PSUN269 Suboptimal Sulfonylurea Therapeutic Response in a Patient with MODY-3 with a Rare HNF1A Pathogenic Genetic Variant
Authors: Villavicencio Camila , Franco-Akel Alberto , Belokovskaya Regina , Adetiloye Adebola 
Published: November 2022

Maturity-onset diabetes of the young (MODY) is a rare non-autoimmune type of diabetes, seen in 1-6% of patients with diabetes, caused by a single gene variant defect that ultimately impairs pancreatic b-cell insulin secretion. MODY-3, caused by mutations in HNF1A gene, accounts for most MODY cases. Misdiagnosis of MODY as type 1 diabetes (T1DM) or young-onset type 2 diabetes (T2DM) due to their overlapping features is common, leading to suboptimal pharmacologic management. When pharmacologic therapy is indicated, patients with MODY-3 typically present an excellent response to sulfonylurea monotherapy. We describe a case of a young adult woman diagnosed with MODY-3, previously treated as T1DM, with an atypical suboptimal response to sulfonylurea therapy possibly attributed to a rare HNF1A pathogenic genetic variant.

A 24-year-old female with a BMI of 21, diagnosed with diabetes at age 13 managed as T1DM on insulin, underwent genetic analysis at age 23 after her 14-year-old sister was found to have MODY-3. DNA sequencing revealed heterozygous HNF1A gene with pathogenic variant c.365A&gt;G (p.Tyr122Cys). Sulfonylurea therapy was initiated with the goal to lower the insulin regimen. Additional workup revealed a new HbA1C 12%, new-onset microalbuminuria, positive glutamic acid decarboxylase (GAD) antibody (0.22 nmol/L), negative islet cell antibody, and zinc transporter-8 antibody (ZnT8), in addition to normal C-peptide level of 1.5ng/mL. Upon follow-up visit, sulfonylurea dose was doubled, and basal and pre-prandial insulin were lowered and discontinued, respectively. Although the HbA1C improved to 9.8%, the patient admitted to self-resuming previous basal and pre-prandial insulin regimen after consistently having hyperglycemia 300 mg/dL when following last pharmacologic adjustments.

MODY usually has autosomal-dominant inheritance although de novo mutations can occur. The molecular diagnosis aims at tailoring the choice of the most appropriate treatment to improve blood glucose control, reduce the risk of hypoglycemia, and prevent long-term micro and macrovascular complications. Typically, patients with MODY-3 are highly sensitive to monotherapy with sulfonylureas especially when shorter diabetes duration, lower BMI, and lower HbA1C are present at the time of genetic diagnosis. Although our patient's HbA1C level improved once sulfonylurea therapy was initiated, HbA1C remains above the goal level and discontinuation of insulin regimen has not been able to be achieved despite increasing sulfonylurea dose. Similar cases of MODY-3 with atypical sulfonylurea therapeutic response have been reported and attributed to the presence of novel HNF1A genetic variants. Moreover, studies have predicted that about 50% of MODY-3 patients require insulin therapy as the disease progresses. Nonetheless, more research is needed to elucidate possible additional contributing factors to a suboptimal sulfonylurea therapeutic response in MODY-3 cases.

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