We report a 24 years old woman who was presumed to have type 1 diabetes following presentation of diabetes ketoacidosis at age 5 months. The family history included type 2 DM in three second-degree relatives. During transition to young adult clinic, given her lack of pancreatic autoantibodies and early onset of diabetes, DNA was sent for evaluation of monogenic diabetes. Results confirmed a heterozygous missense mutation at p.R89C of the INS gene. Subsequent testing confirmed marked insulin deficiency with a fasting C-peptide level of 0.04nmol/L when blood glucose was 18.0mmol/L.
Neonatal diabetes (ND) is a rare form of monogenic diabetes defined as onset of diabetes during the first 6 month of life. Estimated prevalence is 1 in 100,000 individuals (1). HLA typing in these patients usually demonstrates an absence of risk genotypes for type 1 DM (2). KCNJ11, ABCC8 and INS mutation are the 3 major causes of ND accounting for 75% of the cases. More than 40 INS gene mutations have been described. De novo mutation and heterozygous autosomal dominant inheritance occur most frequently in non-consanguineous family (3).
INS gene mutation results in synthesis of structurally abnormal preproinsulin or proinsulin. This leads to Endoplasmic reticulum stress and ultimately beta-cell apoptosis (3). Highly variable clinical presentation between and within kindred of the same INS mutation suggests genetic polymorphism and environmental factors are likely to play a role in beta cell dysfunction (4). An example includes mutation in CHOP gene in Akita rats have shown to delay onset of diabetes in INS mutants (5).
Detection of the genetic basis for ND can alter treatment, clinical outcomes and genetic counselling of patients. Successful transition from insulin to high dose sulfonylureas can be achieved in patients with KCNJ11 and ABCC8 mutation but usually not in patients with INS mutation (6).