Late-onset Pompe disease

Last updated April 13, 2023, by Susie Strachan
Fact-checked by Patrícia Silva, PhD

Adult-onset Pompe disease typically begins after 1 year of age through to adulthood, and the disease is then known as late-onset Pompe disease.

The disease is characterized by symptoms that include slowly progressive respiratory problems and skeletal muscle weakness. Generally, the earlier the disease is diagnosed in life, the more severe the symptoms.

Pompe disease also is known as glycogen storage disease type 2 (GSD2), as it is caused by mutations in the GAA gene. This leads to absent or reduced levels of an enzyme that breaks down a complex sugar called glycogen into glucose, a molecule that the body uses for energy.

There are three types of Pompe disease, first identified in 1932 by Dutch pathologist Johannes Cassianus Pompe. Along with late-onset Pompe disease, classic infantile Pompe disease is evident within a few months after birth. The nonclassic infantile-onset form sees symptoms arise during the first year of life, but typically later than in the classic form.

Causes of late-onset Pompe disease

Pompe disease is caused by mutations in the GAA gene, located on chromosome 17, that encodes the instructions for making the GAA enzyme. The Pompe disease database lists hundreds of variants of the GAA gene.

A mutation in the GAA gene can either lead to the production of a GAA enzyme that doesn’t work correctly or prevents the production of the enzyme entirely.

Glycogen is a type of sugar the body stores to be used as energy. When the body needs energy, this large molecule is broken down into glucose (a simpler sugar molecule) in a process that requires the acid alpha-glucosidase (GAA) enzyme.

In people with Pompe disease, the GAA enzyme is absent or defective; therefore, glycogen cannot be broken down and eventually builds up to toxic levels inside cells. Muscle cells are especially affected by this, as glycogen usually serves as a main source of energy in these cells to power muscle movements.

Those with late-onset Pompe disease can have enzyme activity levels 40% or less of what is considered normal. In comparison, infantile-onset Pompe patients typically have less than 1% of GAA enzyme activity, while those with nonclassic forms usually have less than 10%.

Pompe disease is inherited when a person receives two mutated copies of the GAA gene, one from each biological parent.

A person with only one mutated copy of the GAA gene is called a Pompe disease carrier. These people will not develop the disease, but may pass the Pompe-causing mutation to their biological children.

Symptoms of late-onset Pompe disease

The progression of glycogen accumulation in a person with late-onset Pompe disease can cause clinical debilitation, organ and system failure, and loss of life.

Symptoms of late-onset Pompe disease can include:

• progressive muscle weakness
• skeletal issues, such as scoliosis and contractures
• respiratory muscle weakness
• difficulty eating
• digestive problems
• trouble hearing
• enlarged heart.

Muscle weakness, particularly in the legs and torso, is a key indicator of late-onset Pompe disease. People may also experience exercise intolerance, weak limb muscles, and lower back pain. Children may have delayed motor development.

People also may develop a sideways curvature of the spine (scoliosis), something that may especially affect adolescents. People with late-onset Pompe disease may experience muscle cramps, as well as headaches and fatigue. More than half of people with late-onset Pompe disease report pain in at least one part of their body.

Cardiac system issues include an enlarged heart (cardiomegaly) and rhythm disturbances.

People with late-onset Pompe disease may also experience difficulty chewing, weight loss, and other digestive problems.

They also can experience breathing difficulties, sleep apnea, dyspnea, and respiratory infections. Respiratory muscle weakness eventually will lead to respiratory failure over time, being the leading cause of mortality.

Some people also may experience hearing impairment.

Diagnosing late-onset Pompe disease

The earlier a person receives a late-onset Pompe disease diagnosis, the sooner treatment can begin. A definite diagnosis typically requires enzyme activity tests and genetic testing.

Enzyme activity tests look for reduced activity in the acid alpha-glucosidase enzyme while genetic testing helps identify disease-causing mutations in the GAA gene.

Genetic screening may be offered to family members.

Muscle weakness can be evaluated:

• by checking the levels of creatine kinase, which are elevated in Pompe disease patients
• via electromyography, a test of the electrical activity in muscles
• by evaluating a patient’s breathing ability through tests like spirometry, a measure of lung function.

Pompe disease can be difficult to diagnose, and can be mistaken for muscular dystrophy, spinal muscular atrophy, rigid spine syndrome, and myasthenia gravis, among others.

Prognosis and treatment

Prognosis of late-onset Pompe disease depends on how early it is diagnosed. Generally, symptoms are more severe when the disease is diagnosed earlier in life.

Life expectancy for people with late-onset Pompe disease can range from early childhood to late adulthood. This is affected by the progression of the disease, respiratory issues, and other co-morbidities.

There are two enzyme replacement therapies (ERT) available for patients with late-onset Pompe disease in the U.S.:

• Lumizyme (alglucosidase alfa), also known as Myozyme outside of the U.S.
• Nexviazyme (avalglucosidase alfa) is approved to treat late-onset Pompe disease in patients 1 and older.

Treatment with ERT has been shown to extend life expectancy for people with Pompe disease, however, ERT is not a cure for late-onset Pompe disease.

Along with ERT, a multidisciplinary team treats the pulmonary, neuromuscular, orthopedic, and gastrointestinal symptoms of late-onset Pompe disease.

Some of these treatment approaches for late-onset Pompe disease include:

• physical and occupational therapy to preserve motor function and assess risk of falling
• exercise, after being assessed by a cardiologist and pulmonologist
• speech therapy to help with communication
• nutritional support for a good diet, comprising 25% to 30% caloric intake of protein
• respiratory therapy
• orthotics to assist with posture and prevent contractures
• assistive devices for mobility, breathing, communication, and feeding.

Physiotherapy also can work on stretching exercises to slow contractures, and set up an exercise plan that may include walking, treadmill, biking, swimming, submaximal aerobic exercise, or muscle strengthening.

A number of experimental therapies are also being explored in Pompe, including clinical trials looking at gene therapy.

A number of international organizations offer support groups for people with late-onset Pompe disease and their families, including Acid Maltase Deficiency Association and the United Pompe Foundation.

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