1. Introduction

Maturity-Onset Diabetes of the Young (MODY) is a monogenic type of diabetes, resultant from single gene mutations [1]. MODY is characterized by mild hyperglycemia, autosomal dominant inheritance, early onset of diabetes (<25 years), insulin resistance, and preservation of endogenous insulin secretion [2,3,4]. The genes involved are crucial for the development, function and regulation of beta cells and can cause glucose sensing and insulin secretion disorders [5,6]. MODY is classified into several subtypes based on the genes involved and clinical phenotypes. Fourteen MODY subtypes have been identified thus far, each caused by a distinct gene mutation ( Table 1 ) [7]. Among the 14 MODY subtypes, mutations in hepatocyte nuclear factor 1-α ( HNF1A ), glucokinase (GCK) , HNF4A , and HNF1B are the underlying cause in more than 95% of MODY cases; the other mutations are uncommon in the Caucasian population [2,8,9,10]. These mutations differ in terms of prevalence, clinical features, the severity of diabetes and related complications, and treatment response. Each mutation encodes proteins involved in glucose homeostasis of pancreatic β-cells [11,12].

GCK: Glucokinase, HNF1A, HNF4A, HNF1B: Hepatic nuclear factor alpha/beta, PDX1/IPF1: Pancreatic and duodenal homeobox 1/Insulin promoter factor 1, NEUROD1: Neurogenic differentiation factor 1, KLF11: Krueppel-like factor 11, CEL: Carboxyl ester lipase, PAX4: Paired Box 4, INS: Insulin, BLK: BLK proto-oncogenes, Src family tyrosine kinase, ABCC8: ATP binding cassette subfamily C member 8, KCNJ11: Potassium voltage-gated channel subfamily J member 11, APPL1: Adaptor protein, phosphotyrosine interacting with PH domain and leucine Zipper 1, DIDMOAD: Diabetes insipidus, diabetes mellitus, optic atrophy, and deafness.

2. Diagnosis of MODY

Misdiagnosis of MODY with type 1 (T1DM) or type 2 diabetes mellitus (T2DM) can be avoided if clinicians can establish a correct molecular diagnosis, and with advances in genetic testing, aided by the development of new techniques (e.g., Next Generation Sequencing) and increased access to genetic testing facilities, diagnosis of MODY can be performed accurately [13]. However, in order to ensure an accurate diagnosis, specific criteria must be met before administering genetic tests [2]. MODY can be distinguished from other types of diabetes based on the age at which the disease first manifested. MODY subtypes with variable age of onset, low penetrance, or atypical presentation may fail to meet the diagnostic criteria for the disease [14,15,16,17]. Additionally, while a family history of diabetes is highly suggestive of MODY, some mutations in MODY-associated genes can occur at high frequencies in individuals without a family history of diabetes, demonstrating the critical nature of genetic testing in individuals without a family history of diabetes [18]. According to the MODY diagnostic guidelines, genetic testing should be performed on individuals diagnosed with diabetes at a young age (25 years), as well as those with a familial history of diabetes, evidence of endogenous insulin secretion, detectable levels of c-peptide, and negative antibody results [19]. Direct sequencing with sensitivity close to 100% and next generation sequencing methods can be successfully used to identify MODY gene mutations [1,9,20]. According to a model proposed by Shields et al., a diagnosis before the age of 30 years is a useful discriminator between MODY and T2DM, whereas a parental history of diabetes produces a 23-fold increased chance that a patient previously diagnosed with T1DM may be diagnosed with MODY at a later stage [9].

3. Significance of MODY Diagnosis

Although MODY accounts for only 1-5% of all diabetes cases, it has significant implications [28]. The diagnosis of MODY is crucial for patients and their families; therefore, it is important to characterize each MODY subtype and distinguish these from other types of diabetes. MODY patients are often misdiagnosed with either T1DM or T2DM, resulting in patients receiving inappropriate treatment [26]. This could be due to overlapping clinical features, which are more common in diabetes, the high cost of genetic testing, and clinicians’ lack of awareness [29]. Accurate diagnosis would enable optimal therapeutic management and treatment strategies that differ significantly from those used for T1DM or T2DM [7]. Patients who had been receiving T1DM treatment can switch to oral agents (i.e., sulfonylureas), which will improve their quality of life and glycemic control [30]. For example, HNF1A -MODY (MODY 3) and HNF4A -MODY (MODY 1) patients are best managed with oral sulfonylureas and can avoid the unnecessary insulin therapy that is generally prescribed before MODY diagnosis [31]. MODY diagnosis is key to providing accurate counselling regarding the predicted clinical outcome, genetic counselling, and identification of affected family members [32].

4. MODY Subtypes and Their Treatments

The pancreatic and duodenal homeobox 1 ( PDXI ) gene is a homeodomain-containing transcriptional factor, which regulates insulin gene expression and pancreatic development [40,56,57]. PDX1 -MODY is a rare type of MODY caused by heterozygous mutations in the PDX1 gene. It is important in the regulation of genes that code for glucagon, insulin, glucose transporter 2 ( GLUT2 ), and glucokinase ( GCK ) enzymes [58]. It acts as the master switch for the pancreas’ hormonal and enzymatic functions [59]. Heterozygous PDX1 mutations can result in defective insulin secretion, whereas homozygous mutations result in permanent neonatal diabetes (PND) and exocrine pancreatic insufficiency [56,60,61]. Patients with PDX1 –MODY present with type 2 diabetes with early onset and no extra-pancreatic involvement. Metformin [62] and dipeptidyl peptidase-4 (DPP-4) inhibitors [63] have been shown to be effective in case reports. Diet, oral anti-diabetes drugs (OADs), and insulin are all options to treat individuals with MODY 4 [34,51].

MODY 11 is caused by heterozygous tyrosine-protein kinase ( BLK ) gene mutations. The BLK gene, which belongs to the SRC proto-oncogenes family, encodes a tyrosine receptor protein that stimulates β-cells to produce and secrete insulin [40]. The BLK gene is expressed in β-cells and is essential for thymopoiesis in immature T cells [91]. BLK -MODY has incomplete penetrance, and as a result not all carriers present with diabetes. Heterozygous mutations in this gene reduce BLK expression and/or activity, leading to PDX1 and NKX6.1 deficiency, impaired glucose-stimulated insulin secretion, and decreased beta cell mass [92]. Environmental and genetic factors are thought to play a role in BLK -MODY, and the most important factor that causes hyperglycemia is excessive body weight [93]. Hyperglycemia is also likely to be influenced by pregnancy [94]. Although insulin is required for the vast majority of patients, some may be treated with diet or OADs [34,50].

MODY 12 is caused by heterozygous ATP binding cassette subfamily C member 8 ( ABCC8 ) gene mutations. ABCC8 encodes for sulfonyl-urea receptor 1 (SUR1), a subunit of an ATP-sensitive potassium (K-ATP) channel found in β-cell membranes [40,65]. ABCC8 is responsible for the secretion of insulin, which controls blood sugar levels [95]. ABCC8 gene mutations can result in congenital hyperinsulinism, which can be caused by dominantly inherited inactivating mutations. As a result of activating mutations or recessive loss-of-function mutations, ABCC8 gene mutations can lead to permanent or transient neonatal diabetes (PNDM or TNDM, respectively) [95]. The majority of patients with MODY 12 are misdiagnosed as having diabetes of a different kind and are mistreated with insulin, resulting in poor control and hypoglycemia episodes [34]. Rafiq et al. proposed that in adulthood, all ABCC8 mutation carriers could be switched to sulfonylureas [96].

MODY 14 is a rare subtype caused by mutations in the adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 ( APPL1 ) gene, which regulates cell proliferation and interaction between the adiponectin and insulin signaling pathways [101,102]. Heterozygous loss-of-function mutations in this gene result in impaired insulin secretion in response to glucose stimulation and decreased beta cell survival [101,102,103]. APPL1 mutations can cause apoptosis in highly expressed tissues; overexpression causes dysmorphic phenotypes and developmental delays [101]. Diet, OADs, and insulin are all possible APPL1 -MODY treatments [34,50].

This entry is adapted from the peer-reviewed paper 10.3390/app11209436