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

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.

Facial Dysmorphic Features in a Patient With Nonketotic Hypoglycemia and a Pathogenic Variant in the AKT2 Gene.

Background/Objective: AKT2 is a serine/threonine kinase that plays a key role in regulating insulin signaling. The phenotype related to the gain-of-function alteration in the AKT2 gene (c.49G>A, p.Glu17Lys) has been described in 5 patients with clinical findings that mimic hyperinsulinemic hypoglycemia but with undetectable levels of insulin and C-peptide. One of the reports highlights the facial dysmorphic features. We report the case of a new patient with the same activating AKT2 alteration leading to autonomous activation of the insulin signaling pathway and dysmorphic features. Moreover, to our knowledge, this is the first report using waxy maize heat-modified starch (WMHMS) in this condition. Case Report: A previously healthy child was evaluated at 6 months of age for episodes of hypoglycemia. The laboratory test results for the critical samples showed hypoketotic hypoglycemia (glucose level, 2.16 mmol/L [38 mg/dL]) with undetectable levels of insulin (<0.2 mU/L) and C-peptide (<0.033 nmol/L [reference range, 0.37-1.47 nmol/L]). Physical examination revealed hypertelorism, prominent proptosis of the eyes, a flat nasal bridge, delayed psychomotor development, and postnatal symmetrical overgrowth. The genetic study of AKT2 showed a pathogenic variant (c.49G>A, p.Glu17Lys). To achieve euglycemia, a diet of regular uncooked cornstarch (UCCS) carbohydrate was started. Subsequently, waxy maize heat-modified starch (WMHMS; Glycosade Vitaflo) was used to increase the fasting period to 4 hours. However, we did not find any advantages in comparison with UCCS. Discussion: The range of phenotypes of this gain-of-function alteration in AKT2 may be broad, including dysmorphic features, although the patients harbor the same pathogenic variant. Conclusion: Regarding the treatment, we observed a similar response with WMHMS compared with UCCS, with no adverse effects.

Development of minimally invasive 13C-glucose breath test to examine different exogenous carbohydrate sources in patients with glycogen storage disease type Ia.

Background: Glycogen storage disease type Ia (GSD Ia) is an autosomal recessive disorder caused by deficiency of glucose-6-phosphatase (G6Pase), resulting in fasting hypoglycemia. Dietary treatment with provision of uncooked cornstarch (UCCS) or a novel modified cornstarch (Glycosade®) is available to treat hypoglycemia, yet choice of carbohydrate to achieve a desirable glycemic control is debated.13C-glucose breath test (13C-GBT) can be used to examine glucose metabolism from different carbohydrate sources via 13CO2 in breath. Objectives: Our objectives were: 1) establishing the use of a minimally invasive 13C-GBT to examine in vivo glucose metabolism in healthy adults, and 2) using 13C-GBT to measure utilization of the standard UCCS vs. Glycosade® in GSD Ia and healthy controls. Design: Experiment 1- Ten healthy adults (6F: 4 M, 22-33y) underwent 13C-GBT protocol twice as a proof-of-principle, once with oral isotope dose (glucose 75 g + [U-13C6] d-glucose 75 mg) and once without isotope (only glucose 75 g) to test sensitivity of natural 13C-enrichment. Breath samples were collected at baseline and every 20 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). Experiment 2- Three GSD Ia (12y, 13y, and 28y) and six healthy controls (2F: 4 M, 10-32y) underwent 13C-GBT protocol twice: with UCCS or Glycosade® (based on their current prescribed dose 42-100 g) after ~4 h fast based on our GSD Ia patients with fasting tolerance. Results: Findings 1- Maximum 13C-enrichments occurred at 200 min without and with [U-13C6] d-glucose in all healthy adults, suggesting natural enrichment is sensitive for the 13C-GBT. Findings 2- Glycosade® utilization was lower than UCCS utilization in 12y and 13y GSD Ia, but was similar in the 28y GSD Ia. Conclusions: 13C-GBT is a novel minimally invasive functional test to examine glucose metabolism in GSD Ia, and test new products like Glycosade®, which has the potential to improve nutritional management and individualized carbohydrate supply in GSD.

Use of waxy maize heat modified starch in the treatment of children between 2 and 5 years with glycogen storage disease type I: A retrospective study.

BACKGROUND: Glycogen storage disease type I (GSDI) is caused by deficiency of the enzyme glucose-6-phosphatase or glucose-6-phosphate transporter. Mainstay of treatment is provision of uncooked cornstarch (and/or continuous nocturnal pump feed (CNPF) to maintain normoglycemia). Waxy maize heat modified starch (WMHMS) is another treatment option to maintain normoglycemia overnight. Our objective was to describe our experience treating children 2-5 years of age with GSDI using WMHMS overnight. METHOD: This is a retrospective case series review (n = 5) comparing the overnight feeding regimen and biochemical control one year before and after nocturnal WMHMS therapy. The WMHMS trial, in which blood glucose and lactate levels were monitored hourly, is reported in detail. RESULTS: Most patients successfully transitioned to nocturnal WMHMS feeds. These patients had stable glucose and lactate throughout the overnight period, permitting a fasting period of 6.5-8 h overnight. Within the time period studied, WMHMS appeared to have improved overnight control of blood glucose levels with fewer reported episodes of hypoglycemia compared to CNPF. CONCLUSION: WMHMS can be an effective substitute treatment to achieve stable nocturnal glucose control in children younger than five years of age. A larger multicenter prospective study is recommended to establish stronger evidence of the efficacy and safety of using WMHMS in treatment of young children with GSDI.