What is Glycogen Storage Disease Type I (Von Gierke disease)?
Glycogen storage disease type I (GSD I), also known as Von Gierke disease, is a condition someone can inherit. It happens when certain enzymes, that help to break down a type of sugar in the body called glycogen, are not working properly. This disease was first identified by Von Gierke in 1929 who found high levels of glycogen in the liver and kidneys during autopsies on two children. There are two main types of GSD I, known as GSD Ia and GSD Ib.
In GSD Ia, the body lacks an enzyme called glucose-6-phosphatase (G6Pase) which contributes to breaking down glycogen into glucose. This leads to low blood sugar, also known as hypoglycemia, and a buildup of lactic acid in the body, referred to as lactic acidosis. On the other hand, patients with GSD 1b have a normal G6Pase enzyme function, but they lack another enzyme known as the glucose-6-phosphate translocase (G6PT).
People with GSD I may start showing signs of low blood sugar and metabolic acidosis, typically around 3 to 4 months of age. If the disease is suspected, genetic testing is the best way to confirm the diagnosis. Dietary treatments can help control the blood sugar levels and increase the life expectancy of these patients. However, to prevent serious long-term complications like liver adenomas (benign tumors) and kidney failure, researchers are using animal models of GSD I to study the disease more closely and develop new treatments, such as gene therapy.
What Causes Glycogen Storage Disease Type I (Von Gierke disease)?
GSD Ia is a medical condition resulting from changes, known as mutations, in a gene called G6PC. This gene is located on chromosome 17q21 and it is responsible for creating the G6Pase-a catalytic subunit, a component of the body’s biological functions.
On the other hand, GSD Ib is due to mutations in a gene called SLC37A4. This gene is found on chromosome 11q23.3. Genes are the basic building blocks of our body’s functions and changes in these genes can lead to various medical conditions.
Risk Factors and Frequency for Glycogen Storage Disease Type I (Von Gierke disease)
Glycogen storage disease type I (GSD I) is a condition that occurs in about 1 out of every 100,000 people. This disease has two subtypes, GSD Ia and Ib, which account for 80% and 20% of the cases respectively. Interestingly, this disease is five times more common in the Ashkenazi Jewish community compared to the rest of the population.
Signs and Symptoms of Glycogen Storage Disease Type I (Von Gierke disease)
Glycogen storage disease type I (GSD I) is a condition that might show itself right after birth with low blood sugar levels and higher levels of lactic acid in the body. Typically though, it’s more common for symptoms to appear between 3 to 6 months of age. This often includes an enlarged liver and signs of low blood sugar, which can even lead to seizures.
Symptoms of low blood sugar can become more noticeable if there’s an increase in the duration between feedings. An infant with GSD I might not display any symptoms at all, instead, one might notice a bigger than usual liver and a distended belly. If the disease is not identified and treated, the baby could start showing features resembling Cushing’s syndrome. This might include a shorter height, a chubby face, and plump cheeks. This is accompanied by failure to gain weight or grow at the expected rate along with delayed development of motor skills.
Repeated instances of low blood sugar could potentially lead to brain damage, affecting normal cognitive development. Also, patients with a specific subtype of this disease, called GSD Ib, can suffer from repetitive bacterial infections because of a lower count of neutrophils, which are a type of white blood cells that fight infections.
Testing for Glycogen Storage Disease Type I (Von Gierke disease)
If a patient is expected to have Glycogen Storage Disease Type I (GSD I), they will undergo certain laboratory tests. These tests may reveal low blood sugar (hypoglycemia), high levels of lactic acid in the blood (lactic acidosis), high levels of uric acid in the blood (hyperuricemia), high cholesterol (hypercholesterolemia), and high levels of triglycerides in the blood (hypertriglyceridemia). In addition, patients with a specific type of this disease, known as GSD Ib, may show neutropenia, which is a low number of a type of white blood cell.
There is a test called a glucagon stimulation test that doctors avoid when they suspect GSD I. This test could increase the risk of a serious complication by causing the amount of lactic acid in the blood to spike without raising the blood sugar level.
It used to be that a liver biopsy (a procedure that removes a small piece of liver to be looked at under a microscope) would be necessary to find out if a person has GSD I. Now, that’s not needed as often. Instead, a patient can undergo a non-invasive molecular genetic test. This test looks at the sequence of genes known as G6PC and SLC37A4 to confirm the diagnosis. This method has a high detection rate, but in certain cases, where it may not be able to identify certain abnormalities in the gene, other techniques like quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification, targeted array or comparative genomic hybridization analysis might be used.
If GSD I is suspected, the first step to confirm this is usually a mutation analysis test. This checks for changes in the DNA that can cause the disease. If patients do not show signs of low white blood cell count (neutropenia), doctors will analyze their complete G6PC gene sequence. If there’s a liver biopsy available, doctors will look for G6Pase enzyme activity to confirm the diagnosis. This enzyme is typically lacking or not working correctly in people with GSD I.
Treatment Options for Glycogen Storage Disease Type I (Von Gierke disease)
The main goal in managing Glycogen Storage Disease type I (GSD I), a rare genetic disorder, is to avoid any sudden metabolic changes, prevent complications, support normal mental growth, and ensure a good quality of life. Achieving these goals often involves changes to diet, lifestyle, and continuous monitoring of blood sugar levels, as the patient’s nutritional needs may change as they grow.
The key concern in GSD I is low blood sugar, so one of the main strategies is to avoid going for long periods without eating and to eat small, frequent meals. These meals should be rich in complex carbohydrates and fiber, which make up about 60-70% of the total calories. Foods high in fructose and sucrose are usually avoided since patients with GSD I struggle to convert these sugars due to a deficiency of a specific enzyme. Consequently, a diet low in these sugars is recommended, limiting foods like dairy that contain high amounts of the sugars galactose and lactose.
Newborn babies with GSD I will need to eat a soy-based, sugar-free formula frequently, about every 2 to 3 hours. As the baby grows and starts to sleep for longer periods, it’s important to ensure hypoglycemia (low blood sugar) doesn’t occur during this sleep period. Therefore, it might be necessary to wake up the baby every few hours to check blood sugar levels and provide food. In some cases, it may be necessary to place a feeding tube, either through the nose or directly into the stomach, so that feeds can be given when needed, especially when the child is unwell or doesn’t want to eat.
One common treatment for maintaining steady blood sugar levels in GSD I patients is cornstarch, as it provides a slow, steady release of glucose. This keeps glucose levels steady for a longer period.
It is important that all patients with GSD I wear a medical alert bracelet. Some patients may have a lactate meter, which helps parents monitor their child’s condition and alert them during emergencies. If hypoglycemia occurs, it must be treated immediately with a fast-acting source of glucose such as cornstarch, special glucose tablets, or certain ready-made glucose polymers.
Patients with GSD Ib might need different treatment if they are at risk of infection following the insertion of a feeding tube, due to low white blood cell counts (neutropenia). Medication may be given to stimulate the production of white blood cells before the tube is inserted, and these patients would require regular blood tests.
Part of managing GSD I also involves making sure the nutritional needs are still being met while limiting certain foods. This means assessing the child’s diet and making sure the right nutrients are included. In some cases, supplements may be needed.
Sometimes, the disease can cause an accumulation of lactic acid (lactic acidosis), and this can be treated with citrate or bicarbonate which help to neutralize excess acid in the urine, reducing the risk of kidney stones. A medication called allopurinol may be used to reduce high uric acid levels and prevent gout, an arthritis-like condition.
Starting from infancy, regular blood pressure measurement and checks for kidney function are important. If there is a persistent presence of albumin (a protein) in the urine, it could be a sign of kidney damage, and in such cases, angiotensin-converting enzyme (ACE) inhibitors are often prescribed to prevent further damage. An echocardiography (a type of heart scan) is recommended every 3 years or earlier if any symptoms arise, to screen for lung hypertension, which is high blood pressure in the lungs.
All GSD I patients have enlarged livers due to fat and glycogen build-up. Therefore, regular liver function tests are done every 6 to 12 months. If there are multiple growing lesions that do not respond to primary treatment, liver transplantation could be an option.
To manage GSD I successfully, several benchmarks are suggested:
- Blood glucose levels before meals should be above a particular level.
- The ratio of urine lactate to creatinine should be below a certain level.
- Blood uric acid levels should be in the high normal range for the patient’s age.
- Certain blood compounds (base excess and bicarbonate) should be above a specific level.
- Blood triglyceride levels should be below a certain level.
- For those with GSD Ib, the concentration of a particular protein in the stool (alpha-1 anti-trypsin) should be normal.
- Body mass index (BMI) should be maintained within a specific range.
What else can Glycogen Storage Disease Type I (Von Gierke disease) be?
It’s essential to distinguish between GSD I and other diseases that also show symptoms of enlarged liver (hepatomegaly) and low blood sugar (hypoglycemia). These include:
- GSD 0 (a deficiency in glycogen synthase)
- GSD III (a deficiency in glycogen debranching enzyme)
- GSD IV (a deficiency in the branching enzyme)
- GSD VI (a deficiency in hepatic phosphorylase)
- GSD IX (a hepatic form of phosphorylase kinase deficiency)
- GSD XI (Fanconi-Bickel syndrome caused by a deficiency in glucose transporter protein 2)
- Disorders of Gluconeogenesis (Fructose-1,6-bisphosphatase deficiency)
- Primary liver disease (Hepatitis)
- Niemann-Pick B disease
- Gaucher disease
- Hereditary fructose intolerance
Possible Complications When Diagnosed with Glycogen Storage Disease Type I (Von Gierke disease)
People with GSD I, a type of metabolic disease, may develop several health problems. This includes blood clotting issues due to poor platelet function, and a higher chance of weak or broken bones due to vitamin D deficiency. To monitor these risks, doctors often do regular checks of vitamin D levels and use a medical imaging technique called DXA to track bone density. If required, they may recommend taking additional vitamin D.
In some cases, GSD I can cause kidney failure because of problems in different parts of the kidney. As kidney function gets worse, the body may produce less EPO. EPO is a hormone that stimulates the production of red blood cells. If the kidneys’ functionality falls below a certain level, patients may develop a type of anemia specific to chronic kidney disease. This condition may worsen due to a lack of iron, chronic metabolic acidosis, or a tendency to bleed easily. If a patient develops this kind of anemia, the doctor may treat them with EPO therapy, but only after checking them for iron deficiency and replenishing their iron levels, if needed. If the levels of certain substances like blood lactate, serum lipids, and uric acid in the body are not well controlled, patients might be at a higher risk for kidney disease, which may necessitate a kidney transplant. Therefore, it is recommended that patients get their kidneys checked by ultrasound every year after their first ten years of life.
Patients with GSD I can also experience severely elevated levels of blood fats and triglycerides. These levels can increase the risk of skin lesions, sudden inflammation of the pancreas, and early hardening of the arteries.
Other possible complications can include heavy menstrual bleeding and polycystic ovaries in women, and gout caused by excessive uric acid levels.
In addition, people with a subtype of GSD I called GSD Ib may have a higher chance of developing inflammatory bowel conditions similar to Crohn’s disease and may also be at risk for hypothyroidism.
Potential Health risks:
- Bleeding disorders
- Osteoporosis and fractures
- Renal failure
- Anemia of chronic kidney disease
- Nephropathy requiring renal transplantation
- Severe hyperlipidemia and hypertriglyceridemia
- Risk of xanthoma formation, acute pancreatitis, and early atherosclerosis
- Menorrhagia and polycystic ovaries in females
- Gout from hyperuricemia
- Crohn’s disease-like enterocolitis and hypothyroidism in GSD Ib
Preventing Glycogen Storage Disease Type I (Von Gierke disease)
Genetic counseling is recommended for parents because each brother or sister of a child with the condition has a 25% likelihood of also having the condition. These siblings also have a 50% chance of carrying the condition without showing any symptoms. Genetic counseling can help parents understand these risks and what they mean for their family.
