GSD I is caused by a deficiency in the glucose-6-phosphatase enzyme system, which normally converts stored glucose-6-phosphate back into free glucose during fasting. When this final step of glycogenolysis and gluconeogenesis fails, glucose-6-phosphate accumulates in liver and kidney cells and the body cannot maintain normal blood sugar between meals. Two molecular forms exist: GSD type Ia, caused by deficient catalytic activity of the enzyme itself, and GSD type Ib, caused by a defect in the transporter that moves glucose-6-phosphate across the endoplasmic reticulum membrane. GSD I is inherited in an autosomal recessive manner, meaning a child must inherit a disease-causing variant from each parent.

GSD I is suspected in an infant or young child with low fasting blood sugar, an enlarged liver, and slowed growth. Suggestive laboratory findings include fasting hypoglycemia, elevated blood lactate, high uric acid, high triglycerides, and elevated liver enzymes. Diagnosis is confirmed in most patients today by molecular genetic testing that identifies disease-causing variants on both copies of the responsible gene; this approach distinguishes GSD type Ia from GSD type Ib. When genetic testing is not informative, enzyme analysis on a liver biopsy specimen can be used. Glucagon or epinephrine challenge testing is no longer recommended. Care should be coordinated with a metabolic specialist familiar with GSD I.

There is no curative therapy for GSD I; treatment focuses on preventing low blood sugar and avoiding long-term complications. The cornerstone is medical nutrition therapy directed by a metabolic team. Frequent daytime feedings rich in complex carbohydrates, scheduled uncooked cornstarch doses (an extended-release waxy maize form is also available), and overnight continuous tube feedings in young children help maintain normal blood glucose. Sucrose, fructose, galactose, lactate-containing fluids, glucagon, and metformin should be avoided. Allopurinol may be used for high uric acid; ACE inhibitors are considered when kidney involvement appears. In GSD Ib, granulocyte colony-stimulating factor (G-CSF) is used for neutropenia. Investigational genetic-medicine programs, including BEAM-301 and mRNA-3745, are currently in early-phase trials.

With careful dietary management, most people with GSD I now reach adulthood, and growth, puberty, and bone density are substantially better than they were a generation ago. Strict adherence to feeding schedules, cornstarch regimens, and continuous glucose monitoring is essential and lifelong. Long-term complications can still develop and require ongoing surveillance: hepatic adenomas may form in the second decade of life and carry a small but real risk of progression to hepatocellular carcinoma; chronic kidney disease may advance toward end-stage kidney disease in some adults; and pulmonary hypertension, gout, hypertension, and osteoporosis are recognised. GSD Ib carries the additional burden of recurrent infections related to neutropenia. Outcomes vary by subtype, by adherence, and by access to specialist metabolic care.

Several active studies are advancing GSD I care. A long-term GSD Ia disease monitoring program (NCT06636383, Ultragenyx) is recruiting patients to characterise outcomes over time. Two early-phase genetic-medicine trials are in progress: a phase 1 study of mRNA-3745 (ModernaTX), which delivers messenger RNA encoding the deficient enzyme, and a phase 1/2 study of BEAM-301 (Beam Therapeutics), an investigational base-editing approach for GSD Ia. Additional trials are evaluating home lactate meters, continuous glucose monitor accuracy, and dietary strategies for metabolic control. Patients can also engage with the Children's Fund for Glycogen Storage Disease Research, a long-standing patient organisation. As with all early-phase work, eligibility, risk, and benefit should be discussed with a metabolic specialist.