Pompe disease, also known as Glycogen storage disease type 2 is an inherited metabolic disorder caused by an inborn lack of the enzyme acid alpha-glucosidase (also known as acid maltase), which is necessary to break down glycogen, a substance that is a source of energy for the body. This enzyme deficiency causes excess amounts of glycogen to accumulate in the lysosomes, which are structures within cells that break down waste products within the cell. This accumulation of glycogen in certain tissues, especially muscles, impairs their ability to function normally. Glycogen storage disease type 2 is a single disease continuum with variable rates of disease progression.
Pompe disease is often divided into subtypes (infantile or late on-set forms) based on the age at which the disease first occurs, the severity of the disease and the rate at which the disease progresses. The amount of acid alpha glucosidase that remains active in individuals with Pompe disease plays a part in determining which type of Pompe disease an individual may have. In general, the more enzyme that is present in individual’s muscles, the later the onset of the disease, however there are exceptions.
Infantile-onset form :
With this form, infants usually present during early infancy (4-8 months of age) with weakness and floppiness, are unable to hold up their heads and cannot do other motor tasks common for their age, such as rolling over. The muscles in the arms and legs look typical, but are very weak. Breathing muscles are also weak. The heart muscle thickens (cardiomyopathy) and progressively fails in its blood pumping function. Without treatment, infants with Pompe disease usually die before 12 months of age due to heart failure and respiratory weakness.
Late/later onset forms (this includes juvenile and adult):
With this form, the disease has a later onset, usually at an age greater than one or two years of age. It progresses more slowly than the infantile form. A decrease in muscle strength is one of the first symptoms observed. Muscles slowly become weaker, especially the large muscles of the legs, trunk and later the arms. Due to muscle weakness, walking/climbing stairs becomes difficult. The involvement of the muscle weakness progresses slowly over the years. Some adults with Pompe disease use a wheelchair or other assistance with mobility
Late onset Pompe disease also involves the muscles required for breathing (diaphragm and other muscles that assist with respiration). Over a period of time breathing becomes difficult. Some patients have presented with pulmonary (lung) insufficiency due to respiratory muscle weakness. An early finding is difficulty with nighttime breathing, and this can be an early clue. Difficulty breathing can be evaluated by an overnight sleep study. It may become necessary to use a Bi-Pap or ventilator machine to assist in breathing. Respiratory failure is the most common cause of death in individuals with adult Pompe disease. Heart muscle involvement does not appear to be a significant feature in late onset Pompe disease, but is seen in some individuals (heart rhythm disturbances and heart muscle thickness).
Mutations in the GAA gene cause glycogen storage disease type 2. The GAA gene provides instructions for producing an enzyme called acid alpha-glucosidase (commonly called acid maltase). This enzyme is active in lysosomes, which are structures that serve as the cell’s recycling center. The enzyme normally breaks down glycogen into a simpler sugar called glucose, which is the main energy source for most cells. Mutations in the GAA gene prevent acid alpha-glucosidase from breaking down glycogen, allowing it to build up in the body’s cells. Over time, this buildup damages cells throughout the body, particularly muscle cells.
The usual initial investigations include chest X ray, electrocardiogram and echocardiography. Typical findings are those of an enlarged heart with non specific conduction defects. Biochemical investigations include serum creatine kinase (typically increased 10 fold) with lesser elevations of the serum aldolase, aspartate transaminase,alanine transaminase and lactic dehydrogenase. Diagnosis is made by estimating the acid alpha glucosidase activity in either skin biopsy (fibroblasts), muscle biopsy (muscle cells) or in white blood cells. The choice of sample depends on the facilities available at the diagnostic laboratory.
In the late onset form, the findings on investigation are similar to those of the infantile form with the caveat that the creatinine kinases may be normal in some cases. The diagnosis is by estimation of the enzyme activity in a suitable sample.
On May 17, 2013 the Secretary’s Discretionary Advisory Committee on Heritable Diseases in Newborns and Children (DACHDNC) approved a recommendation to theSecretary of Health and Human Services to add Pompe to the Recommended Uniform Screening Panel (RUSP). The HHS secretary must first approve the recommendation before the disease is formally added to the panel.
Glycogen storage disease type 2 is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
The prognosis for individuals with Pompe disease varies according to the onset and severity of symptoms. Without treatment the disease is particularly lethal in infants and young children.
Myozyme (alglucosidase alfa) is a recombinant form of the human enzyme acid alpha-glucosidase, and is also currently being used to replace the missing enzyme. In a study which included the largest cohort of patients with Pompe disease treated with enzyme replacement therapy (ERT) to date findings showed that Myozyme treatment clearly prolongs ventilator-free survival and overall survival in patients with infantile-onset Pompe disease as compared to an untreated historical control population. Furthermore, the study demonstrated that initiation of ERT prior to 6 months of age, which could be facilitated by newborn screening, shows great promise to reduce the mortality and disability associated with this devastating disorder. Taiwan and several states in the United States have started the newborn screening and results of such regimen in early diagnosis and early initiation of the therapy have dramatically improved the outcome of the disease; many of these babies have reached the normal motor developmental milestones.
Another factor affecting the treatment response is generation of antibodies against the infused enzyme, which is particularly severe in Pompe infants who have complete deficiency of the acid alpha-glucosidase. Immune tolerance therapy to eliminate these antibodies has improved the treatment outcome.
A Late Onset Treatment Study (LOTS) was published in 2010.The study was undertaken to evaluate the safety and efficacy of aglucosidase alfa in juvenile and adult patients with Pompe disease. LOTS was a randomized, double-blind, placebo-controlled study that enrolled 90 patients at eight primary sites in the United States and Europe. Participants received either aglucosidase alfa or a placebo every other week for 18 months. The average age of study participants was 44 years. The primary efficacy endpoints of the study sought to determine the effect of Myozyme on functional endurance as measured by the six-minute walk test and to determine the effect of aglucosidase alfa on pulmonary function as measured by percent predicted forced vital capacity.
The results showed that, at 78 weeks, patients treated with aglucosidase alfa increased their distance walked in six minutes by an average of approximately 25 meters as compared with the placebo group which declined by 3 meters (P=0.03). The placebo group did not show any improvement from baseline. The average baseline distance walked in six minutes in both groups was approximately 325 meters. Percent predicted forced vital capacity in the group of patients treated with aglucosidase alfa increased by 1.2 percent at 78 weeks. In contrast, it declined by approximately 2.2 percent in the placebo group (P=0.006).
The preliminary results in the low-dose cohort show the gene therapy to be safe and that all three patients were able to stop taking enzyme replacement therapy after being treated with gene therapy. The gene therapy, known as ACTUS 101, uses the adeno-associated virus (AAV) that specifically targets the liver to promote the production of acid alpha-glucosidase (GAA), the enzyme that is reduced in Pompe disease patients.
To learn more about Pompe Disease and other lysosomal storage disorders, visit https://checkrare.com/diseases/lysosomal-storage-disorders/
For more information about Pompe Disease, visit the National Center for Advancing Translational Sciences’ Genetic and Rare
Diseases Information Center at https://rarediseases.info.nih.gov/diseases/5714/glycogen-storage-disease-type-2