Mody 1 E11.-

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).

In MODY1 there is a defect in the gene for the "Hepatic nuclear factor-4 alpha" HNF4A, a transcription factor located on chromosome 20. This transcription factor regulates the transcription of various genes involved in the production and secretion of insulin in pancreatic beta cells. The mutations cause pathologically decreased insulin production.

In about 8% of MODY cases, "de novo" mutations occur for the first time in the family. About 8-9% of < 30-year-old MODY patients are not slim but overweight.

Mody1 patients are usually characterized by an increasingly severe clinical course. They are slim patients without type 1 diabetes. The initial manifestation of familial diabetes occurs in early adolescence (between 12-30 years of age); renal glucosuria persists. If left untreated, MODY 1 patients develop almost all late complications that are also seen in type 2 diabetics (diabetic angiopathy, neuropathy, nephropathy).

MODY 1 patients respond excellently to therapy with low-dose sulfonylureas. In advanced age, insulin therapy becomes necessary in about every third patient. Note: This statement also applies to MODY variants 3, 12 and 13. These are genotypically different, but phenotypically largely identical with progressive hyperglycemia.

Especially slim pregnant women with glucose tolerance disorders are highly likely to be carriers of a GCK gene mutation (see MODY 2) or a HNF4A gene mutation (MODY 1). Pregnant women with gestational diabetes and a mutation in the HNF4A gene have a particularly high risk of developing fetal hyperinsulinism in their child (without a mutation of the HNF4 gene present). The consequences of this hyperinsulinism can be strong fetal growth during pregnancy and high fetal weight at birth (macrosomia).

Therefore, the knowledge of a carrier for an HNF4A mutation of the mother (and possibly also of the child) is therefore very important in order to prepare for the birth through optimal management.

Indication for genetic analysis:

• Manifestation age of diabetes in early adolescence
• No GAD and/or IA2 antibodies (exclusion of type 1 diabetes)
• Positive family history, autosomal dominant inheritance
• Diabetes without obesity
• Progressive hyperglycaemia in old age
• Gestational diabetes
• No insulin resistance

1. Anık A et al. (2015) Maturity-onset diabetes of the young (MODY): an update. J Pediatric Endocrinol Metab 28:251-63.https://www.ncbi.nlm.nih.gov/pubmed/25581748