Glycogen Storage Disease Type I

Etiology

Each disease subtype has the following genetic etiologies:

1. GSD Ia results from mutations in the G6PC gene on chromosome 17q21 that encodes for G6Pase.[1][3][5] Without G6Pase activity, G6P cannot be converted into free glucose, leading to glycogen and fat accumulation in hepatocytes and renal cells.
2. GSD Ib results from mutations in the SLC37A4 gene on chromosome 11q23.3 that encodes for G6PT.[1][3] The defective transport process in GSD Ib leads not only to glycogen accumulation but also to altered neutrophil function, resulting in chronic neutropenia and increased infection susceptibility.

The defect in either enzyme impairs the final step of glycogenolysis and gluconeogenesis, preventing the release of glucose from stored glycogen, triggering compensatory metabolic pathways, eg, lipolysis and proteolysis. The downstream effects include elevated free fatty acids, hyperlipidemia, hyperuricemia, and severe lactic acidosis due to the rerouting of excess G6P into glycolysis.[1][3][4][6]

Epidemiology

The incidence of GSD I in the overall population is 1 in 100,000 live births, with GSD Ia being more common (80%) than GSD 1b (20%). The Ashkenazi Jewish population has a 5 times greater prevalence compared to the rest of the population.[1][6][7] Other populations at higher risk for being carriers have been found in Mexican-Hispanics and people of Japanese decent.[8]

Carrier screening in these populations has enabled early diagnosis and proactive management, significantly improving quality of life and long-term prognosis.

Pathophysiology

The enzyme G6Pase is primarily expressed in the liver, kidney, and intestine, localized to the endoplasmic reticulum's lumen. The deficiency of G6Pase (in GSD 1a) or G6PT (in GSD 1b) leads to an accumulation of glycogen in tissues, including the liver, kidneys, and intestines. This accumulation disrupts normal cellular function and leads to hepatomegaly, nephromegaly, and metabolic derangements, eg, lactic acidosis and hyperuricemia.[1][5]

G6Pase has its active site on the luminal side of the endoplasmic reticulum. Glucose-6-phosphate translocase is responsible for translocating G6P from the cytoplasm into the endoplasmic reticulum lumen. The complex of G6Pase and G6PT catalyzes the final step of both glycogenolysis and gluconeogenesis for glucose production. Deficiency of either causes an accumulation of glycogen and fat in the liver, kidney, and intestinal mucosa.[1][3][5]

Histopathology

Although genetic testing has largely replaced the need for liver biopsy, liver histology in GSD I shows hepatocytes filled with periodic acid-Schiff (PAS)-positive and diastase-sensitive glycogen.[9] In some cases, liver biopsy may be performed in patients with unexplained hepatomegaly or when genetic testing is inconclusive.[6]

History and Physical

Some patients with GSD I may present with hypoglycemia and lactic acidosis in the neonatal period. However, they are more likely to present at 3 to 6 months of age with hepatomegaly or signs and symptoms of fasting hypoglycemia, including seizures. Thus, symptoms of hypoglycemia appear with increased intervals between feeds. Sometimes, the infant may remain asymptomatic and would present with an enlarged liver and protruding abdomen. Those left untreated would develop an appearance similar to that seen in Cushing’s syndrome, eg, short stature, round face (“doll facies”), and full cheeks.[1][3][10]

Recurrent hypoglycemia may lead to developmental delays and cognitive impairment. They have a failure to thrive along with delayed motor development. Cerebral damage resulting from recurrent hypoglycemic episodes may lead to abnormal cognitive development. In addition, patients with GSD Ib present with recurrent bacterial infections due to neutropenia.[1][3][4]

Evaluation

The diagnosis of GSD I involves a combination of clinical assessment, biochemical tests, and genetic confirmation.

Laboratory Studies

Laboratory findings typically reveal hypoglycemia, lactic acidosis, hyperuricemia, hypercholesterolemia, and hypertriglyceridemia. In GSD Ib, neutropenia of varying severity is also present.[1][3] A glucagon stimulation test should be avoided in suspected cases, as it can trigger acute acidosis and metabolic decompensation by significantly raising blood lactate levels without a corresponding increase in blood glucose.[1][3]

Genetic Studies

Genetic testing is the preferred diagnostic approach, eliminating the need for invasive liver biopsy. Full gene sequencing of G6PC (GSD Ia) and SLC37A4 (GSD Ib) detects nearly all mutations, though certain variants may be missed. In such cases, additional techniques like quantitative polymerase chain reaction (PCR), long-range PCR, multiplex ligation-dependent probe amplification, targeted array, or comparative genomic hybridization analysis can be used.[1][11]

Mutation analysis is the first-line test for confirming GSD I. If neutropenia is absent, complete G6PC sequencing is performed. In cases where liver biopsy tissue is available, G6Pase enzyme activity may also be analyzed to support the diagnosis.[1][3]

Treatment / Management

The primary management of GSD I comprises preventing acute metabolic crises, minimizing complications, ensuring normal psychological development, and improving quality of life and life expectancy.[1][4][5](A1)

Dietary Management

Management relies on a strict dietary regimen that includes:

• Frequent, high-carbohydrate meals: Regular intake of complex carbohydrates prevents hypoglycemia.[4]
• Uncooked cornstarch: A slow-releasing carbohydrate that helps maintain glucose levels during fasting, particularly overnight. Dosage is individualized and adjusted over time.[1][4]
• High-protein, low-fat diet: Supports gluconeogenesis while limiting fat intake to manage hyperlipidemia.[1]][7]
(A1)

Blood glucose monitoring should be ongoing as nutritional needs change with growth. Fasting must be avoided, and small, frequent carbohydrate-rich meals with fiber are recommended, making up 60% to 70% of total calories.[1] Due to enzyme deficiencies, fructose and galactose are not metabolized to glucose-6-phosphate, necessitating a diet low in fructose and sucrose, with galactose and lactose intake limited to 1 serving per day.[7](A1)

Infants require soy-based, sugar-free formula every 2 to 3 hours to prevent hypoglycemia. As sleep duration increases beyond 3 to 4 hours, overnight hypoglycemia risk rises. Parents should be trained to use a nasogastric tube, or a G-tube may be placed for easier administration, especially during illness or feeding refusal.[6] Cornstarch remains a cornerstone treatment, providing steady glucose release. Recommended doses are 1.6 g/kg every 3 to 4 hours for young children and 1.7 to 2.5 g/kg for older children and adults. Patients should wear a medical alert bracelet, and hypoglycemia should be treated promptly with fast-acting glucose sources, including cornstarch, glucose polymers, or diabetic glucose tablets.[12]

Management of Associated Complications

In GSD Ib, neutropenia increases the risk of G-tube site infections, so granulocyte colony-stimulating factor (G-CSF) is administered before placement, with monthly CBC and spleen monitoring required.[12] Evidence now supports empagliflozin (0.3–0.4 mg/kg/d, single morning dose) for neutropenia and neutrophil dysfunction, initiated in an outpatient setting with weight-based adjustments. It should be paused during dehydration risk or major surgeries, and discontinuation of G-CSF should be attempted. If available, 1,5-AG should be monitored. Due to empagliflozin’s glycosuric effect, patients previously intolerant to starch should attempt reintroduction.[13][14][15](B3)

Safety measures, including bed-wetting detectors, infusion pump alarms, safety adapters, connectors, and secure taping, help prevent pump failures and tubing issues. Children on lactose- and sucrose-restricted diets should be assessed for nutritional deficiencies and supplemented with micronutrients.[12] Persistent lactic acidosis is treated with oral citrate or bicarbonate to alkalinize urine and reduce the risk of urolithiasis. Allopurinol helps prevent gout by lowering uric acid levels, while colchicine is preferred during acute attacks [1]. Hyperlipidemia responds partially to statins, niacin, fibrates, and fish oil, though liver transplantation has led to resolution in some cases.[9][16](A1)

Monitoring Recommendations

Routine monitoring includes blood pressure checks at every visit from infancy, with serum creatinine measured every 3 to 6 months. Persistent microalbuminuria warrants ACE inhibitor therapy, while echocardiography every 3 years is advised for pulmonary hypertension screening.[10][12] Hepatomegaly is universal due to fat and glycogen deposition, with common liver lesions including fatty infiltration, focal nodular hyperplasia, peliosis hepatis, hepatocellular adenoma (HCA), and hepatocellular carcinoma (HCC). Liver function tests should be performed every 6 to 12 months, and liver transplantation is considered for progressive, nonresponsive lesions. Females with GSD I should avoid combined oral contraceptives due to the HCA risk.[1][3][12](A1)

The European collaborative guidelines [10] recommend the following biomedical targets for GSD I management:(A1)

• Preprandial blood glucose >3.5 to 4.0 mmol/L (63–72 mg/dL)
• Urine lactate/creatinine ratio <0.06 mmol/mmol
• Serum uric acid in the high-normal range for age
• Venous blood base excess >-5 mmol/L and bicarbonate >20 mmol/L (20 meq/L)
• Serum triglycerides <6 mmol/L (531 mg/dL)
• Normal fecal alpha-1 antitrypsin for GSD Ib
• Body mass index between 0.0 and +2.0 standard deviations

Differential Diagnosis

Differentiating GSD I from other diseases that present with hepatomegaly or hypoglycemia is essential, including:

• GSD 0 (glycogen synthase deficiency)
• GSD III (glycogen debranching enzyme deficiency)
• GSD IV (branching enzyme deficiency)
• GSD VI (hepatic phosphorylase deficiency)
• GSD IX (hepatic form of phosphorylase kinase deficiency)
• GSD XI (Fanconi-Bickel syndrome due to glucose transporter protein 2 deficiency) [1][3][12][17]
• Disorders of Gluconeogenesis (Fructose-1,6-bisphosphatase deficiency)
• Primary liver disease (Hepatitis)
• Niemann-Pick B disease [18]
• Gaucher disease [18]
• Hereditary fructose intolerance

Pertinent Studies and Ongoing Trials

Dietary therapy remains the first-line treatment for GSD I. However, long-term complications such as hepatocellular adenoma (HCA), hepatocellular carcinoma (HCC), and renal failure highlight the need for alternative therapeutic approaches. Gene therapy in animal models has shown promising results, paving the way for future human trials.[5]

Gene therapy offers the potential to correct the underlying genetic defect in GSD I rather than just managing symptoms. Current research focuses on delivering functional copies of G6PC and SLC37A4 genes to liver cells to restore normal glucose metabolism and prevent glycogen accumulation. This represents a significant shift in the approach to metabolic disease treatment, with gene therapy at the forefront of potentially curative interventions.[19]

Ongoing clinical trials are evaluating the safety and efficacy of gene therapy in GSD I patients, while additional experimental approaches, such as mRNA therapy and CRISPR-Cas9 gene editing, are also being explored. These novel therapies remain investigational but hold promise for future treatment strategies.[19][20]

Dietary therapy maintains the patient's blood glucose levels and reduces the early symptoms. However, to avoid long-term complications such as HCA, HCC, and renal failure, gene therapies in GSD I mice models showed promise. In early 2018, the FDA approved the first gene therapy clinical trial at Connecticut Children’s Medical Center and UConn Health.[GeneTherapyTrial]

Prognosis

The prognosis for GSD I patients has dramatically improved with enhanced metabolic management and early diagnosis. With optimal treatment, many patients reach adulthood and lead relatively normal lives. However, they continue to face risks of liver complications, including hepatocellular adenomas and HCC, which necessitate regular imaging, such as ultrasound or MRI, for early detection [3], as well as renal complications and cardiovascular issues later in life. Liver transplantation may be considered for patients with severe liver involvement or complications that do not respond to conventional management.[12]

Complications

With early diagnosis and diligent management, the life expectancy of patients with GSD I has significantly improved. Long-term complications of untreated glycogen storage disease type I (GSD I) affect multiple organ systems, including:

• Growth and development: Poor growth and short stature are common but can improve with strict dietary management. Delayed puberty can be normalized with metabolic control.[11]
• Bone health: Osteoporosis and fractures occur due to low vitamin D and calcium intake, with metabolic control improving bone mineral density.[11] Therefore, routine monitoring of vitamin D levels, along with dual-energy x-ray absorptiometry (DXA) scans, are recommended to assess bone density and determine the need for vitamin D supplementation.[12]
• Renal complications: Proteinuria, hypertension, nephrocalcinosis, and kidney dysfunction can progress to end-stage kidney disease, requiring transplantation. Poorly controlled blood lactate, serum lipids, and uric acid levels may further increase the risk of nephropathy. Early metabolic control and angiotensin-converting enzyme (ACE) inhibitors help prevent deterioration.[11] Annual kidney ultrasounds are recommended starting in the second decade of life.[12]
• Metabolic and cardiovascular risks: Hyperuricemia can lead to gout, while systemic hypertension often appears later in life, particularly with kidney disease progression. Pulmonary hypertension may occur, especially in those with coexisting conditions. Cardiovascular disease risk remains controversial, but poor metabolic control increases the likelihood of premature atherosclerosis.[11]
• Liver: Hepatic adenomas, with a risk of malignant transformation into hepatocellular carcinoma, are common.[11] Diagnosis is often challenging due to the presence of multiple adenomas, making biopsy difficult, as well as the frequent absence of elevated tumor markers such as alpha-fetoprotein and carcinoembryonic antigen.[10] To facilitate early detection of hepatic adenomas, liver ultrasound is recommended every 12 to 24 months until age 16, followed by computed tomography or magnetic resonance imaging (MRI) every 6 to 12 months thereafter. If an adenoma is identified, follow-up imaging with ultrasound or MRI should be performed every 3 to 6 months. Given the increased risk of hepatic adenomas, female patients with GSD I should avoid taking combined oral contraceptives.[12]
• Pancreatic issues: Pancreatitis can develop due to severe hypertriglyceridemia.[11] 
• Neurological and cognitive effects: Brain MRI abnormalities, cognitive impairment, and increased risk of cerebral arteriopathy have been reported, often correlating with poor metabolic control.[11] 
• Hematologic disorders: Anemia is common due to dietary restrictions, chronic illness, and kidney disease. Bleeding diathesis arises from platelet dysfunction and von Willebrand factor abnormalities.[11]
• Immune dysfunction: GSD Ib is linked to neutropenia, recurrent infections, and inflammatory bowel disease. Recent evidence suggests empagliflozin may improve neutrophil function.[11]
• Reproductive and endocrine effects: Polycystic ovaries, irregular menstrual cycles, and increased thyroid autoimmunity are noted, particularly in GSD Ib.[11]