GSD1 affects roughly 1:100,000 people, with an average of 80% of GSD1 patients exhibiting type 1a. Type 1a has a higher incidence within those of Ashkenazi Jewish descent.

Genetic basis

Chromosomes are bundles of genetic material, or DNA, that children inherit from their parents. Typically, each person has 23 pairs of chromosomes, with one of each pair inherited from the mother (maternal copy) and the other inherited from the father (paternal copy). Each chromosome has a long (q) and short (p) arm, along which different genes and gene-regulating elements are located. Genes encode proteins, which execute functions within the cell.

GSD1 is a glycogen storage disorder caused by autosomal recessive mutations in the G6PC gene on chromosome 17 (type 1a) or the SLC37A4 gene, which is located on chromosome 11 (type 1b). When a condition is inherited in an autosomal recessive manner, individuals with two defective copies of the responsible gene are affected, while those with only one defective copy are asymptomatic carriers. Carriers do not exhibit signs and symptoms of the disease but can pass on the disease-causing mutation to their children. If both parents are carriers, the chance of having an affected child is 25% with each pregnancy, while the chance of having a child who is a carrier themself is 50%.

Cellular and molecular basis

Glycogen is composed of branched glucose (simple sugar) subunits and is stored mainly in the liver and skeletal muscle. In response to fasting (withholding food) or exercise, it is normally broken down to release glucose into the blood or muscles, respectively. Glucose can be further broken down to release adenosine triphosphate (ATP), which is an energy-carrying molecule.

An intermediate in the breakdown of glycogen into glucose (a process called glycogenolysis) is glucose-6-phosphate (G6P), which has a similar structure to glucose but with a negatively charged chemical group attached. An enzyme complex called G6Pase maintains glucose homeostasis by breaking down G6P into glucose. This complex is composed of alpha-glucose-6-phosphatase (G6Pase-alpha) enzyme, encoded by the G6PC gene, and glucose-6-phosphate translocase (G6PT) enzyme (or GDE), encoded by the SCL37A4 gene.

GDE moves G6P into the endoplasmic reticulum (ER), a subcompartment within the cell, for removal of its negatively charged phosphate group by G6Pase-alpha. When an individual inherits one mutated copy of either the G6Pase-alpha or G6PT enzyme from their mother and another mutated copy of the same enzyme from their father, G6P cannot be broken down. Rather, it is converted back into glycogen and fat to be stored within cells. Patients experience hypoglycemia, or low blood sugar, and fat accumulation that can lead to kidney and liver enlargement (hepatomegaly and nephromegaly, respectively), ultimately causing those organs to fail. 

A similar phenomenon happens when building glucose from non-carbohydrate substrates, or building blocks (as opposed to creating it from the breakdown of glycogen). This process, called gluconeogenesis, also relies on G6P as an intermediate and utilizes GDE and G6Pase-alpha to generate glucose.

GSD1a

Patients typically show signs and symptoms by 6 months of age.

• Fasting hypoglycemia (low blood sugar) sometimes causing seizures

• Lactic acidemia (increased lactic acid in the blood)

• Hyperlipidemia (increased fats in the blood)

• Anemia

• Hepatomegaly (enlarged liver) causing distended abdomen

• Nephromegaly (enlarged kidneys)

• Short stature

• Impaired growth and delayed puberty

• Puffy cheeks

• Kidney impairment: nephropathy, chronic kidney disease, polycystic kidney and renal cancer, hyperuricemia (increased uric acid in the blood), kidney stones, renal tubular acidosis, etc.

• Osteoporosis (bone thinning)

• Gout (joint inflammation and pain resulting from uric acid crystals)

• Polycystic ovarian syndrome (abnormal development of female ovaries)

• Hepatic adenomas (benign) or hepatocellular carcinoma (malignant or cancerous)

• Diarrhea

• Xanthomas (cholesterol deposits under the skin)

• Pulmonary hypertension (high blood pressure to lungs)

• Pancreatitis (inflammation of the pancreas)

• Impaired platelet function leading to easy bruising and epistaxis (nosebleeds)

GSD1b

Patients generally exhibit the above symptoms plus the following:

• Neutropenia and impaired neutrophil function

• Inflammatory bowel disease (IBD) (inflammation of intestinal walls)

• Intestinal ulcers (sores)

• Thyroid autoimmunity or hypothyroidism

• Oral issues: mouth ulcers (sores), gingivitis (inflammation of the gums), abnormal tooth development, cavities, etc.

Though prenatal genetic testing is possible, patients are usually diagnosed postnatally before 1 year of age as clinical signs develop. When babies start sleeping through the night and feeding less regularly, they experience low blood sugar which may cause fatigue, irritability, and seizures. Diagnosis involves enzyme activity assays showing hypoglycemia, lactic acidosis (high levels of lactate), hypertriglyceridemia and hyperlipidemia (high levels of fats in the blood), and hyperuricemia (high levels of uric acid in the blood). Ultrasound may reveal increases in liver and/or kidney size, and molecular genetic testing will show mutation of G6PC or SLC37A4.

Molecular genetic testing - sequence analysis of G6PC and SLC37A4 genes

Biopsy of liver or kidney - removal of a small sample of tissue for analysis in the laboratory

Abdominal ultrasound - medical imaging using soundwaves to detect liver and kidney size

Blood tests - assay glucose, lactic acid, triglycerides, uric acid, etc.

Prenatal genetic testing on chorionic villus, a part of the placenta

Treatment for GSD1 predominantly involves maintaining normoglycemia, or level blood sugar. This often involves frequent feeding, including use of a nasogastric or gastrostomy tube overnight. A nasogastric tube is a removable feeding tube that runs from the nose to the stomach, while a gastrostomy tube, also known as a G-tube, can deliver food directly to the stomach. Modified cornstarch, which is a complex carbohydrate that is slow to digest and release sugars, may also be used to prevent hypoglycemia overnight.

Some patients choose to avoid fruit or milk sugar (supplement with soy milk or formula) or restrict their intake to simple sugars, including fructose, sucrose, and galactose to avoid lactic acidosis. To control hyperuricemia, a doctor may recommend avoiding a high-protein diet or taking the drug allopurinol. Allopurinol is the most common treatment for gout-like episodes and arthritis. There are also nutritional approaches for balancing hyperlipidemia, including supplementing with fibrates, statins, niacin, fish oil, or medium-chain triglyceride milk. The degree to which these supplements and/or restrictions are necessary is debated, and a doctor must be consulted for each individual case.

In severe disease with renal or hepatic failure, kidney or liver transplantation may be necessary. It may also be necessary to undergo surgery for removal of hepatic adenomas.

Patients with GSD1b-related neutropenia and IBD may be candidates for granulocyte colony-stimulating (G-CSF), a growth factor that helps white blood cells decrease severity of infection.

Ongoing drug therapy trials for both GSD1a and b can be found by searching ClinicalTrials.gov.

Early intervention gives the best chance for reducing the risk of severe complications. With successful treatment, many patients are able to live into adulthood and some even choose to have children. However, severe hypoglycemic events could lead to lasting cognitive impairment or premature death. Kidney and/or liver involvement may also shorten lifespan.

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