A novel genetic mutation in a Portuguese family with GCK-MODY

Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous form of diabetes mellitus, with autosomal dominant inheritance. It accounts for 2%-5% of all diabetes cases. Glucokinase-MODY is the second most frequent form, which has been shown to be the result of mutations in the glucokinase (GCK) gene. It mostly presents with mild hyperglycemia, and, usually, no diabetes-related complications occur.

A 9-year-old female was admitted to the Endocrine Clinic to study her fasting hyperglycemia. Despite her obesity (body mass index 28 kg/m2), her physical examination had no other abnormalities. Blood tests showed a 6.3% hemoglobin A1c, with normal standard oral glucose tolerance test result, normal insulin value and normal C-peptide level. Insulin autoantibodies and antibodies against glutamate decarboxylase were negative. She began metformin and adequate diet. She had a strongly positive family history for diabetes. The patient's mother, uncle, grandfather, great-aunt and great-grandfather on her mother's side were diagnosed with diabetes. Complete sequencing of the GCK gene, carried out in the patient, identified a novel mutation c.1268T>A (p.Phe423Tyr) in exon 10 of the gene GCK in heterozygosity. Further studies revealed the same mutation in her mother and maternal grandfather.

Finding the same mutation in three different generations of diabetic patients, in the same family, is highly suggestive of its pathogenicity. To the authors' knowledge, this is the first time it is described in the literature. Correct molecular diagnosis of MODY predicts better the clinical course of diabetes and facilitates individualised management.