KCNJ11 Mutation in One Family is Associated with Adult-Onset Rather than Neonatal-Onset Diabetes Mellitus

ABSTRACT Objective: To present a case of adult-onset familial diabetes mellitus in which a genetic etiology typical for neonatal diabetes was identified. Methods: We conducted whole-exome and Sanger sequencing, assessed clinical presentation and family history, and performed a literature review. Results: A 40-year-old, thin woman presented with a 10-year history of mildly elevated fasting glucose and A1C levels. Her mother had diabetes mellitus since her 40s and is on insulin, and her daughter presented with diabetes mellitus at age 21. The patient and her daughter underwent whole-exome sequencing and were found to have a mutation in the KCNJ11 gene, c.G685A, p.E229K. This mutation is known to be associated with neonatal presentation of diabetes mellitus, which neither of these family members had a history of. Given her known mutation and postprandial hyperglycemia, a trial of low-dose sulfonylurea was initiated in the daughter but failed due to hypoglycemia. She was found to have a CYP2C9 genotype associated with poor oral drug clearance. Conclusion:KCNJ11 mutation should be screened for in patients and families meeting criteria for maturity-onset diabetes of the young, even without evidence of neonatal onset in the family. Furthermore, even though sulfonylurea therapy is successful in the majority of patients with KCNJ11 mutations, there may be a role for other interacting environmental or genetic modifiers, such as CYP2C9 geno-type, that affect sulfonylurea metabolism. Those patients who have delayed onset of disease and milder courses may be less ideal candidates for this treatment. Abbreviations: BMI = body mass index;KATP = ATP-sensitive potassium channel;MODY = maturity-onset diabetes of the young;NDM = neonatal diabetes mellitus