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MODY syndrome

Orpha number ORPHA552
Synonym(s) Maturity-onset diabetes of the young
Prevalence 1-5 / 10 000
Inheritance Autosomal dominant
Age of onset Adult
ICD-10
  • E11.8
ICD-O -
OMIM
UMLS -
MeSH -
MedDRA -

Summary

MODY (maturity-onset diabetes of the young) is a rare, familial, clinically and genetically heterogeneous form of diabetes characterized by young age of onset (generally 10-45 years of age) with maintenance of endogenous insulin production, lack of pancreatic beta-cell autoimmunity, absence of obesity and insulin resistance and extra-pancreatic manifestations in some subtypes.

MODY is the most common form of monogenic diabetes. Prevalence is estimated to be about 1/10,000 in adults and 1/23,000 in children. No specific ethnic predilection has been reported. It has been estimated that around 80% of cases are misdiagnosed as type 1 or type 2 diabetes, thus complicating prevalence and incidence estimations.

The clinical features of MODY vary depending on the genetic etiology. The most frequent subtypes are HNF1A-MODY (30-50%), GCK-MODY (30-50%), HNF4A-MODY (10%), and HNF1B-MODY (1-5%). The latter is also known as renal cysts and diabetes syndrome (see this term). At least 9 other genetic subtypes have been described but are very rare. Patients with HNF1A and HNF4A mutations have slowly progressing beta-cell dysfunction and respond well to treatment with low-dose sulfonylureas, which are recommended as first line therapy. Vascular complications of diabetes are observed with a similar frequency to type 1 or type 2 diabetes. Low C-Reactive Protein is seen in HNF1A-MODY and neonatal hypoglycaemia and macrosomia are reported in babies with HNF4A-MODY. GCK-MODY is characterized by asymptomatic non-progressing mild fasting hyperglycemia with low post-prandial glucose excursions from birth, is not associated with vascular complications and does not require treatment.

Mutations in at least 13 genes have been reported to be associated with a MODY phenotype: common causes (>5% of cases): HNF1A (12q24.31), GCK (7p15.3-p15.1), HNF4A (20q13.12); rare causes (about 1% of cases): KCNJ11 (11p15.1), ABCC8 (11p15.1), INS (11p15.5), HNF1B (17q12); and very rare (described in only a few families, genetic evidence not compelling for some): CEL (9q34.3), PDX1 (13q12.1), NEUROD1 (2q32), PAX4 (7q32.1), KLF11 (2p25) and BLK (8p23-p22).

Criteria for genetic testing for MODY include diabetes onset in adolescence or young-adulthood, maintenance of endogenous insulin production, and usually a significant family history of diabetes. Subjects will also have absence of typical features of type 1 or type 2 diabetes. Although de novo mutations can arise, cascade screening of family members is essential to ensure that those with diabetes get the correct diagnostic label and those at risk of inheriting the mutation are tested for diabetes and/or consider predictive genetic testing.

Expert reviewer(s)

  • Dr Katharine OWEN

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Detailed information

Guidance for genetic testing
  • EN (2014,pdf)
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