BACKGROUND: Glycogen storage disease type 0a (GSD0a) is a rare autosomal recessive disorder caused by glycogen synthase deficiency. Short stature is a characteristic feature in 29% of GSD0a patients, but isolated short stature as the only presenting symptom is exceedingly rare, with only 2 cases reported worldwide.
METHODS: A 4-year-old girl presented with persistent growth retardation despite previous treatment for renal tubular acidosis.
METHODS: Based on clinical presentation and whole exome sequencing results, the patient was diagnosed with GSD0a.
METHODS: Uncooked cornstarch therapy was initiated at 2 g/kg every 6 hours.
RESULTS: After 3 years of treatment, the patient\'s height SDS improved from -2.24 to -1.06, with enhanced glycemic control and no complications.
CONCLUSIONS: This case emphasizes considering GSD0a in unexplained short stature and the value of continuous glucose monitoring. Early diagnosis and treatment can optimize growth in GSD0a patients.

Type I glycogen storage diseases (GSD-I) consist of two major autosomal recessive disorders, GSD-Ia, caused by a reduction of glucose-6-phosphatase-α (G6Pase-α or G6PC) activity and GSD-Ib, caused by a reduction in the glucose-6-phosphate transporter (G6PT or SLC37A4) activity. The G6Pase-α and G6PT are functionally co-dependent. Together, the G6Pase-α/G6PT complex catalyzes the translocation of G6P from the cytoplasm into the endoplasmic reticulum lumen and its subsequent hydrolysis to glucose that is released into the blood to maintain euglycemia. Consequently, all GSD-I patients share a metabolic phenotype that includes a loss of glucose homeostasis and long-term risks of hepatocellular adenoma/carcinoma and renal disease. A rigorous dietary therapy has enabled GSD-I patients to maintain a normalized metabolic phenotype, but adherence is challenging. Moreover, dietary therapies do not address the underlying pathological processes, and long-term complications still occur in metabolically compensated patients. Animal models of GSD-Ia and GSD-Ib have delineated the disease biology and pathophysiology, and guided development of effective gene therapy strategies for both disorders. Preclinical studies of GSD-I have established that recombinant adeno-associated virus vector-mediated gene therapy for GSD-Ia and GSD-Ib are safe, and efficacious. A phase III clinical trial of rAAV-mediated gene augmentation therapy for GSD-Ia (NCT05139316) is in progress as of 2023. A phase I clinical trial of mRNA augmentation for GSD-Ia was initiated in 2022 (NCT05095727). Alternative genetic technologies for GSD-I therapies, such as gene editing, are also being examined for their potential to improve further long-term outcomes.

BACKGROUND: Glycogen storage disease type Ia (GSD-Ia) is one of the most common hepatic GSD. Its treatment mainly consists of a diet including a high intake of slow-digestion carbohydrates such as raw cornstarch and the restriction of simple sugars. This enables the maintenance of euglycemia and prevents secondary metabolic disorders. Starch is a glucose polymer formed by amylose and amylopectin, which can be obtained from distinct sources. Although uncooked cornstarch has been successfully used in the treatment of GSD-Ia, it can lead to hyperglycemia and weight gain. in vitro andin vivo tests indicated that sweet manioc starch can be potentially used in the treatment of GSD-Ia.
RESULTS: The moisture analysis revealed a variation from 10.3 to 12.8% in the sweet manioc starch samples, whereas the moisture content of uncooked cornstarch ranged from 7.3 to 11.1%. Quantifiable sugar was detected in 3/5 samples of sweet manioc starch and 1/3 samples of uncooked cornstarch. Notably, this uncooked cornstarch brand is widely employed in GSD-Ia treatment in Brazil. Products B and E had higher values of amylopectin and undetectable levels of sugars. A clinical trial is warranted to compare samples F and G and determine the impact of sugar trace in the same dietary source of starch.
CONCLUSIONS: Collectively, the results demonstrated possible therapeutic alternatives for GSD-Ia in addition to traditional uncooked cornstarch.

No sensitive tumor marker for hepatocellular carcinoma (HCC) is available for patients with glycogen storage disease type Ia (GSDIa), in whom alpha-fetoprotein and carcino-embryonic antigen levels often remain normal. We describe increased levels of the HCC tumor marker des-gamma-carboxy prothrombin (DCP) in GSDIa patients with HCC. In one case DCP levels normalized after liver transplantation. We recommend including DCP as a screening HCC tumor marker in the surveillance of patients with GSDIa.

UNASSIGNED: Glycogen storage disease type 1b (GSD-1b) is characterized by neutropenia and neutrophil dysfunction generated by the accumulation of 1,5-anhydroglucitol-6-phosphate in neutrophils. Sodium-glucose co-transporter 2 inhibitors, such as empagliflozin, facilitate the removal of this toxic metabolite and ameliorate neutropenia-related symptoms, including severe infections and inflammatory bowel disease (IBD). Our case series presents the treatment of three pediatric GSD-1b patients with empagliflozin over a follow-up of three years; the most extended reported follow-up period to date.
UNASSIGNED: A retrospective analysis of empagliflozin treatment of three pediatric GSD-1b patients (two male and one female; ages at treatment initiation: 4.5, 2.5 and 6 years) was performed. Clinical and laboratory data from a symmetrical period of up to three years before and after the therapy introduction was reported. Data on the clinical course of the treatment, IBD activity, the need for antibiotic treatment and hospitalizations, neutrophil count and function, and markers of inflammation were assessed. Prior the introduction of empagliflozin, patients had recurrent oral mucosa lesions and infections, abdominal pain, and anemia. During empagliflozin treatment, the resolution of aphthous stomatitis, termination of abdominal pain, reduced frequency and severity of infections, anemia resolution, increased appetite, and improved wound healing was observed in all patients, as well as an increased body mass index in two of them. In a patient with IBD, long-term deep remission was confirmed. An increased and stabilized neutrophil count and an improved neutrophil function enabled the discontinuation of G-CSF treatment in all patients. A trend of decreasing inflammation markers was detected.
UNASSIGNED: During the three-year follow-up period, empagliflozin treatment significantly improved clinical symptoms and increased the neutrophil count and function, suggesting that targeted metabolic treatment could improve the immune function in GSD-1b patients.

Patients with glycogen storage disease type Ib (GSD-Ib) frequently have inflammatory bowel disease (IBD). however, the underlying etiology remains unclear. Herein, this study finds that digestive symptoms are commonly observed in patients with GSD-Ib, presenting as single or multiple scattered deep round ulcers, inflammatory pseudo-polyps, obstructions, and strictures, which differ substantially from those in typical IBD. Distinct microbiota profiling and single-cell clustering of colonic mucosae in patients with GSD are conducted. Heterogeneous oral pathogenic enteric outgrowth induced by GSD is a potent inducer of gut microbiota immaturity and colonic macrophage accumulation. Specifically, a unique population of macrophages with high CCL4L2 expression is identified in response to pathogenic bacteria in the intestine. Hyper-activation of the CCL4L2-VSIR axis leads to increased expression of AGR2 and ZG16 in epithelial cells, which mediates the unique progression of IBD in GSD-Ib. Collectively, the microbiota-driven pathomechanism of IBD is demonstrated in GSD-Ib and revealed the active role of the CCL4L2-VSIR axis in the interaction between the microbiota and colonic mucosal immunity. Thus, targeting gut dysbiosis and/or the CCL4L2-VISR axis may represent a potential therapy for GSD-associated IBD.

BACKGROUND: Glycogen storage disease (GSD) is a disease caused by excessive deposition of glycogen in tissues due to genetic disorders in glycogen metabolism. Glycogen storage disease type I (GSD-I) is also known as VonGeirk disease and glucose-6-phosphatase deficiency. This disease is inherited in an autosomal recessive manner, and both sexes can be affected. The main symptoms include hypoglycaemia, hepatomegaly, acidosis, hyperlipidaemia, hyperuricaemia, hyperlactataemia, coagulopathy and developmental delay.
METHODS: Here, we present the case of a 13-year-old female patient with GSD Ia complicated with multiple inflammatory hepatic adenomas. She presented to the hospital with hepatomegaly, hypoglycaemia, and epistaxis. By clinical manifestations and imaging and laboratory examinations, we suspected that the patient suffered from GSD I. Finally, the diagnosis was confirmed by liver pathology and whole-exome sequencing (WES). WES revealed a synonymous mutation, c.648 G > T (p.L216 = , NM_000151.4), in exon 5 and a frameshift mutation, c.262delG (p.Val88Phefs*14, NM_000151.4), in exon 2 of the G6PC gene. According to the pedigree analysis results of first-generation sequencing, heterozygous mutations of c.648 G > T and c.262delG were obtained from the patient\'s father and mother. Liver pathology revealed that the solid nodules were hepatocellular hyperplastic lesions, and immunohistochemical (IHC) results revealed positive expression of CD34 (incomplete vascularization), liver fatty acid binding protein (L-FABP) and C-reactive protein (CRP) in nodule hepatocytes and negative expression of β-catenin and glutamine synthetase (GS). These findings suggest multiple inflammatory hepatocellular adenomas. PAS-stained peripheral hepatocytes that were mostly digested by PAS-D were strongly positive. This patient was finally diagnosed with GSD-Ia complicated with multiple inflammatory hepatic adenomas, briefly treated with nutritional therapy after diagnosis and then underwent living-donor liver allotransplantation. After 14 months of follow-up, the patient recovered well, liver function and blood glucose levels remained normal, and no complications occurred.
CONCLUSIONS: The patient was diagnosed with GSD-Ia combined with multiple inflammatory hepatic adenomas and received liver transplant treatment. For childhood patients who present with hepatomegaly, growth retardation, and laboratory test abnormalities, including hypoglycaemia, hyperuricaemia, and hyperlipidaemia, a diagnosis of GSD should be considered. Gene sequencing and liver pathology play important roles in the diagnosis and typing of GSD.

Glycogen storage disease type Ib (GSD-Ib) is a rare inborn error of glycogen metabolism caused by mutations in SLC37A4. Patients with GSD-Ib are at high risk of developing inflammatory bowel disease (IBD). We evaluated the efficacy of empagliflozin, a renal sodium‒glucose cotransporter protein 2 (SGLT2) inhibitor, on colonic mucosal healing in patients with GSD-associated IBD. A prospective, single-arm, open-label clinical trial enrolled eight patients with GSD-associated IBD from Guangdong Provincial People\'s Hospital in China from July 1, 2022 through December 31, 2023. Eight patients were enrolled with a mean age of 10.34 ± 2.61 years. Four male and four female. The endoscopic features included deep and large circular ulcers, inflammatory hyperplasia, obstruction and stenosis. The SES-CD score significantly decreased at week 48 compared with before empagliflozin. Six patients completed 48 weeks of empagliflozin therapy and endoscopy showed significant improvement or healing of mucosal ulcers, inflammatory hyperplasia, stenosis, and obstruction. One patient had severe sweating that required rehydration and developed a urinary tract infection. No serious or life-threatening adverse events. This study suggested that empagliflozin may promote colonic mucosal healing and reduce hyperplasia, stenosis, and obstruction in children with GSD-associated IBD.

BACKGROUND: Glycogen storage disease type Ib (GSD Ib) is a rare disorder characterized by impaired glucose homeostasis caused by mutations in the SLC37A4 gene. It is a severe inherited metabolic disease associated with hypoglycemia, hyperlipidemia, lactic acidosis, hepatomegaly, and neutropenia. Traditional treatment consists of feeding raw cornstarch which can help to adjust energy metabolism but has no positive effect on neutropenia, which is fatal for these patients. Recently, the pathophysiologic mechanism of the neutrophil dysfunction and neutropenia in GSD Ib has been found, and the treatment with the SGLT2 inhibitor empaglifozin is now well established. In 2020, SGLT2 inhibitor empagliflozin started to be used as a promising efficient remover of 1,5AG6P in neutrophil of GSD Ib patients worldwide. However, it is necessary to consider long-term utility and safety of a novel treatment.
RESULTS: In this study, we retrospectively examined the clinical manifestations, biochemical examination results, genotypes, long-term outcomes and follow-up of thirty-five GSD Ib children who visited our department since 2009. Fourteen patients among them underwent empagliflozin treatment since 2020. This study is the largest cohort of pediatric GSD Ib patients in China as well as the largest cohort of pediatric GSD Ib patients treated with empagliflozin in a single center to date. The study also discussed the experience of long-term management on pediatric GSD Ib patients.
CONCLUSIONS: Empagliflozin treatment for pediatric GSD Ib patients is efficient and safe. Increase of urine glucose is a signal for pharmaceutical effect, however attention to urinary infection and hypoglycemia is suggested.

UNASSIGNED: Neutropenia and neutrophil dysfunction in glycogen storage disease type 1b (GSD1b) are caused by the accumulation of 1,5-anhydroglucitol-6-phosphate in granulocytes. The antidiabetic drug empagliflozin reduces the concentration of 1,5-anhydroglucitol (1,5-AG), thus restoring neutrophil counts and functions, leading to promising results in previous case reports. Here, we present a comprehensive analysis of neutrophil function in 7 patients with GSD1b and 11 healthy donors, aiming to evaluate the immediate (after 3 months) and long-term (after 12 months) efficacy of empagliflozin compared with the reference treatment with granulocyte-colony stimulating factor (G-CSF). We found that most patients receiving G-CSF remained neutropenic with dysfunctional granulocytes, whereas treatment with empagliflozin increased neutrophil counts and improved functionality by inhibiting apoptosis, restoring phagocytosis and the chemotactic response, normalizing the oxidative burst, and stabilizing cellular and plasma levels of defensins and lactotransferrin. These improvements correlated with the decrease in serum 1,5-AG levels. However, neither G-CSF nor empagliflozin overcame deficiencies in the production of cathelicidin/LL-37 and neutrophil extracellular traps. Given the general improvement promoted by empagliflozin treatment, patients were less susceptible to severe infections. G-CSF injections were therefore discontinued in 6 patients (and the dose was reduced in the seventh) without adverse effects. Our systematic analysis, the most extensive reported thus far, has demonstrated the superior efficacy of empagliflozin compared with G-CSF, restoring the neutrophil population and normal immune functions. This trial was registered as EudraCT 2021-000580-78.