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

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.

Fig. 1

Experimental design for the ¹³C-glucose breath test (¹³C-GBT) in the adolescent with glycogen storage disease type Ib (GSD Ib). ^aNasogastric (NG) tube was weighted prior to feeding = 10 g; and then was weighted after feeding = 13 g. There was some residual amounts ∼3 g of UCCS or Glycosade® at each study day. Therefore, the actual dose that the subject received of UCCS or Glycosade® was 77 g.

Fig. 2

¹³C-glucose breath test (¹³C-GBT) and finger-prick blood glucose concentrations in the adolescent with GSD Ib. A. Glucose oxidation in GSD Ib (18 y, F) from UCCS (pre-HSCT), UCCS (3 & 5 months post-HSCT), and Glycosade® (6 months post-HSCT) during the minimally invasive 4-h study protocol. Data are presented every 60 min instead of every 30 min due to the variability in the patient responses that might be related to hepatomegaly and splenomegaly. B. Finger-prick blood glucose concentrations in GSD Ib measured hourly using glucometer.