described by Tattersall in 1974–19751,2 and since then newer gene mutations and subgroups of MODY have been identified. The exact prevalence of MODY is not known however it is estimated to be responsible for 2 to 5% of cases of non-insulin dependent diabetes mellitus.3 Approximately 15 to 20% of patients in the United Kingdom who presented with clinical features of MODY had no mutation identified.4 It is likely that the prevalence has been under-estimated as MODY shares clinical features with the other more common forms of diabetes mellitus. The clinical characteristics that define MODY include age of onset often before 25 years, negative pancreatic auto-antibodies, non-insulin dependent diabetes mellitus and autosomal dominant inheritance.

Advantages of Genetic Testing

Genetic testing to confirm a clinical diagnosis of MODY has important implications for both the patient and their family. Once the responsible mutation is detected discussion of whether the patient has Type 1 or Type 2 diabetes mellitus is no longer necessary, and treatment and monitoring can be tailored according to the particular subtype of MODY. For example patients with MODY subtype GCK have a mild nonprogressive condition that does not require insulin and they are unlikely to develop diabetic complications. Conversely MODY subtype HNF1A and HNF4A can be initially managed with sulfonylurea medication but because of progressive β cell dysfunction approximately one third of patients eventually require insulin and diabetic complications can occur. In addition certain subtypes of MODY are associated with specific medical problems, such as renal disease in MODY subtype HNF1B, and these abnormalities can then be tested for. Discovery of a mutation in a proband also establishes that other first degree relatives with diabetes mellitus are likely to have MODY and that each full sibling has a 50% chance of inheriting the same mutation. Predictive testing, as opposed to diagnostic testing, is then possible in asymptomatic family members.

Pathophysiology

MODY is caused by mutations in nuclear transcription factors and glucokinase genes which result in pancreatic ß cell dysfunction in the production of insulin hormone. Glucose from the circulation gets transported through glucose transporters (GLUT 2) present on the cell membrane of ß cells. Glucokinase is an intracellular enzyme that senses glucose and converts it into Glucose-6-phosphate which then undergoes glycolysis in mitochondria to produce Adenosine Triphosphate (ATP). Using energy from ATP, intracellular potassium is pumped out of the cells through ATP dependent potassium channels. The resultant change in membrane potential leads to influx of calcium into the ß cell which in turn stimulates release of insulin already formed.3 Hepatic Nuclear Factors and nuclear transcription factors are important for synthesis of insulin from ß cells (see Figure 1).

Figure 1.
Illustration of insulin production by a pancreatic ß cell.

Types of MODY and Genetics

HNF4A subtype

HNF4A is a nuclear transcription factor responsible for the regulation of hepatic and pancreatic ß cell gene expression.5,6 Heterozygous mutation in human HNF4A gene located in chromosome 20 results in progressive decrease in insulin production.7 This MODY subtype may require insulin therapy and can develop vascular complications. Pancreatic polypeptide secretion is also impaired in patients with the MODY subtype, indicating that the effects of HNF4A deficiency are not limited to pancreatic ß cells. As HNF4A is also expressed in the liver these patients may have alteration in triglyceride and apolipoproteins AII, CIII, and Lp(a). In a study, it was found that a common variant of HNF4A was associated with high serum lipids and metabolic syndrome.8 Interestingly macrosomia and neonatal hypoglycaemia have also been reported in MODY subtype HNF4A kindred’s.9 Gupta et al. described HNF4A as also being important in the functioning of Kir6.2 receptor and therefore it is required in insulin secretion from ß cells.10

GCK Subtype

Heterozygous mutations of the glucokinase gene result in MODY subtype GCK,11 one of the more common forms of MODY.12 Unlike the other MODY subtypes the pathophysiology involves impaired glucose sensing by the pancreatic β cell, resulting in mild non-progressive hyperglycaemia (5.5 – 8 mmol/L) that is often asymptomatic. Velho et al. concluded that the blood glucose threshold for secretion of insulin from ß cells is raised in the presence of glucokinase mutation.13 Heterozygous loss-of-function mutation of glucokinase results in MODY but heterozygous activating mutations cause hyperinsulinism. Only 2% of patients require insulin therapy and diabetes associated complications are rare. However about 50% of female carriers develop gestational diabetes while infants with heterozygous mutations born to non-affected mothers may have a reduction in birth weight.14, 15Homozygous mutations result in permanent neonatal diabetes mellitus.16

HNF1A Subtype

MODY subtype HNF1A is the most common form of MODY and is due to mutations in the HNF1A gene on chromosome 12.17 Like MODY subtype HNF4A it is characterised by a progressive reduction in insulin secretion so that over time patients may require insulin and develop vascular complications.17 Initially however sulfonylurea may be very effective in controlling hyperglycaemia. Impaired glucagon secretion and pancreatic exocrine dysfunction, along with a low renal threshold for glucose have also been reported in patients with MODY subtype HNF1A.18 The clinical phenotype is dependent upon type and location of HNF1A mutation.19 In one study the age of onset is later (25.5 yrs) if mutation is at HNF1A (A) isomer than that of the remaining isomers of HNF1A (18 yrs).20 Stride et al. reported intrauterine exposure to hyperglycaemia increases the penetrance of HNF1A mutation.21 In a Norwegian study faecal elastase deficiency was noted in 12.7% of adult patients with this MODY subtype and all of the six available subjects were tested positive for increased faecal fat excretion.18

IPF1 Subtype

IPF1 has been described as a master switch for both endocrine and exocrine function of pancreas. IPF1 mutation can lead to pancreas agenesis and MODY.3,22 In a study it is suggested that Homozygosity for the mutation is associated with agenesis of pancreas and heterozygosity with MODY.22

HNF1B Subtype

Mutation of HNF1B results in MODY and congenital anomalies of the urogenital tract.3,23 Moreover, the mutation carriers have agenesis of body and tail of pancreas. In a study, five individuals from two families underwent Computerised Tomography (CT) and Magnetic Resonant Cholangiopancreatography (MRCP), as well as measurements of faecal elastase, serum vitamin D and E. All five carriers have agenesis of body and tail of pancreas as well as absent faecal elastase.24 Another study described significant prevalence of HNF1B in eighty infants with renal anomalies.25 The findings support increased awareness of MODY in patients with such renal anomalies. Prevalence of HNF1B mutation may be underestimated as 60% of patients with the phenotype of HNF1B subtype do not have point mutation. In a study, using Quantitative Multiplex PCR of Short Fluorescent Segment, a large rearrangement of the gene was found in a third of the patients with features of the MODY subtype which may have been missed by conventional testing.26

NEUROD1 Subtype

The role of the gene is for neuronal differentiation and pancreatic morphological development.27 In a review article the author suggested that mutation of transcription factor NEUROD1 is the cause of MODY.3 The mutation was found in autosomal dominant type 2 diabetes mellitus in two families and one of them fits the definition of MODY with evidence of defective insulin secretion from beta cells.28

KLF11 Subtype

KLF 11 regulates exocrine cells growth and behaves like a tumour suppressor for pancreatic malignancy.29 It was also reported to play a role in glucose signalling in beta cells of pancreas and its gene variant is associated with MODY-like diabetes.29,30

CEL Subtype

CEL gene controls both exocrine and endocrine function of the pancreas. In a case study 65 family members that met the diagnostic criteria for MODY, who were negative for known MODY candidate genes, were found to have deletion in CEL gene that resulted in premature stop codon. The family members had abdominal pain and presence of a spectrum of faecal elastase deficiency.31 CEL mutation has been considered as a subtype of MODY.32

PAX4 Subtype

PAX4 is a crucial transcription factor for beta cells development. In a study on 46 Thai probands with clinical MODY but with no known MODY genetic lesion were found to have pathological PAX4 mutation33 and its mutation is considered as a subtype of MODY.34

Molecular Testing and What is Available

To date over 800 different mutations have been shown to be associated with MODY. Most of the mutations are familial mutations with the exception of Pro291fs in HNF1A. About 70% of affected individuals have mutations in either the HNFIA or the GCK. The ratio of GCK to HNF1A mutations varies from country to country mainly due to the different recruitment criteria used for genetic testing. About 5% have mutations in either the HNF4A or HNF1B, while the remaining candidate genes account for less than 5% of MODY cases. Mutation screening methodologies such as DNA sequencing, denaturing high-performance liquid chromatography (dHPLC), conformation-sensitive capillary electrophoresis (CSCE) and fluorescent single-strand conformation polymorphism (SSCP) have been described. The most widely used screening technique would be DNA sequencing. This routinely involves sequencing the coding region, associated splice sites and selected promoter regions of the HNFIA, GCK and HNF4A. Gene copy number analysis by a technique such as multiplex ligase dependant probe amplification (MLPA) should also be performed when MODY is suspected and a mutation has not been detected by screening.

Testing for MODY subtypes HNF4A, GCK, HNF1A and HNF1B is currently available through the Molecular Genetics Laboratory of the Mater Hospital, Brisbane, Queensland, Australia. We sequence the genes depending upon the phenotype and the glucose tolerance test result. For rarer forms of MODY please see the Gene Tests website for a list of testing laboratories.35 The European Molecular Genetic Quality Network runs an annual quality assurance scheme for monogenetic diabetes36 and has published the Best Practice Guidelines for molecular genetic testing in monogenetic diabetes.

The Molecular Genetics Laboratory of the Mater Hospital has found that in patients with family history of diabetes and absence of pancreatic auto-antibodies, there is a 71% positive detection rate for MODY mutations. Our data shows that out of all the probands, 20% have HNF4A subtype, 53% have GCK subtype and 27% have HNF1A subtype.

Clinical Features

Case 1

A 24 year old pregnant mother was found to have mild hyperglycaemia and was treated with insulin during pregnancy. The result of her post partal oral glucose tolerance test was similarly abnormal to one done whilst pregnant with slight worsening in her 2 hours glucose (8.3 mmol/L). There is an extensive family history of diabetes mellitus originating from her paternal side (see Figure 2). Most of her siblings were diagnosed with diabetes at a young age and are either on dietary control or oral antidiabetic drugs. She was found to have GCK mutation.

Figure 2.
Family tree of a proband with MODY GCK Subtype.

Case 2

A four year old girl whose mother was diagnosed with diabetes mellitus since the age of 18 years was admitted to the Paediatric Intensive Care Unit at the Mater Children’s Hospital for lower respiratory tract infection. She was found to have hyperglycaemia on a random sample. She was not over-weight and had no acanthosis nigricans. Her haemoglobin A1c was 7.5% at the time and an Oral Glucose Tolerance Test (OGTT) revealed she had impaired glucose tolerance as her fasting blood glucose was 4.3 mmol/L and glucose two hours post glucose load was 8.2 mmol/L. After recovering from the respiratory disease, she had a repeat OGTT and haemoglobin A1c which were normal. She was followed clinically and at the age of 11 years she developed symptoms such as polyuria and polydipsia. Her OGTT at the time became abnormal. Her fasting blood glucose level was 10 mmol/L and glucose 2 hour post glucose load was 21.6 mmol/L. The fasting serum insulin was 3.5 mU/L and at 2 hours post glucose load was 6.9 mU/L. The C-Peptide at 2 hours post glucose load was 1 mmol/L. Pancreatic autoantibodies were negative on many occasions. A more detailed family history revealed autosomal dominant pedigree illustrated in Figure 3. Genetic testing on proband and mother confirmed the diagnosis of MODY subtype HNF1A.

Figure 3.
Family tree of a proband with MODY HNF1A subtype.

Discussion

Figure 4 is the algorithm for approach of hyperglycaemia in children. Awareness needs to be promoted regarding MODY since it may be misdiagnosed as other types of diabetes mellitus. MODY should be suspected and tested for if there are clinical features such as:

  1. Age of onset of diabetes before 25 years of age.
  2. Mild diabetes at presentation without significant ketoacidosis.
  3. Family history of diabetes in at least two generations in autosomal dominant fashion. The family members may be misdiagnosed as type 1 or type 2 diabetes mellitus.
  4. The absence of pancreatic auto-antibodies.
  5. Glycosuria seen inappropriately with euglycaemia or mild hyperglycaemia, in absence of albuminuria and poorly controlled diabetes.37 Low renal threshold that results in glycosuria is a specific feature of HNF1A mutation.37
  6. Low insulin requirement. Even outside honeymoon period insulin requirement in MODY is less than that of type 1 diabetes mellitus.
  7. Marked sensitivity to insulin secretagogue (sulfonylurea) in subtypes HNF1A and HNF4A. In a cross over study, patients with HNF1A subtype had a five fold greater response to sulfonylurea than Metformin and nearly a four fold greater response than those with type 2 diabetes mellitus.38 In a case report, patients with HNF1A mutation had marked improvement in diabetes control after commencement of sulfonylurea with one previously poorly controlled patient with hypoglycaemia on a low test dose of sulfonylurea.39
  8. Features inconsistent with other types of diabetes. No significant obesity or absence of acanthosis nigricans or evidence of insulin resistance in youngonset type 2 diabetes mellitus with family history of diabetes.
  9. Race. Some authors suggested MODY is more common in people of European descent but there is evidence that other races, although less commonly, have MODY mutations.33,40,41
  10. GCK mutation may present as Gestational Diabetes Mellitus when a pregnant mother may have mild hyperglycaemia at antenatal screening. GCK mutation should be considered if there is significant family history.
Figure 4.
Algorithm for investigation of hyperglycaemia. DM- Diabetes Mellitus, LADA- Latent Autoimmune Diabetes in Adults, CFRD- Cystic Fibrosis Related Diabetes Mellitus, AD- Autosomal Dominant Inheritance.
Table 1
Different MODY subtypes, gene mutations and other clinical features.
Table 2
Features that may help differentiate Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus and MODY.

Footnotes

Competing Interests: None declared.

References

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