Glycogen Storage Disease Type II (GSD2, Pompe Disease)

What is Glycogen Storage Disease Type II (GSD2, Pompe Disease)?

Glycogen storage disease type II, also known as Pompe Disease, is a medical condition caused by genetic traits where there’s too much glycogen (a type of sugar) in the cells, specifically within the muscles. This condition can begin either early in infancy (known as infantile or classic) or later in life (known as non-classic).

When the disease starts early in life, its effects can be very severe and even fatal if not treated quickly. Both early and late-onset types of this disease can cause severe issues with breathing, which is a common reason for its severity. However, how soon these problems arise can differ between early and late-onset types. For babies and infants with this disease, another common fatal condition can be a blockage in the blood flow from the heart’s left ventricle.

Preventive treatment for Pompe Disease often includes replacing a missing enzyme (alglucosidase alfa), making sure up-to-date immunizations are received, and protection against a common respiratory virus (respiratory syncytial virus, RSV). If adults develop signs of having trouble breathing, doing respiratory exercises or using a machine to assist with breathing can be beneficial. This type of treatment could also be beneficial for children.

What Causes Glycogen Storage Disease Type II (GSD2, Pompe Disease)?

The GAA gene, located on chromosome 17q25.3, creates a substance called acid alfa-glucosidase. This is an enzyme, a kind of protein that speeds up chemical reactions in our body. Specifically, this one helps break down a sugar storage molecule called glycogen inside little compartments in our cells known as lysosomes.

If there are changes or mutations in this gene, passed down from both parents (this is what “autosomal recessive” means), it produces an unstable form of messenger RNA. Messenger RNA is the ‘blueprint’ that cells use to produce proteins. This unstable RNA can’t do its job properly, so it either makes a faulty version of the enzyme or no enzyme at all.

Risk Factors and Frequency for Glycogen Storage Disease Type II (GSD2, Pompe Disease)

The occurrence rate of a certain condition differs based on ethnicity and area. For instance, in the U.S., it is about 1 in 40,000 people, and for African Americans, it is about 1 in 14,000. This includes all forms of the condition referred to as GSD2.

Additionally, specific ethnic groups may experience a unique mutation linked to their ancestry. For instance, p.Asp654Glu is commonly found in patients from Taiwan and China. As for p.Arg854Ter, it is more prevalent in individuals of African descent.

Signs and Symptoms of Glycogen Storage Disease Type II (GSD2, Pompe Disease)

There are two main types of a medical condition: early onset and late onset.

The early-onset version often displays symptoms before a child’s first birthday. Common health concerns include:

Weak muscles and delayed motor skills (96% of cases)
Enlarged heart, often hypertrophic cardiomyopathy (92% of cases)
Enlarged liver (90% of cases)
Fat tongue (macroglossia) in 62% of cases
Poor feeding or failure to grow at the expected rate (53% to 57% of cases)

Respiratory infections or difficulty breathing can result in severe respiratory failure, which is the leading cause of death in the disease. It can also cause hearing loss.

On the other hand, late-onset patients usually start showing symptoms in childhood or later, and these can vary from case to case. The symptoms usually come in the form of muscle weakness, specifically focused in the upper part of the body.

The progression of the symptoms is slower than that of the early-onset type, but they can ultimately lead to weakness in the lower limbs and breathing failure due to the involvement of the diaphragm. It is rare to see heart-related problems in patients with late-onset of the disease. However, a small group of grown-ups have shown signs of arterial troubles. In teenagers and adults, a history of “clumsiness” during physical activities could be a sign leading to the diagnosis of this disease.

Testing for Glycogen Storage Disease Type II (GSD2, Pompe Disease)

For early identification of certain conditions when newborn screening isn’t available, there are tests that can be done. Specifically, doctors might examine the amount of a protein called creatine kinase (CK) in your blood and check for specific sugars in your urine.

A test called an acid alpha-glucosidase enzyme assay might also be done. This test checks for specific enzymes (proteins that help speed up chemical reactions in the body) in either whole or dried blood samples. However, the most accurate way to measure these enzymes is to get them from cultured fibroblasts (skin cells grown in a lab) or muscle. This could take a bit longer to get the results back. Low levels of activity (below 1%) from this test suggest an infant disease onset, while levels from 2% to 40% are associated with a late disease onset.

For a definite diagnosis, doctors may turn to gene sequencing of the acid alpha-glucosidase (GAA) gene. As different groups of people may require a detailed or a general gene sequence analysis, decision on the type of sequence analysis needs to be considered, taking into account potential benefits of each.

Lastly, due to the variation of symptoms which can often coincide with other muscle disorders, doctors may initially perform additional tests such as an electromyogram (EMG, a test that measures the electrical activity of muscles), nerve conduction studies (tests that measure how well and fast the nerves can send electrical signals), and a muscle biopsy (where a small sample of muscle tissue is taken for testing) with a specific staining process to search for a specific type of sugar accumulation in the cells.

Treatment Options for Glycogen Storage Disease Type II (GSD2, Pompe Disease)

After a diagnosis, the first steps usually involve taking a chest X-ray, performing an electrocardiogram, and conducting an echocardiogram. This is done to check the heart’s condition especially in early onset cases.

In late-onset cases, doctors may try to examine how well your lungs are working. However, this can be tricky with infants, who might not be able to follow instructions for the lung function tests. Regardless of when symptoms start, it’s important for patients to get immediate help if they start to cough, wheeze, or have trouble breathing.

If eating or swallowing becomes difficult, your doctor might suggest using a feeding tube that goes through your nose or mouth. Additionally, a special x-ray while swallowing (video swallow study) might be done – particularly in late-onset cases – to prevent food or drink from going into the lungs (aspiration) and to check for acid backup from the stomach into the esophagus (gastroesophageal reflux).

Enzyme replacement therapy (ERT) is currently the best available treatment. With ERT, you receive an enzyme that’s similar to the one that’s missing or not working properly in your body. This helps reduce the build-up of a complex sugar called glycogen in your heart and skeletal muscles. The earlier the diagnosis, the better the response to this treatment. But it’s also important to test for something called “cross-reactive immunologic material” (CRIM) either before or during the early stages of treatment. This is because some patients’ immune systems might develop antibodies against the enzyme provided, which makes the treatment less effective. To counter this, doctors might prescribe medications like antihistamines, steroids, and others that help modulate the immune response.

Treatments for specific complications will be determined on a case-by-case basis. For example, in heart-related complications, certain medications can actually worsen the heart condition and should be avoided initially. Physical therapy can greatly help with muscle weakness, especially to prevent stiffness and tightness of the hips, which in extreme cases could require surgery. In the late-onset version of disease, other treatments like speech/swallow therapy and breathing aids like CPAP or BiPAP might be necessary.

When a doctor is trying to identify the cause of early-onset muscle weakness, they would think about several conditions that may produce similar symptoms but have key differences:

Spinal muscular atrophy 1 – Unlike the other conditions, this doesn’t affect the heart.
Danon disease – This is a condition that is inherited through the X-chromosome.

For those experiencing muscle weakness later in life, the doctor might consider:

Limb-girdle muscular dystrophy – In this condition, the muscles around the hips and shoulders are not affected.
Duchenne-Becker muscular dystrophy – This is also a condition that is inherited through the X-chromosome.

Other conditions related to the body’s ability to store energy, like glycogen storage disorders, might also be considered. But for most of these disorders, unlike GSD2, they don’t result in low blood sugar.

Frequently asked questions

Glycogen Storage Disease Type II (GSD2, Pompe Disease) is a medical condition caused by genetic traits where there is an excess of glycogen in the cells, particularly in the muscles. It can start early in infancy or later in life and can be severe and even fatal if not treated quickly.

The occurrence rate of Glycogen Storage Disease Type II (GSD2, Pompe Disease) is about 1 in 40,000 people in the U.S. and about 1 in 14,000 for African Americans.

The signs and symptoms of Glycogen Storage Disease Type II (GSD2), also known as Pompe Disease, can vary depending on whether it is early onset or late onset. For early-onset GSD2, the following signs and symptoms are commonly observed: - Weak muscles and delayed motor skills, which occur in 96% of cases. - Enlarged heart, often hypertrophic cardiomyopathy, seen in 92% of cases. - Enlarged liver, present in 90% of cases. - Macroglossia, or a fat tongue, is observed in 62% of cases. - Poor feeding or failure to grow at the expected rate is seen in 53% to 57% of cases. In addition, respiratory infections or difficulty breathing can lead to severe respiratory failure, which is the leading cause of death in this disease. Hearing loss can also occur. Late-onset GSD2 patients typically start showing symptoms in childhood or later. The symptoms primarily manifest as muscle weakness, particularly in the upper part of the body. The progression of symptoms is slower compared to early-onset GSD2. However, over time, weakness in the lower limbs and breathing failure due to diaphragm involvement can occur. Heart-related problems are rare in late-onset cases, but a small group of adults have shown signs of arterial troubles. In teenagers and adults, a history of "clumsiness" during physical activities could be a sign leading to the diagnosis of this disease.

Glycogen Storage Disease Type II (GSD2, Pompe Disease) is caused by changes or mutations in the GAA gene, which is located on chromosome 17q25.3. These changes or mutations are passed down from both parents and result in the production of an unstable form of messenger RNA. This unstable RNA either produces a faulty version of the enzyme acid alfa-glucosidase or no enzyme at all, leading to the accumulation of glycogen in lysosomes and causing the symptoms of GSD2.

The doctor needs to rule out the following conditions when diagnosing Glycogen Storage Disease Type II (GSD2, Pompe Disease): - Spinal muscular atrophy 1 - Danon disease - Limb-girdle muscular dystrophy - Duchenne-Becker muscular dystrophy - Other conditions related to the body's ability to store energy, like glycogen storage disorders.

The types of tests needed for Glycogen Storage Disease Type II (GSD2, Pompe Disease) include: - Examination of the amount of creatine kinase (CK) in the blood - Checking for specific sugars in the urine - Acid alpha-glucosidase enzyme assay, which can be done using whole or dried blood samples, cultured fibroblasts, or muscle - Gene sequencing of the acid alpha-glucosidase (GAA) gene - Additional tests such as electromyogram (EMG), nerve conduction studies, and muscle biopsy with specific staining process - Chest X-ray, electrocardiogram, and echocardiogram to check the heart's condition - Lung function tests to examine lung function (more applicable to late-onset cases) - Feeding tube and video swallow study to address difficulties with eating and swallowing - Enzyme replacement therapy (ERT) and testing for cross-reactive immunologic material (CRIM) - Treatments for specific complications on a case-by-case basis, such as medications for heart-related complications, physical therapy for muscle weakness, and speech/swallow therapy and breathing aids for late-onset cases.

Glycogen Storage Disease Type II (GSD2), also known as Pompe Disease, is treated with enzyme replacement therapy (ERT). ERT involves receiving an enzyme that is similar to the one that is missing or not working properly in the body. This helps reduce the build-up of a complex sugar called glycogen in the heart and skeletal muscles. The earlier the diagnosis, the better the response to this treatment. However, it is important to test for "cross-reactive immunologic material" (CRIM) either before or during the early stages of treatment, as some patients' immune systems might develop antibodies against the enzyme provided, which can make the treatment less effective. Medications like antihistamines and steroids may be prescribed to help modulate the immune response. Treatments for specific complications will be determined on a case-by-case basis.

The prognosis for Glycogen Storage Disease Type II (GSD2, Pompe Disease) can vary depending on the age of onset and severity of symptoms. If the disease starts early in infancy, it can be very severe and even fatal if not treated quickly. However, with early diagnosis and appropriate treatment, including enzyme replacement therapy, the prognosis can be improved.

A geneticist or a metabolic specialist.