P084: High efficacy on low-dose empagliflozin efficacy in glycogen storage disease-1b sibling pair

Treatment and Management: Patient 1: She was treated with a schedule of frequent feeds and supplementation with corn starch.She required repeated hospital admissions for antibiotic and granulocytic colony-stimulating factor (GCSF) therapy for her infections.At the age of 7, she was started on empagliflozin 6.25 mg/day (0.2 mg/kg/day).Patient 2: He was treated with a schedule of frequent feeds and supplementation with corn starch but required GCSF therapy for his neutropenia.At the age of 3, he was started on empagliflozin 3.125 mg/day (0.16 mg/kg/day).Outcome and Follow-Up: Patient 1: In spite of her dietary regimen, she continued to experience a low ANC and recurrent infections.After starting empagliflozin, however, she exhibited significant and rapid clinical improvement in her oral ulcers.Additionally, she a normal ANC, normal neutrophil oxidative burst, and fewer infections requiring hospital admissions.Two years after beginning empagliflozin, she was diagnosed with juvenile idiopathic arthritis which is currently well-controlled with tofacitinib and tocilizumab.Her parents were concerned about the potential effect of empagliflozin on her JIA, so she was maintained at that absolute dose which is currently equivalent to 0.13 mg/kg/day.Patient 2: He also experienced a rapid improvement with his oral ulcers resolving within days and normalization of his neutropenia.He continues his starting dose of 3.125 mg/day (0.16 mg/kg/day).Discussion: Empagliflozin is a SGLT2 inhibitor improves clinical outcomes in GSD1b patients with qualitative and quantitative neutrophil deficits.Though recent publications recommend starting dosage for children should be 0.3-0.4mg/kg/day, our patients experienced swift resolution of neutrophil-associated sequela at lower doses with subsequent improvement in neutropenia.Importantly, these gains have been sustained with no episodes of hypoglycemia, a known side-effect of SGLT2 inhibitors.Conclusion: Lower doses of empagliflozin can be an effective tool in treating neutrophil-related abnormalities in GSD1b patients who experience or seek to avoid worrisome side effects at higher drug levels.Introduction: Glycogen storage disease type 1b (GSD1b) is a disorder of glycogen metabolism notable for neutropenia and neutrophil dysfunction secondary to accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) within granulocytes.This intracellular 1,5-AG6P is produced by the phosphorylation of 1,5anhydroglucitol (1,5-AG), the renal resorption of which is inhibited competitively by glucose.Empagliflozin is an antidiabetic drug that inhibits the renal sodium-glucose cotransporter type 2 (SGLT2), causing higher glucosuria and, consequently, increased 1,5-AG excretion.Recently published consensus from an international workshop recommends starting GSD1b children with evidence of neutropenia and neutrophil dysfunction on empagliflozin 0.3-0.4mg/kg/day.We report two siblings with GSD1b with improvement of neutrophil-associated sequelae on lower-than-recommended doses of empagliflozin.Case Presentation: Patient 1: An 11-year-old girl presented at 7 months of age with vomiting and altered mental status after overnight fasting.She was found to have severe hypoglycemia, lactic acidosis, hypertriglyceridemia and hepatomegaly.Neutropenia was noted with an absolute neutrophil count (ANC) as low as 100/L with a low neutrophil oxidative burst.She experienced repeated bacterial infections including gingivitis, mastoiditis, cellulitis, recurrent oral ulcers, and sepsis.Nephromegaly was detected on renal ultrasound.Patient 2: A 3-year-old male sibling of Patient 1 was diagnosed with GSD1b via prenatal testing.Within the first year of life, he was found to be severely neutropenic with an ANC as low as 0/L.Over time, he required multiple hospital admission for treatment of neutropenic fevers.He also experienced repeated skin infections, oral ulcers, and hepatomegaly.Diagnostic Workup: Patient 1 & 2: Two heterozygous, pathogenic variants in SLC374A consisting of a frameshift deletion in exon 9 [c.1042_1043delCT (p.Leu348ValfsX5)] and a deletion of 5.9 kb with insertion of 36 nucleotides in Exon 1-3 [chr11:g.118899171-118905119delins(p.?)] were identified in both siblings.