SCIENTIFIC BACKGROUND

ABCC8, APPL1, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEUROD1, PAX4, PDX1

Scientific Background

Maturity-onset diabetes of the young (MODY) refers to a group of autosomal dominant inherited, clinically heterogeneous forms of diabetes that are not always insulin-dependent and are characterized by various disturbances in pancreatic beta cell function.

 

MODY is the most common form of monogenic diabetes and is responsible for up to 5% of all diabetic disease in Europe. The disease is usually discovered before the age of 25 and is often diagnosed initially as diabetes mellitus type 1 or type 2. However, if no antibodies against GAD, IA-2, and/or islet cells can be detected in normal weight individuals with diabetic metabolic status, MODY should be considered. Where gestational diabetes occurs, MODY should also be considered, as it can be detected in about 25% of affected pregnancies.

 

Diagnostic criteria for a suspected diagnosis of MODY are:

  • Manifestation in adolescence or early adulthood (<35 years)
  • Antibodies GAD and IA-2 and/or islet cells not detected
  • Exclusion of diabetes type 1 and type 2 or metabolic syndrome
  • Moderate (fasting) hyperglycemia (130-250 mg/dl or 7-14 mM) before the age of 30
  • Positive glucose challenge test
  • Pregnancy diabetes
  • Permanently low insulin demand (e.g., <0.5 U/kg/d)
  • Cystic kidney diseases in the patient (or close relatives)
  • Glucosuria
  • First degree relative with MODY

 

Pathology of the MODY types

The different forms of MODY diabetes are classified according to their clinical presentation and the corresponding genes affected by pathogenic variants. Currently, 14 MODY types are differentiated, with MODY type 2 and type 3 being the most common forms.

 

MODY types 1, 3, 12 and 13

MODY types 1, 3, 12, and 13 have a clinically similar phenotype and are characterized by pronounced progressive hyperglycemia. The affected patients respond very well to therapy with low-dose sulfonylureas, but during therapy they suffer from above-average frequency of episodes of hypoglycemia. It is caused by variants in the HNF4A and HNF1A genes, which code for transcription factors, and in the ABCC8 and KCNJ11 genes, which form the subunits of the ATP-sensitive potassium channel. Molecular genetic testing of the ABCC8 and KCNJ11 genes should be considered if the patient responds to sulfonylureas and MODY types 1 and 3 have already been excluded.

 

MODY type 2

Patients with MODY type 2 show persistent, mild hyperglycemia, which does not usually require drug therapy and can be treated by a suitable diet. The disease is caused by pathogenic variants in the glucokinase gene (GCK). Since MODY type 2 is associated with very mild symptoms, it is often only discovered by chance during routine diagnostics, such as in pregnant women during screening for impaired glucose tolerance.

 

MODY type 4

MODY type 4 belongs to the rare MODY forms and is caused by pathogenic variants in the PDX1 gene, which encodes insulin promoter factor-1. It is associated with a mild course of disease with mild hyperglycemia and is phenotypically similar to MODY type 2.

 

MODY type 5

In addition to pronounced hyperglycemia, polycystic kidney disease (renal cysts and diabetes syndrome, RCAD) or malformations of the urogenital tract can distinguish MODY type 5 from the other MODY forms. MODY type 5 is caused by pathogenic variants in the gene for the transcription factor HNF1B.

 

MODY types 6-11 and 14

A clear description of the clinical symptoms of MODY types 6-11 and 14 is not yet possible due to their rarity. These types are caused by pathogenic variants in the NEUROD1, KLF11, CEL, PAX4, INS, BLK and APPL1 genes, respectively.

 

As causative variants in the corresponding genes are not found in all patients with MODY, it is assumed that there are other genes associated with MODY that are not yet known.

 

References

Hoffmann et Jialal 2019, StatPearls [Internet], https://www.ncbi.nlm.nih.gov/books/NBK532900/
/ Naylor et al. 2018, GeneReviews® [Internet], https://www.ncbi.nlm.nih.gov/books/NBK500456/ / Hattersley et Patel 2017 Diabetologia 60:769 / Amed et Ram 2016, Can J Diabetes pii: S1499-267130035-6 / Kim 2015, Diabetes Metab J 39:468 / Schwitzgebel 2014, J Diabetes Investig 5:121 / Yorifuji et al. 2012, Pediatr Diabetes 13:26 / Thanabalasingham et Owen 2011, BMJ 343:d6044 / Ellard et al. 2008, Diabetologia 51:546 / Bellanne-Chantelot et al. 2008, Diabetes 57:503

GENES

ABCC8, APPL1, BLK, CEL, GCK, HNF1A, HNF1B, HNF4A, INS, KCNJ11, KLF11, NEUROD1, PAX4, PDX1
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