Genetic testing for glucokinase mutations in clinically selected patients with MODY: a worthwhile investment.

The differential diagnosis for children with diabetes includes a group of monogenic diabetic disorders known as maturity-onset diabetes of the young (MODY). So far, six underlying gene defects have been identified. The most common subtypes are caused by mutations in the genes encoding the transcription factor HNF-1a (MODY 3) and the glycolytic enzyme glucokinase (GCK) (MODY 2). MODY 2 is the most benign form of diabetes as the threshold for glucose sensing is elevated resulting in mild, regulated hyperglycemia. MODY 2 may usually be treated with diet alone without risk of microvascular complications. Patients with MODY usually present as children or young adults. Genetic testing for MODY in diabetic subjects is often not performed because of the costs and its unavailability in Switzerland. We describe the impact of the genetic analysis for MODY 2 on diabetes management and treatment costs in a five-year-old girl. The patient and her diabetic mother were both found to have a heterozygous missense mutation (V203A) in the glucokinase gene. The five-year-old girl was started on insulin therapy for her diabetes but because her HbA1c remained between 5.8-6.4% (reference 4.1-5.7%) and her clinical presentation suggested MODY insulin was discontinued. She is now well controlled on a carbohydrate controlled diet regimen only. Omission of insulin treatment made regular blood glucose monitoring unnecessary and removed her risk of hypoglycemia. Costs for the genetic analysis were 500 Euro. At our centre costs for diabetes care of a patient with type 1 diabetes are approximately 2050 Euro/year compared to 410 Euro/year for the care of a patient with MODY 2. In addition, a diagnosis of MODY 2 may reassure patients and their families, as microvascular complications are uncommon. Thus there are both health and financial benefits in diagnosing MODY 2. We recommend genetic testing for MODY 2 in clinically selected patients even though this analysis is currently not available in Switzerland and costs are not necessarily covered by the health insurances.

[1]  T. Barrett,et al.  Acquired non-type 1 diabetes in childhood: subtypes, diagnosis, and management , 2004, Archives of Disease in Childhood.

[2]  D. Dunger,et al.  First UK survey of paediatric type 2 diabetes and MODY , 2004, Archives of Disease in Childhood.

[3]  A. Hattersley,et al.  Genetic cause of hyperglycaemia and response to treatment in diabetes , 2003, The Lancet.

[4]  A. Hattersley,et al.  Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations. , 2003, Diabetes.

[5]  S. Ellard,et al.  Heterogeneity in young adult onset diabetes: aetiology alters clinical characteristics , 2002, Diabetic medicine : a journal of the British Diabetic Association.

[6]  T. Hansen,et al.  The genetic abnormality in the beta cell determines the response to an oral glucose load , 2002, Diabetologia.

[7]  A. Hattersley,et al.  Maturity-onset diabetes of the young: from clinical description to molecular genetic characterization. , 2001, Best practice & research. Clinical endocrinology & metabolism.

[8]  A. Hattersley,et al.  Influence of maternal and fetal glucokinase mutations in gestational diabetes. , 2001, American journal of obstetrics and gynecology.

[9]  R. Lorini,et al.  High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI , 2001, Diabetologia.

[10]  J. Silverstein,et al.  Molecular and genetic bases for maturity onset diabetes of youth. , 2000, Current opinion in pediatrics.

[11]  W. Winter.  Molecular and biochemical analysis of the MODY syndromes , 2000, Pediatric diabetes.

[12]  C. Buettger,et al.  Cell-biological assessment of human glucokinase mutants causing maturity-onset diabetes of the young type 2 (MODY-2) or glucokinase-linked hyperinsulinaemia (GK-HI). , 1999, The Biochemical journal.

[13]  M. Magnuson,et al.  Mutants of glucokinase cause hypoglycaemia- and hyperglycaemia syndromes and their analysis illuminates fundamental quantitative concepts of glucose homeostasis , 1999, Diabetologia.

[14]  Sian Ellard,et al.  Mutations in the glucokinase gene of the fetus result in reduced birth weight , 1998, Nature Genetics.

[15]  P. Froguel,et al.  Diagnostic Heterogeneity of Diabetes in Lean Young Adults: Classification Based on Immunological and Genetic Parameters , 1997, Diabetes.

[16]  J. Beckmann,et al.  Familial hyperglycemia due to mutations in glucokinase. Definition of a subtype of diabetes mellitus. , 1993, The New England journal of medicine.

[17]  A. Hattersley,et al.  Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[18]  P. Froguel,et al.  Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families , 1997, Diabetologia.