Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening inherited carbohydrate metabolism disorder caused by biallelic pathogenic G6PC gene variants resulting in deficiency of glucose-6-phosphatase. DTX401 is an investigational AAV8 vector containing the human G6PC gene. DTX401-CL301 is a pivotal, phase 3, double-blind, randomized, placebo-controlled trial of DTX401 in patients ≥ 8 years with GSDIa. The primary endpoint was percent change from Baseline to Week 48 in daily cornstarch intake for the DTX401 versus placebo group. Participants were randomly assigned (1:1) to blinded DTX401 or placebo. After the 48-week Primary Efficacy Analysis Period (PEAP), participants crossed over in a blinded manner for an additional 48-week blinded Crossover Period. Following randomization: 21 participants received DTX401; 25 received placebo. At Week 48, DTX401 treatment resulted in a statistically significant least squares (LS) mean (SE) daily cornstarch intake reduction of 41% (4.6) versus 10% (4.1) for Placebo (p < 0.0001). Clinical meaningfulness was evidenced by a mean desired percent reduction in daily cornstarch intake among those reporting in Baseline interviews (n = 33) of 45% (median = 41%). Greater and faster reductions in cornstarch were observed at Week 96 for the Crossover DTX401 group compared with the DTX401 group in the PEAP. The DTX401 safety profile was acceptable, and expected hepatic reactions consisting of transaminase elevations were managed with prophylactic corticosteroids. Treatment with DTX401 resulted in both a statistically significant and clinically meaningful reduction in cornstarch intake in the 48-week PEAP versus placebo, with greater cornstarch reductions in both groups at Week 96.

Background Hepatic glycogen storage diseases (GSDs) are rare inborn metabolic disorders characterised by fasting hypoglycaemia and requiring demanding, lifelong dietary management. Despite the considerable burden this places on patients and families, the psychosocial impacts of hepatic GSDs remain under-researched. This study qualitatively explored the lived experiences of adult patients with hepatic GSD and caregivers of affected children, focussing on psychosocial wellbeing. Semi-structured interviews with 15 international participants (five patients, ten caregivers) representing a range of hepatic GSDs were analysed using reflexive thematic analysis. Results Four themes reflecting psychosocial impacts were identified. (1) Fear of Hypoglycaemia caused intense anxiety and severe sleep disruption, and restricted social life and physical activity. Continuous glucose monitors and gastric tubes were valued as important tools for mitigating this fear and maintaining glycaemic control. (2) Trauma and Hypervigilance arose from prolonged diagnostic journeys, distressing medical experiences, severe hypoglycaemic events, and constant treatment demands. (3) Intense and Difficult Relationship with Eating included pressure to eat for metabolic stability, disordered body and eating attitudes linked to hepatomegaly and dietary treatment, and widespread picky eating and oral aversion. (4) Living In a System That Doesn't Understand GSD encompassed alienation in daily life, the burden of self-advocacy, the centrality of peer networks in filling gaps left by formal care, and a clear, unmet need for psychosocial support. Conclusions Hepatic GSD carries a substantial, under-recognised psychosocial burden. Routine psychological support should be integrated into care pathways, particularly at diagnosis and during developmental transitions. Condition-specific psychosocial interventions may be required, particularly to address fear of hypoglycaemia. Improved access to continuous glucose monitoring and GSD specialists, alongside early signposting to peer networks, is also needed. Addressing the full impact of hepatic GSD requires psychosocial care to be embedded within standard clinical management.

# Background Glycogen storage disease type Ia (GSDIa) is a rare, inherited, autosomal recessive deficiency of glucose-6-phosphatase (G6Pase), an enzyme necessary in glycogenolysis and gluconeogenesis. To maintain normal blood glucose levels and ensure survival, individuals living with GSDIa must frequently consume complex carbohydrates (eg, uncooked cornstarch). Dietary management can result in chronic complications and significant patient burden. DTX401 (pariglasgene brecaparvovec) is an investigational adeno-associated virus serotype 8 vector (AAV8)–based gene therapy designed to restore endogenous glucose production. # Objectives Patient experience interviews were conducted as part of an open-label, phase 1/2 dose-escalation trial (NCT03517085) evaluating the safety and efficacy of DTX401 in adults ≥18 years with GSDIa. # Methods Telephone interviews were conducted at Weeks 24, 52, and 104, using a semistructured interview guide. Qualitative interview data were audio recorded, transcribed, coded, and analyzed. # Results Most (86%; n = 6/7) reported overall symptom improvement and reduced burden following DTX401 treatment. Three (43%) reported no negative outcomes following gene therapy; 4 (57%) mentioned at least one negative change attributed to instances of blood sugar instability, lifestyle, or diet adjustments. Satisfaction fluctuated across timepoints; however, most were somewhat satisfied/very satisfied with gene therapy at Weeks 24 (80%), 52 (86%), and 104 (86%). No participants reported being very dissatisfied. # Discussion Following DTX401 treatment, most participants reported substantial reduction in cornstarch intake and corresponding improvements in symptoms, physical function, diet management, emotional function, self-perception, social function, sleep quality, work performance, and overall health. Few negative changes were reported. While some results regarding met expectations were mixed, most indicated they would still want gene therapy even if they had to continue cornstarch and if they had continued diet restrictions, and most reported satisfaction with treatment. While the study had limitations, interview results suggest that DTX401 helps to address aspects of the condition and treatment that patients have identified as burdensome. # Conclusions Most interviewees in this open-label trial of investigational DTX401 described positive experiences, including substantial reduction in burden and improved health-related quality of life following treatment throughout the trial. To optimize patient outcomes and experience with gene therapy, guidance on and close monitoring of dietary changes during implementation should be provided.

PURPOSE:Health care and clinical trials for persons with liver glycogen storage diseases (GSD) can be improved by a consensus-based standard set of person-centered health outcomes, including patient-reported outcome measures. METHODS:Persons with GSD (n = 6), caregivers (n = 17), multidisciplinary health care providers (n = 38), industry representatives (n = 7), and value-based health care experts (n=4) from 25 countries participated in an international, iterative nominal consensus process to identify the most important health outcomes and case-mix variables for liver GSD. RESULTS:The following 14 health outcomes are recommended for measurement: (1) cure; (2) life-threatening GSD-related events; (3) glycemic control; (4) metabolic control; (5) acute metabolic decompensations; (6) GSD-related complications; (7) time to treatment of intercurrent complications; (8) time to return to functional status; (9) access and availability of GSD expertise care; (10) access and availability of GSD-related diagnostic, monitoring, and treatment products; (11) quality of life; (12) independence; (13) treatment adherence; and (14) food intake problems. A list of 29 case-mix variables was composed of demographic, diagnostic, clinical, and treatment factors. Recommendations were formulated on frequency of measurements. CONCLUSION:An international consensus-based standard set of person-centered health outcomes for liver GSD was developed to apply in health care, registries, and clinical trials.

Glycogen storage disease type Ia (GSDIa) is a rare, life-threatening, inherited carbohydrate metabolism disorder caused by glucose-6-phosphatase (G6Pase) deficiency, which is essential for glycogenolysis and gluconeogenesis. GSDIa management includes a strict medically prescribed diet that typically includes daily uncooked cornstarch doses, including overnight, to maintain euglycemia. DTX401 is an investigational adeno-associated virus serotype 8 vector expressing the human G6PC1 gene that encodes G6Pase. This open-label, phase 1/2, dose-escalation, 52-week gene therapy trial evaluated the safety and efficacy of a single DTX401 infusion in 12 adults with GSDIa (ClinicalTrials.gov Identifier: NCT03517085). Three participants in Cohort 1 received DTX401 2.0 × 1012 genome copies (GC)/kg, and three participants each in Cohorts 2, 3, and 4 received 6.0 × 1012 GC/kg. Corticosteroids were administered to mitigate vector‑induced inflammatory response. All participants experienced a treatment-emergent adverse event (TEAE) and a related TEAE. No participant experienced a dose-limiting toxicity, TEAE leading to study discontinuation, TEAE leading to death, or serious treatment-related TEAE. Mean (SD) time to hypoglycemia in minutes/gram of carbohydrate during a controlled fasting challenge was 5.0 (1.6) at baseline and 6.9 (2.7) at Week 52, a mean (SD) increase of 46% (72%). Mean total daily cornstarch intake was 284 g at baseline and 85 g at Week 52 in the 10 participants with available values at both time points, a mean (SD) total daily cornstarch intake reduction of 68% (20%); p < 0.001. DTX401 showed a favorable safety and efficacy profile at Week 52. Participants in all cohorts showed significant cornstarch need reductions from baseline to Week 52.

Sick children often have a decreased appetite and experience vomiting and diarrhea; however, hypoglycemia (plasma glucose concentration ≤50 mg/dL or 2.8 mmol/L) is rare. Ketotic hypoglycemia (KH) is the most common cause of hypoglycemia presenting to an Emergency Department in a previously healthy child between 6 months and 6 years of age. Ketosis and hypoglycemia are now well understood to be normal physiologic responses of young children to prolonged fasting.There is now substantial evidence that the term KH describes a variety of conditions including both the lower end of the normal distribution of fasting tolerance in young children as well as numerous rare disorders that impair fasting adaptation. Recent advances in molecular genetic testing have led to the discovery of these rare disorders. Idiopathic pathological KH is a diagnosis of exclusion that describes rare children who have abnormally limited fasting tolerance, experience recurrent episodes of KH, or develop symptoms of hypoglycemia despite elevated ketone levels, and in whom an explanation cannot be found despite extensive investigation. This review provides an approach to distinguishing between physiological KH and pathological KH and includes recommendations for management.

Abstract Hepatic glycogen storage diseases (GSD) are characterized by recurrent episodes of hypoglycemia, and anemia has been recognized as a frequent complication of these disorders.This was a convenience cross-sectional study to evaluate hepcidin and IL-6 concentrations in patients with hepatic GSD and their association with anemia and other parameters of iron metabolism.Levels of hepcidin, IL-6, and markers of iron metabolism were measured in 32 patients receiving uncooked cornstarch therapy for GSD (GSD Ia= 18; Ib= 7; III= 3; IXa= 3; IXb= 1; median age 9.5 years). IL-6 concentrations were compared to those of 8 individuals heterozygous for GSD. Nine patients were anemic and five patients had hepatic adenomas. IL-6 levels were higher in patients than in heterozygotes. Eight patients had hyperferritinemia, and one had elevated transferrin saturation as well. Hepcidin correlated positively with ferritin levels. IL-6 correlated with hemoglobin, iron, transferrin, and transferrin saturation. There was no correlation between hepcidin and IL-6 levels. Patients with GSD Ib had the highest IL-6 levels.Anemia is a common finding in hepatic GSD, especially in GSD Ib, the type of GSD associated with the highest IL-6 levels. These findings suggest that inflammation is strongly associated with development of anemia in GSD Ib.

CONTEXT:Glycogen storage disease type Ia (GSDIa) is an inborn metabolic disorder characterized by impaired endogenous glucose production (EGP). Monitoring of patients with GSDIa is prioritized because of ongoing treatment developments. Stable isotope tracers may enable reliable EGP monitoring. OBJECTIVE:The aim of this study was to prospectively assess the rate of appearance of endogenous glucose into the bloodstream (Ra) in patients with GSDIa after a single oral D-[6,6-2H2]-glucose dose. METHODS:Ten adult patients with GSDIa and 10 age-, sex-, and body mass index-matched healthy volunteers (HVs) were enrolled. For each participant, 3 oral glucose tracer tests were performed: (1) preprandial/fasted, (2) postprandial, and (3) randomly fed states. Dried blood spots were collected before D-[6,6-2H2]-glucose administration and 10, 20, 30, 40, 50, 60, 75, 90, and 120 minutes thereafter. RESULTS:Glucose Ra in fasted HVs was consistent with previously reported data. The time-averaged glucose Ra was significantly higher in (1) preprandial/fasted patients with GSDIa than HV and (2) postprandial HV compared with fasted HV(P < .05). A progressive decrease in glucose Ra was observed in preprandial/fasted patients with GSDIa; the change in glucose Ra time-course was directly correlated with the change in capillary glucose (P < .05). CONCLUSION:This is the first study to quantify glucose Ra in patients with GSDIa using oral D-[6,6-2H2] glucose. The test can reliably estimate EGP under conditions in which fasting tolerance is unaffected but does not discriminate between relative contributions of EGP (eg, liver, kidney) and exogenous sources (eg, dietary cornstarch). Future application is warranted for longitudinal monitoring after novel genome based treatments in patients with GSDIa in whom nocturnal dietary management can be discontinued.

GM1-gangliosidosis (GM1) is a lysosomal storage disorder caused by mutations in the galactosidase beta 1 gene (GLB1) that leads to reduced beta-galactosidase (beta-gal) activity. This enzyme deficiency results in neuronal degeneration, developmental delay, and early death. A sensitive assay for the measurement of beta-gal enzyme activity is required for the development of disease-modifying therapies. We have optimized fluorometric assays for quantitative analysis of beta-gal activity in human cerebrospinal fluid (CSF) and serum for the development of a GLB1 gene replacement therapy. Assay analytical performance was characterized by assessing sensitivity, precision, accuracy, parallelism, specificity, and sample stability. Sensitivity of the CSF and serum beta-gal activity assays were 0.05 and 0.20 nmol/mL/3 h, respectively. Assay precision represented by inter-assay percent coefficient of variation of the human CSF and serum was <15% and <20%, respectively. The effect of pre-analytical factors on beta-gal activity was examined, and rapid processing and freezing of samples post-collection was critical to preserve enzyme activity. These assays enabled measurement of CSF and serum beta-gal activities in both healthy individuals and patients with GM1-gangliosidosis. This CSF beta-gal activity assay is the first of its kind with sufficient sensitivity to quantitatively measure beta-gal enzyme activity in CSF samples from GM1 patients.

Abstract Objectives Ketone production is a physiological phenomenon that occurs during beta-oxidation of free fatty acids. Distinguishing physiologic ketosis from pathologic over-production/underutilization of ketones is critical as part of the diagnostic evaluation of disorders of carbohydrate metabolism, but there is limited literature on normal ketone production with fasting. Our aim is to measure fasting serum beta-hydroxybutyrate (BHB) concentrations in healthy children after an overnight fast. Methods Children ≤18 years of age were prospectively recruited from elective procedures through our surgery centers. Exclusion criteria included a history of diabetes, hypopituitarism, adrenal, metabolic or inflammatory disorders, dietary restrictions, trauma, or use of medications that might affect blood glucose. Serum glucose, cortisol, and BHB were assessed after an overnight fast. Results Data from 94 participants (mean 8.3 ± 5.7 years, 54 % male, 46 % female, were analyzed. Children ≤3 years of age (19) have significantly higher mean (0.40 ± 0.06 mmol/L) and median (0.4, IQR 0.2–0.6 mmol/L) BHB concentrations compared to children >3 years of age (75) with mean (0.21 ± 0.02 mmol/L) and median BHB (0.1, IQR 0.1–0.2 mmol/L) (p<0.0001). Fasting BHB levels of >1.0 mmol/L was rare (2 %, N=2) and 74 % (N=70) of participants had BHB levels <0.3 mmol/L. Conclusions BHB concentrations are significantly higher in young children (≤3 years of age) compared to older children. Fasting BHB levels >1.0 mmol/L are rare within our population and therefore may identify a value above which there may a greater concern for pathologic ketotic hypoglycemia. It is imperative to establish the normative range in children to differentiate physiological from pathological ketotic hypoglycemia.

Guanidinoacetate methyltransferase deficiency is an autosomal recessively inherited disorder of creatine biosynthesis. We report a new patient with guanidinoacetate methyltransferase deficiency and her >3-year treatment outcome.This is a 6-year-old girl who was diagnosed with guanidinoacetate methyltransferase deficiency at the age of 28 months. She presented with moderate global developmental delay, one afebrile seizure, and hypotonia between 6 and 18 months of life. She was treated with creatine and ornithine supplementation and a strict arginine-restricted diet for 42 months.Mutation analysis (compound heterozygous mutations, a known c.327G>A and a novel c.58dupT [p.Trp20LeufsX65]) and enzyme studies in primary fibroblasts confirmed the diagnosis. After 33 months of therapy, her cerebrospinal fluid guanidinoacetate level decreased from 47 to 5.3 times the normal level. Brain creatine by proton magnetic resonance spectroscopy increased by >75% but did not normalize in the basal ganglia and white matter after 3 years of therapy. Additional treatment with sodium benzoate for 17 months did not further improve plasma guanidinoacetate levels, which questions the relevance of this therapy.Treatment did not improve moderate intellectual disability or normalize guanidinoacetate accumulation in the central nervous system.

Glycogen storage disease type Ia (GSDIa) is an inherited metabolic disorder caused by mutations in the enzyme glucose-6-phosphatase-α (G6Pase-α). Affected individuals develop renal and liver complications, including the development of hepatocellular adenoma/carcinoma and kidney failure. The purpose of this study was to identify potential biomarkers of the evolution of the disease in GSDIa patients. To this end, we analyzed the expression of exosomal microRNAs (Exo-miRs) in the plasma exosomes of 45 patients aged 6 to 63 years. Plasma from age-matched normal individuals were used as controls. We found that the altered expression of several Exo-miRs correlates with the pathologic state of the patients and might help to monitor the progression of the disease and the development of late GSDIa-associated complications.