Did you know enzyme replacement therapy is the only available treatment for Pompe disease? Read on to know the causes, symptoms and diagnosis of this rare genetic disorder.
Pompe disease is a rare fatal genetic disorder characterized by the abnormal buildup of a complex sugar molecule, called glycogen, in the body’s cells. This buildup damages different organs and tissues, especially the heart and skeletal muscles. Deficiency of an enzyme called acid alfa glucosidase (GAA), which breaks downs complex sugars in the body for energy, is linked to Pompe disease. Mutations in a gene that makes GAA, called GAA gene, is thought to either reduce or completely prevent the production of this essential enzyme. Hence, in people with Pompe disease, glycogen builds up to toxic levels inside cells.
Pompe disease is an autosomal recessive disorder, meaning it occurs only when an individual inherits two mutated GAA genes, one from each parent.
People who have only one mutated GAA gene, do not show symptoms of the disease. But they can pass the disease-causing mutation to their biological children, and so they are called “carriers” of the disease. If both parents are carriers, there is 25% chance that their biological child will inherit both mutated copies of the gene and develop Pompe disease.
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Types and Symptoms of Pompe disease
The severity of Pompe disease and the age of onset are related to the degree of enzyme deficiency. And depending on the disease’s severity and age of onset, it is classified into three types: the classic infantile form, non-classic infantile form, and late-onset form.
Individuals with complete or near complete deficiency of GAA usually have more severe disease (i.e., classic infantile form), while those with a partial deficiency of GAA have more mild disease (i.e., late-onset form).
In classic infantile form, symptoms are evident within months of birth. Common symptoms include slower growth rate (often due to feeding problems), poor weight gain, muscle weakness, floppiness, head lag, and difficulties breathing, moving, and swallowing. Many infants with Pompe disease also have an enlarged tongue, liver, and heart. Without treatment, most babies die complications before their first birthday from cardiac or respiratory complications.
In non-classic infantile form, symptoms usually start to develop by within the first year of life. Damage to the heart muscle tends to progress more slowly in babies with this form of disease, compared to those with classic infantile form. Muscle weakness and delay in motor development are also common symptoms associated with non-classical form.
Late-onset Pompe disease (or juvenile/adult Pompe disease) can appear anytime from late childhood to adolescence, or even in adulthood. People with this form may develop muscular weakness particularly in the legs, trunk, and respiratory system progressing to motor difficulties, breathing problems, and fatigue. Here the prognosis is dependent upon the age of onset, i.e. the later the age of onset, the slower the progression of the disease. Respiratory failure is the main cause of death in such cases. The heart is usually not involved in late onset form of Pompe.
Diagnosis and treatment of Pompe disease
A diagnosis of Pompe disease can be confirmed by assessing the activity of the GAA enzyme in cells obtained from the skin, muscles, or blood samples. Screening for GAA gene mutations can help confirm the diagnosis or identify if you’re a carrier of the disease.
Treatment of Pompe disease usually involves a multidisciplinary team of specialists, including cardiologists, neurologists, pulmonologists, respiratory therapists, dietitians, orthopedists, occupational/speech therapists, geneticists, and genetic counselors.
In enzyme replacement therapy (ERT) for Pompe disease, a purified version of the GAA enzyme are injected into the bloodstream of patients to reduce the buildup of glycogen inside cells and slow the progression of the disease.
In the U.S., the Food and Drug Administration (FDA) has approved alglucosidase alfa (Myozyme) to treat infantile-onset Pompe disease. The therapy manufactured by Sanofi Genzyme is also approved in the European Union. In addition, the US FDA has also approved Lumizyme for treatment of patients 8 years and older with late onset Pompe disease, and avalglucosidare alfa-ngpt (Nexviazyme) for patients one year of age and older with late-onset Pompe disease.
Some people with Pompe disease may also benefit from non-drug treatments, such as physical therapy, occupational therapy, and speech therapy.
New hope for Pompe disease patients
Enzyme replacement therapy is the only available treatment for this rare genetic disorder. As it must be injected regularly, sometimes every few days, for life, the treatment costs a lot.
Providing new hope to people with life-threatening Pompe disease, researchers from the University of Maryland have found a way to make enzyme replacement therapy more efficient, less expensive and less frequent.
Generally, only a small amount of the GAA enzyme infected reaches the cells’ machinery where it is needed. Hence, a large quantity of the enzyme needs to be injected and the cost can go up to a half-million dollars per patient a year, according UMD Chemistry and Biochemistry Professor Lai-Xi Wang, the corresponding author of the study.
Wang and his team have developed a simple method of modifying the enzyme that demonstrated much enhanced receptor binding, cellular uptake and glycogen degrading activity in cells.
They found a ligand — a binding molecule — that was easily recognized by a specific receptor in the cellular transport system. They then developed a simple method to attach it to the GAA enzyme. When tested in model cells, the engineered GAA enzyme with the attached ligand was found to be much more efficient at delivering GAA to the target machinery than the current enzyme replacement therapy.
Xiao Zhang, a postdoctoral associate in UMD’s Department of Chemistry and Biochemistry and the lead author of the study, believes that this new method could dramatically reduce the amount of enzyme needed to be injected as well as the frequency of injections required to treat Pompe disease.
The details about their new method were published on August 19, 2021, in the journal Chemical Science. Working with colleagues from the National Institutes of Health (NIH), the research team is now doing further studies to evaluate the effects of the combined GAA-ligand therapy in animals, hoping to move to human trials soon. They also believe that this new method could lead to improved treatments for other similar lysosome storage diseases.
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Source: | This article originally belongs to thehealthsite.com
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