SAT078 A Case Of MODY Due To A Rare Activating Variant In The ABCC8 Gene

Abstract

Abstract Disclosure: J. Milosavljevic: None. J.M. Greally: None. S. Milman: None. Background: ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene encodes the sulfonylurea receptor 1 (SUR1) regulatory subunit of the beta cell ATP-sensitive K+ channel (KATP). Activating mutations in the ABCC8 cause both neonatal and maturity-onset diabetes of the young (MODY). The majority of patients (85%) with diabetes due to ABCC8 gene mutations could be successfully treated with oral sulfonylureas. A substitution c.2473C>T in the ABCC8 gene results in R825W change in the nucleotide-binding domain 1 of SUR1 and in activation of the KATP channel. We report a case of MODY with an activating mutation of ABCC8 gene (R825W). Clinical Case: A 23-year old woman with a history of ventricular septal defect was diagnosed with diabetes mellitus after she presented with a 2-month history of polyuria and polydipsia. At the time of diagnosis, random serum glucose level was 242 mg/dL, Hemoglobin A1c 7.6%, and BMI was 18 kg/m2. There was absence of acanthosis nigricans on exam or a family history of diabetes, although paternal medical history was unknown. A history of low birth weight was reported, but no developmental delays, neonatal diabetes or history of hypoglycemia. A history of seizure during childhood was also noted but was not associated with hypoglycemia. Additional work-up revealed absence of glutamic acid decarboxylase, islet cell, and insulin autoantibodies. C-peptide level was 2.0 ng/mL with blood glucose 113 mg/dL. The patient did not experience microvascular complications of diabetes. Genetic testing was negative for known mutations in HNF1A, HNF1B, HNF4A, GCK, and PPX1 genes. The patient was initially treated with metformin, but never achieved adequate glycemic control and experienced side effects. She was subsequently treated with sitagliptin and ertugliflozin, however, glycemic control remained inadequate (HbA1C 8.1%). At the age of 33 she was referred for clinical exome sequencing. This detected heterozygous ABCC8 variant c.2473 C>T; p.(R825W). Glucose control improved once therapy was switched to glipizide, resulting in the most recent HbA1C of 6.0%. Conclusion: Activating mutations of ABCC8 gene are infrequent genetic causes of diabetes in adults. Sequencing of the ABCC8 gene should be considered in select adult patients, as diagnosis can guide management decisions. Presentation: Saturday, June 17, 2023