ModyE11.90

MODY is the acronym for "Maturity-onset Diabetes of the Young" and describes a group of autosomal-dominantly inherited, genetically heterogeneous, not always insulin-dependent forms of diabetes. The MODY forms of diabetes are caused by various disorders of beta cell function in the pancreas. The body weight of MODY patients is usually normal. Neither are any of the autoimmune phenomena characteristic of type 1 diabetes observed. Rare are other associated organ dysplasias (eyes, pancreas, intestine).

The different forms of MODY diabetes (n=14) are classified according to clinical symptoms and gene mutation as follows.

• MODY1: Caused by autosomal dominant mutations in the hepatocyte nuclear factor (HNF)1A/4A gene, also known as the HNF4A gene. The gene encodes a transcription factor that regulates HNF1A/PDX1 transcription. Frequency in the MODY collective: 3-5%.
• MODY 2: Caused by mutations in the glucokinase gene (> 40 mutations known to date). Glucokinase catalyzes the reaction glucose to glucose-6-phosphate. Frequency in the MODY collective: 30-50%.
• MODY 3: Mutation in the hepatocyte nuclear factor (HNF)1A/4A gene. The HNF1A gene encodes the transcription factor HNF1alpha, which regulates the transcription of genes involved in insulin production and secretion in pancreatic beta cells. Incidence: about 70% of MODY cases are caused by mutations in the HNF1A gene (MODY 3).
• MODY 4: Rare mutation in the PDX1 gene (chromosome 12q24.31). The PDX1 gene encodes the transcription factor IPF1, which plays a critical role in the development and function of the pancreas and pancreatic beta cells. Incidence: MODY-4 affects approximately 1% of MODY cases.-.
• MODY 5: Mutations in the HNF1B gene (chromosome 17cen-q21.3). The HNF1B gene encodes the transcription factor TCF2, which regulates the transcription of genes involved in insulin production and secretion in pancreatic beta cells, among others. The mutation leads to pathologically decreased insulin production. Frequency: The mutation affects about 3-5% of MODY cases.
• MODY 6: In the rare MODY 6 variant, mutations are present in the NEUROD1 gene, a gene encoding a transcription factor. By binding to the promoter region of the insulin gene, the transcription factor modifies the expression of the INS gene. Frequency <1% of MODY cases.
• MODY 7: In the rare MODY 7 variant, mutations are present in the gene KLF11. This gene encodes a zinc finger transcription factor and is located on the short arm of chromosome 2 (2p25). In pancreatic beta cells, the transcription factor KLF11 regulates the transcription of genes involved in insulin production and secretion. Frequency <1% of MODY cases.
• MODY8: In the very rare MODY 8 variant, mutations are present in the CEL gene, the carboxyl ester lipase gene located on chromosome 9q34.13 (Torsvik J et al 2010), which encodes bile salt dependent lipase (carboxyl ester lipase). Incidence: <1% of MODY cases.
• MODY 9: In the very rare MODY 9 variant, mutations are present in the PAX 4 gene, which encodes a transcription factor, and is located on the long arm of chromosome 7 (7q32.1). The encoded transcription factor plays a critical role in pancreatic islet cell differentiation.
• MODY 10: In the very rare MODY 10 variant, monogenic autosomal dominant inherited mutations are present in the INS gene. The INS gene, which codes for peptide hormoneinsulin , is located on the short arm of chromosome 11 (11p15.5) and regulates insulin levels through its glucose-regulated activity. Incidence: <1% of MODY cases.
• MODY11: Very rare MODY 11 is caused by monogenic, autosomal-dominant inherited mutations in the BLK gene, located on the short arm of chromosome 8p23.1. The BLK gene encodes a transcription factor (B-lymphocyte tyrosine kinase) that regulates the transcription of genes involved in insulin production and secretion in pancreatic beta cells. Incidence: <1% of MODY cases.
• MODY12: MODY 12 is caused by monogenic, autosomal dominant inherited mutations in the ABCC8 gene (ATP-binding cassette transporter sub-family C member 8) which encodes sulfonylurea receptor 1 (SUR1). Incidence: <1% of MODY cases.
• MODY13: MODY 13 is caused by heterozygous mutations in the KCNJ11 gene (Potassium Voltage-Gated Channel Subfamily J member 11) which is located on chromosome 11p15 and encodes KIR6.2, a subunit of the ATP-sensitive potassium channel. Incidence: <1% of MODY cases.
• MODY 14: MODY 14 is caused by a heterozygous inherited mutations in the APPL1 gene. The gene is located on chromosome 3p14.3 and encodes the adaptor protein in insulin and adiponectin signaling.

In the total group of diabetics, 1.0-6.3% suffer from a monogenic form of diabetes mellitus, depending on the population studied (Aykut A et al. 2018; Delvecchio M et al. 2017).

Despite considerable fluctuations in the prevalence of MODY subtypes in the different populations, the most frequent mutations are found in genes of the hepatocyte nuclear factor 1alpha (HNF1A) and glucokinase (GCK). These mutations cause MODY 3 and MODY 2, respectively, and these two subtypes account for up to 90% of all MODY cases. In some European countries, including the UK, the Netherlands and Denmark, the most common form of monogenic diabetes is MODY 3 (mutation of HNF1A), but in Spain, Italy, France, Germany and the Czech Republic the most common form is MODY 2 (mutation of GCK).

MODY subtypes 1-5 are the best studied and most thoroughly described forms of the disease. The other subtypes are very rare. Accordingly, data on their clinical features and treatment options are correspondingly scarce. (Ovsyannikova AK et al. 2016).

Maturity onset diabetes of the young is caused by mutations in various genes involved in the secretion of insulin in the beta cells. Insulin action itself is not disturbed, so there is no insulin resistance.

To date, 14 forms of MODY diabetes have been clearly defined. They are based on mutations in various genes of the glucose metabolism. 7 of these genes code for the transcription factors: hepatic nuclear factor (HNF)-1alpha,transcription factor 2 (HNF-1beta), HNF-4alpha, insulin promoter factor-1, NeuroD/BETA2, KLF11,PAX4. These genes are expressed in the insulin producing beta cells of the pancreatic islets and when mutated induce disorders of organ differentiation or insulin secretion.

Mody is usually discovered before the age of 25 and is often first clinically diagnosed as type 1 or type 2 diabetes and therefore insufficiently treated. In practical everyday life, this form of monogenic diabetes should be considered when normal-weight persons with diabetic metabolic condition are diagnosed with diabetes but no antibodies against GAD, IA-2 and/or islet cells can be detected. In terms of differential diagnosis it is also important to exclude monogenic diabetes when gestational diabetes occurs (see also MODY2).

Clinical criteria for a suspected diagnosis of MODY:

• Manifestation in adolescence or early adolescence (< 35 years).
• Negative antibody detection against GAD, IA-2 and/or islet cells
• Exclusion of type 1 and type 2 diabetes or metabolic syndrome
• Moderate (fasting) hyperglycemia (130-250 mg/dl) before 30 years of age
• Positive glucose load test
• Existing gestational diabetes
• Permanent low insulin requirement (e.g. <0.5 u/kg/d)
• Cystic kidney disease, possibly with a family history
• Glucosuria
• Detection of MODY mutations in 1st degree relatives

According to recent studies, the above criteria are not applicable to all cases of MODY. For example, missing diabetes cases in the family do not exclude MODY, because the mild forms of diabetes are often not recognized. Moreover, about 40% of MODY patients are not diagnosed until after the age of 25. In about 8% of MODY cases, "de novo" mutations occur for the first time in the family and about 8-9% of MODY patients under the age of 30 are not slim but overweight.

1. McDonald TJ et al (2013) Maturity onset diabetes of the young: identification and diagnosis. Ann Clin Bioch em 50:403-415.
2. Bonnefond A et al (2012) Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One 7:e37423.
3. Delvecchio M et al (2014) Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital. Diabetes Care 37:e258-e260.
4. Ovsyannikova AK et al (2016) ABCC8-Related Maturity-Onset Diabetes of the Young (MODY12): Clinical Features and Treatment Perspective. Diabetes Ther 7: 591-600.
5. Thanabalasingham G et al (2011) Diagnosis and management of maturity onset diabetes of the young (MODY) BMJ 343:d6044.
6. Shields BM et al (2010) Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 53:2504-2508.