Zebra of the Week: Glycogen storage disease type Ia

Glycogen storage disease type Ia (GSDIa) is a rare inherited metabolic disorder caused by pathogenic variants in the G6PC gene, which encodes the enzyme glucose-6-phosphatase. This enzyme catalyzes the final step of both glycogenolysis and gluconeogenesis, allowing the liver to release glucose into the bloodstream during fasting. When the enzyme is deficient, glycogen and fat accumulate primarily in the liver and kidneys, while the body's ability to maintain normal glucose levels is impaired.

Although severe hypoglycemia may occur in the newborn period, many patients first present between 3 and 4 months of age. The classic clinical picture includes hepatomegaly, recurrent fasting hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, and faltering growth. Some infants experience hypoglycemic seizures, while others develop xanthomas, diarrhea, or bleeding manifestations related to impaired platelet function, with recurrent epistaxis serving as a potential diagnostic clue.

As patients age, the disease burden often extends beyond glucose regulation. Characteristic findings may include short stature, delayed puberty, nephromegaly, declining kidney function, focal segmental glomerulosclerosis, gout, and the classic "doll-like" facial appearance described in many affected children. Chronic metabolic abnormalities can contribute to progressive hepatic and renal complications if not adequately managed.

For decades, treatment has centered on meticulous nutritional therapy aimed at preventing fasting-induced hypoglycemia. Patients typically require frequent meals and scheduled doses of uncooked cornstarch throughout the day and night to provide a continuous source of glucose. This regimen can be highly burdensome for patients and caregivers, requiring constant vigilance to avoid severe hypoglycemia and its potentially life-threatening consequences.

FDA approval of Genglycos

In August 2026, FDA granted accelerated approval to Genglycos (pariglasgene brecaparvovec-opnr), the first therapy designed to address the underlying genetic defect in GSDIa and the first FDA-approved gene therapy for the disorder. The treatment is indicated for adults and children aged 8 years and older with GSDIa to reduce daily cornstarch requirements as an adjunct to nutritional management.

Approval was based on the phase 3 GlucoGene study, which demonstrated a significant reduction in cornstarch requirements among treated patients compared with placebo. By restoring expression of the missing glucose-6-phosphatase enzyme, the therapy aims to improve the body's ability to generate glucose during fasting and periods of metabolic stress. For patients and families who have long relied on round-the-clock dietary intervention, the approval represents a landmark advance in the management of this ultra-rare disease.

Sources:

NIH GARD. Glycogen Storage Disease Due to Glucose-6-Phosphatase Deficiency Type IA

Ultragenyx Pharmaceutical Inc. (2026 Aug 19) Ultragenyx Announces U.S. FDA Approval of GENGLYCOS™ Gene Therapy, the First-Ever FDA-Approved Treatment Designed to Treat the Underlying Cause of Glycogen Storage Disease Type Ia (GSDIa)