Introduction: Heterozygous loss-of-function mutations in the glucokinase (GCK) gene cause MODY 2. Conversely, homozygous loss-of-function mutations in the same gene give rise to permanent neonatal diabetes mellitus (DM). Previously, two patients diagnosed with DM in adolescence and had homozygous GCK mutations were reported. Variants in these patients have been shown to exhibit inactivated kinetics that are indistinguishable from neonatal onset mutations, but exhibit thermostability properties, which alleviate disease severity.
Aim: To present genotypic and phenotypic features of a patient diagnosed with DM at the age of 3 years due to a homozygous variant in the GCK gene.
Case: We examimed medical records of a 13-year-old male with DM, who had good metabolic control (HbA1c 6-7%) under treatment with a single daily dose (0.2 units/ kg) of insulin glargine and no ketoacidosis attacks since diagnosis. He was diagnosed with DM at the age of three years with the complaints of polyuria and polydipsia. At the time of diagnosis, he had a fasting venous glucose, 172mg/dL with no ketonuria and acidosis; C-peptide, 1.1 ng / mL (N, 0.9-7.1 ); insulin, <2 mIU / mL (N, 1.9-23); HbA1c, 7% (N, 4-6); and negative diabetes auto-antibodies. His parents were first degree cousins. There was no history of DM in the family except the grandmother with type 2 DM. On examination; weight was +0.18 SDS, height +0.74 SDS, puberty Tanner stage II and other physical examinations were normal. Owing to the inappropriate low dose insulin requirement beyond honeymoon period and negative diabetes auto-antibodies that are not compatible with type 1 DM, a next generation sequencing of MODY genes (GCK, HNF1A, HNF1B ve HNF4A genes), which revealed a novel homozygous variant c.1222 G>T in GCK gene was identified. His mother and father had same heterozygous variant in the GCK gene and were diagnosed with MODY 2 (mild fasting hyperglycemia and elevated HbA1c) after genetic counselling.
Conclusion: In GCK mutations, the homozygous and heterozygous status of the variant, as well as protein instability and thermostability properties may also contribute to the genotype-phenotype correlation. Despite the homozygous mutation in our patient, he had late-onset and mild disease, which can be related to the thermostability of GCK protein. Molecular genetic analysis of MODY genes in patients, whose clinical and laboratory findings do not match with type 1 DM can define novel mutations and provide a better understanding of the genotype-phenotype correlation in MODY.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology