Type I Glycogen Storage Disease

Synonyms:
von Gierkes disease, Type I Glycogenosis, Hepatorenal Glycogenosis

Type I Glycogen Storage Disease accounts for about 25% of all cases of GSD diagnosed in the USA and in Europe and has an estimated incidence of about 1 in 100,000 live births.

In Type I Glycogen Storage Disease (GSD I), the most frequent first symptoms include an enlarged liver and low blood sugar (hypoglycemia). After we eat, excess glucose is stored as glycogen mostly in the liver to be used later when we are fasting (not eating for 3-4 hours) to maintain normal glucose levels in our body. In GSD I the metabolic problem is centered in the liver because the enzyme needed to release glucose from glycogen is missing.

There are two different subtypes of Type I Glycogen Storage Disease - called type Ia and type Ib. GSD Ia is caused by a deficiency of the glucose-6-phosphatase (G6Pase) enzyme in liver, kidney and other organs of the body. GSD Ib is caused by a deficiency in glucose-6-phosphate translocase, or transporter (G6PT) enzyme, that helps in transporting G-6-Pase enzyme from one point to another. These two enzymes work together to help the body break down the storage form of sugar (glycogen) in to free glucose (sugar) for use when we are not eating. When a person does not have enough of either of these two enzymes, they usually have many of the same signs and symptoms early on in life.

Individuals with Type I Glycogen Storage Disease are unable to release glucose from glycogen mainly in the liver (see What is a Glycogen Storage Disease?). They cannot maintain their blood glucose (sugar) levels and within a few hours after eating they will develop hypoglycemia (low blood sugar). The low levels of glucose in the blood of these individuals often result in chronic hunger, fatigue, and irritability. These symptoms are especially noticeable in infants. Symptoms of hypoglycemia often appear when the time between feedings increases and the infant sleeps through the night. In infants, children and adults, symptoms may also be present when an illness prevents normal feeding routine and time. If the blood sugar is very low, some individuals may have seizures (hypoglycemic seizures).

Since people with Type I GSD are able to store glucose as glycogen but not able to release it normally, with time the stores of glycogen build up in the liver causing the liver to swell (hepatomegaly). This is much like being able to place groceries from the store into your kitchen cabinets, but not being able to get the food out of the cabinets when needed. Levels of hormones, lactic acid, triglycerides, lipids (fats), uric acid and other by-products of metabolism increase in the blood as the body tries to raise blood sugar. Fats get stored in the liver along with the glycogen, which leads to the enlargement of the liver. The liver does its many other functions normally, and there is not usually any evidence of liver failure. The kidneys are also enlarged due to increased glycogen storage.

The continued presence of low blood sugar can eventually lead to delayed growth and development as well as abnormal levels of some metabolites (substances) in the blood and urine. High blood pressure has also been seen in a number of individuals and when this occurs, appropriate treatment is needed.

In addition to the problems described above, individuals with Glycogen Storage Disease Type Ib can develop frequent bacterial and fungal infections, due to abnormal functioning of the white blood cells called neurophils. These are the fighter cells of the body. Therefore, people with GSD Ib can have low levels of neutrophils in their blood (a finding called neutropenia). Many people with GSD Ib use a medicine called GCSF to increase the number of neutrophils in the body. People with Glycogen Storage Disease Type Ib may also develop chronic pancreatitis, chronic inflammatory bowel disease, and Crohn's disease.

The diagnosis of Type I GSD will always include blood studies such as blood glucose, cholesterol, triglycerides, lactate, and uric acid, measurements of growth, and ultrasound or other imaging studies to measure the size of the liver and kidneys. By looking for changes in the genes associated with GSD I, genetic (DNA) testing can be used to diagnose the majority of individuals with GSD Type Ia and Ib. Sometimes liver biopsy analysis will be needed to examine the enzyme levels of someone suspected to have Type I Glycogen Storage Disease, especially in situations when DNA testing is negative and the clinical suspicion of GSD I is high.

The treatments of Type I Glycogen Storage Disease are aimed at correcting the metabolic changes in the body and promoting growth and development. Current treatments consist of providing small, frequent feedings during the day. Most agree that fructose and galactose should be restricted, but the degree of restriction is still debated. The restriction of these sugars translates to no fruit, juice, table sugar, cake, pie, syrup, jelly, honey, and candy; and limited amounts of dairy foods including milk, yogurt and cheese. The majority of medical centers recommend the use of uncooked cornstarch, mixed in water, soy formula or soy milk (sucrose, fructose and lactose free). Cornstarch should not be mixed in drinks that contain high amounts of ascorbic or citric acid and the cornstarch drink should not be heated as this may alter its structure rendering it less effective. Cornstarch is digested slowly so it provides a steady release of glucose in between feedings. In some cases, an overnight tube feeding is required to provide a continuous delivery of glucose. Formulas should be sucrose, fructose and lactose free. The rate of the tube feeding is based on the liver’s normal glucose delivery rate and the age and weight of the child. Due to the many restrictions for the GSD I diet, it is necessary to supplement the diet with a multivitamin. Additional calcium supplementation may also be required. Because the diet for Type I Glycogen Storage Disease is complex, the ideal treatment team should include a dietitian and a physician familiar with the long-term care and maintenance related to GSD I.

Patients with Type I Glycogen Storage Disease may develop benign tumors in the liver called hepatic adenomas. Adenomas are usually first noted around the time of puberty. They typically do not cause symptoms and are identified by routine imaging studies of the liver. In rare instances these can develop into liver cancer.

Renal (kidney) disease is another complication in GSD I patients, and most patients with type I glycogen storage disease older than age 20 yr have proteinuria (proteins excreted in urine). Many also have hypertension (high blood pressure), and kidney stones, among other changes in kidney functions. More severe kidney injury may occur with large amounts of protein in the urine, high blood pressure, and decreased ability of the kidneys to filter waste products due to damage to the filtering units of the kidney (glomeruli). In some patients with the advancement of renal/kidney disease, kidney failure can happen which can require dialysis and eventually kidney transplantation.

Other complications can include pulmonary hypertension, radiographic (X-ray) evidence of osteopenia (weak bones), and fractures.

In the past, many patients with Type I Glycogen Storage Disease did not survive infancy and childhood. Today, maintenance of normal or near normal blood sugar/glucose levels with effective therapy improves the metabolic abnormalities and reverses the severe growth failure characteristic of the untreated patients. It is still unclear whether long-term complications can all be prevented by dietary therapy. However, with earlier diagnosis, appropriate diet, and better metabolic control, many individuals with GSD I are doing very well and many adults are living longer and healthier lives.

Guidelines

“Diagnosis and Management of Glycogen Storage Disease Type I: A Practice Guideline of the American College of Medical Genetics and Genomics”, created by the AGSD and the American College of Medical Genetics and Genomics