Impact of hematopoietic stem cell transplantation in glycogen storage disease type Ib: A single-subject research design using 13C-glucose breath test

Abrar Turki; Sylvia Stockler; Sandra Sirrs; Kathleen Duddy; Gloria Ho; Rajavel Elango

doi:10.1016/j.ymgmr.2023.100955

Impact of hematopoietic stem cell transplantation in glycogen storage disease type Ib: A single-subject research design using ¹³C-glucose breath test

Mol Genet Metab Rep. 2023 Jan 3:34:100955. doi: 10.1016/j.ymgmr.2023.100955. eCollection 2023 Mar.

Authors

Abrar Turki^{1

2}, Sylvia Stockler^{1

2

3}, Sandra Sirrs^{4

5}, Kathleen Duddy³, Gloria Ho³, Rajavel Elango^{1

2

6}

Affiliations

¹ BC Children's Hospital Research Institute, Vancouver, British Columbia, Canada.
² Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada.
³ Division of Biochemical Genetics, BC Children's Hospital, Vancouver, British Columbia, Canada.
⁴ Department of Medicine, Division of Endocrinology, University of British Columbia, Vancouver, British Columbia, Canada.
⁵ Vancouver Costal Health, Adult Metabolic Diseases Clinic, Vancouver, British Columbia, Canada.
⁶ School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.

Abstract

Background: Glycogen storage disease type Ib (GSD Ib) is an autosomal recessively inherited deficiency of the glucose-6-phosphate translocase (G6PT). Clinical features include a combination of a metabolic phenotype (fasting hypoglycemia, lactic acidosis, hepatomegaly) and a hematologic phenotype with neutropenia and neutrophil dysfunction. Dietary treatment involves provision of starches such as uncooked cornstarch (UCCS) and Glycosade® to provide prolonged enteral supply of glucose. Granulocyte colony-stimulating factor (G-CSF) is the treatment of choice for neutropenia. Because long-term stimulation of hematopoiesis with G-CSF causes serious complications such as splenomegaly, hypersplenism, and osteopenia; hematopoietic stem cell transplantation (HSCT) has been considered in some patients with GSD Ib to correct neutropenia and avoid G-CSF related adverse effects. Whether HSCT also has an effect on the metabolic phenotype and utilization of carbohydrate sources has not been determined.

Objective: Our objective was to measure the utilization of starch in a patient with GSD Ib before and after HSCT using the minimally invasive ¹³C-glucose breath test (¹³C-GBT).

Design: A case of GSD Ib (18y; female) underwent ¹³C-GBT four times: UCCS (pre-HSCT), UCCS (3, 5 months post-HSCT) and Glycosade® (6 months post-HSCT) with a dose of 80 g administered via nasogastric tube after a 4 h fast according to our patient's fasting tolerance. Breath samples were collected at baseline and every 30 min for 240 min. Rate of CO₂ production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose <4 mmol/L). Biochemical and clinical data were obtained from the medical records as a post-hoc chart review.

Results: UCCS utilization was significantly higher in GSD Ib pre-HSCT, which reduced and stabilized 5 months post-HSCT. UCCS and Glycosade® utilizations were low and not different at 5 and 6 months post-HSCT. Blood glucose concentrations were not significantly different at any time point.

Conclusions: Findings show that HSCT stabilized UCCS utilization, as reflected by lower and stable glucose oxidation. The results also illustrate the application of ¹³C-GBT to examine glucose metabolism in response to various carbohydrate sources after other treatment modalities like HSCT in GSD Ib.

Keywords: 13C-GBT, 13C-glucose breath test; 13C-glucose; ALT, alanine aminotransferase; AML, acute myeloid leukemia; ANOVA, analysis of variance; AST, aspartate aminotransferase; AUC, area under the curve; BIA, bioelectrical impedance analysis; BMI, body mass index; Breath test; CF-IRMS, continuous flow isotope ratio mass spectrometer; CGM, continuous glucose monitor; CRP, C-reactive protein; Cmax, maximum peak enrichment in 13CO2 oxidation; ER, endoplasmic reticulum; FFM, fat free mass; FM, fat mass; G-CSF, granulocyte colony-stimulating factor; G6P, glucose-6-phosphate; G6PT, glucose-6-phosphate translocase; G6Pase-ß, glucose-6-phosphatase-β; G6Pase-α, glucose-6-phosphatase-α; GGT, gamma glutamyltransferase; GSD I, glycogen storage disease type I; GSD III, glycogen storage disease type III; GSD Ia, glycogen storage disease type Ia; GSD Ib, glycogen storage disease type Ib; Glycogen storage disease type Ib; Glycosade®; HSCT/BMT, hematopoietic stem cell transplantation / bone marrow transplantation; Hematopoietic stem cell transplantation; IBD, inflammatory bowel disease; IM, intramuscular; NG, nasogastric; TBW, total body water; UCCS, uncooked cornstarch; Uncooked cornstarch; VCO2, rate of carbon dioxide production.; tmax, time to reach maximum 13CO2 oxidation.