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Inherited Mutant Gene Leading to Pompes Disease Research Paper

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Updated: Apr 30th, 2022


“Pompes Disease” remains one of the most perilous diseases in the society. It is caused by mutation of the acid-α-glucosidase (GAA) gene on chromosome 19 which results in the formation of impaired mRNA. Due to the condition, lysosomes cannot hydrolyze glycogen leading to accumulation of glycogen to toxic levels within the cells. The main challenge in treating the disease lies in the manner in which it rapidly progresses and the high rates of mortality associated with it. The disease is genetically influenced and results in interference with the glycogen metabolism in lysosomes of affected animals. The disease affects a wide range of mammals including human beings, cattle, cats, dogs, and mice among others. The prevalence of the disease varies among human beings depending on their ethnicity and geographical location. In cattle, the disease has been noted to be more prevalent among the Brahman and Shorthorn breeds. The paper analyzes Pompes disease and discusses some of the available treatment options that have been used to treat the disease.

Keywords: Pompes disease, gene therapy, Enzyme Replacement Therapy (ERT), acid-α-glucosidase, and GAA.


Pompes disease was named after Joannes C. Pompe, a Dutch pathologist who discovered and reported it in 1932. During his research, he noted that the disease caused continuous muscle weakness in a seven months old patient who eventually died due to cardiac hypertrophy at the age of eight months. In 1954, G. T. Cori classified Pompes disease as a glycogen type II storage disease based on her works on glycogen catalytic metabolism. The disease was recognized as a genetic disorder in 1963 after a series of scientific studies were conducted and determined that the disease could be linked to an inheritable kind of deficiency in the acid-α-glucosidase (GAA) gene. The disease is inheritable and arises due to insufficient acid-α-glucosidase (GAA). The disease affects a wide range of mammals and it has been identified among human beings, cats, and dogs among others. In cattle, the disease has been identified to have a relatively high prevalence among the Brahman and Shorthorn breeds. Acid-α-glucosidase (GAA) is responsible for breaking down glycogen into glucose and hence providing energy in muscle cells. The insufficiency of GAA results in accumulation of glycogen in the lysosomes and cytoplasm of the affected animals. This results in swelling and eventually rupturing of the lysosomes, and alteration of the structures of the mitochondria. Various treatment approaches have been tried before and the earliest attempt at treating the disease involved bone marrow transplant, even though it was not successful. In recent times, therapeutic measures such as Enzyme Replacement Therapy (ERT), gene therapy, and Transcription Factor EB (TFEB) have been used to treat the disease.

How the mutation and abnormal protein function alters the activity of the cells and bridging that to behavior/disease

Pompes disease results from mutation of the acid-α-glucosidase (GAA) gene on chromosome 19 leading to the formation of impaired mRNA. The disease is inherited from recessive genes that are transmitted by autosomal chromosomes and it is caused by missense mutation. In cattle, there are three disease-inducing mutations that researchers have been able to identify with the GAA gene (Tammen, Larsson, Bergknut, Barendse, Moran, & Dennis, 200). In human beings, the prevalence of Pompes disease varies widely depending on the ethnicity and geographical locations while in cattle, the disease mostly affects the Brahman and Shorthorn breeds. In Brahman cattle with Pompes disease, glycogen in the lysosomes is not degraded due to inadequate activity of acid-α-glucosidase (GAA) gene.

This results from the 1057delTA mutations that occur in gene coding for the acid-α-glucosidase gene. In the Brahman cattle, this mutation commonly occurs in the E7 (exon 7) site. The mutation also occurs in the E13 site even though the second type of mutation is very rare. Partial deletion or mutation of the acid-α-glucosidase gene results in the formation of an unstable mRNA (Wisselaar, et al., 1993). The inadequate glycogen degradation causes accumulation of glycogen in the cytoplasm and lysosomes, leading to the swelling of the lysosomes, damage to cells, hypertrophy, and organ failure (Geel, McLaughlin, Leij, Ruiters, &Niezen-Koning, 2007).

Analysis of Pompes Disease and Available Treatment Options

As indicated earlier, the disease is caused by failure of the lysosomes to hydrolyze glycogen leading to accumulation of glycogen to toxic levels. Hydrolysis of glycogen occurs in the cytoplasm whenever glucose is required by the liver cells to maintain the blood glucose levels or when it is needed to provide energy in muscle cells. During such instances, the lysosomes take up the glycogen and break it down into glucose. As the glycogen continues to be accumulated in the lysosomes, they increase in size and number and later start rupturing. This results in the glycogen that had been initially stored in the lysosomes being released in the cytoplasm. The mitochondrial structure becomes altered. This results into the fatigue witnessed in affected animals. Storage of glycogen in myocytes found in the cardiac, skeletal, and smooth muscles results in failure of muscles to contract and also a generalized muscle weakness. The muscle weakness also results in fatigue in the affected animals. Inability of glycogen to be degraded in the lysosomes results into a powerful autophagicreactionin in the myoblasts. Autophagy has two important roles in the homeostasis of the skeletal muscles since it lead to degeneration of muscles or enhance survival of cells by providing compensatory mechanisms (Bonaldo & Sandri, 2013). In addition to storage of glycogen in the lysosome due to deficiency in the activities of the acid-α-glucosidase (GAA), Pompes disease also results in an increase in the creatine kinase levels in plasma and the levels of liver transaminase have also been noted to increase (Geel, McLaughlin, Leij, Ruiters, &Niezen-Koning, 2007). The GAA activities also become extremely low in the fibroblasts of affected animals (Wisselaar, et al., 1993).

In a study on Pompes disease in human beings, GAA was purified from a human placenta and its analysis indicated that GAA in human beings exists in two forms of 76-kDa and &0-kDa (Moreland, et al., 2011). Proteolytic cleavage changes the 76-kDa GAA form into the 70-kDa form and the resulting maturation of the acid-α-glucosidase results in increased affinity for the substrate glycogen. The efficacy of converting the 76-kDa form into the 70-kDa form is determined by the amino acid found at position 201 of acid-α-glucosidase. This plays an important part in determining the proteolytic cleavages order in mammals. In Brahman cattle, the increased glycogen affinity occurs principally in the 70-kDa form of GAA. In the cattle, leucine is contained in the proteolytic site in amino acid 197 while tyrosine is contained in the proteolytic site in amino acid 206.

Researchers have sought to find the best ways of treating the disease in human beings. Animal models have been used in studying the treatment options. The processes involved targeting GAA, its biosynthesis and lysosomal processing are highly complicated (Moreland, et al., 2011). Studies seeking appropriate treatment options have in the past been based on viral vectors and recombinant protein indicated that gene transfer targeting affected cells can be effective in treating Pompes disease (Nayak, Sivakumar, Cao, Daniell, Byrne, & Herzog, 2012). Cross-correction which involves extracelluar acid-α-glucosidase (GAA) uptake through mannose-6-phosphate receptor can also be used in treating the disease. It has been noted that the major problem facing the Enzyme Replacement Therapy (ERT) treatment option is the fact that high doses are need in order to be effective and this normally results in negative side effects. The infused recombinant acid-α-glucosidase (rhGAA) normally results in the formation of antibodies and this result in reduced effectiveness of ERT, allergies, and tissue toxicities. In recent times, researchers have been conducting experiments aimed at creating a better comprehension of the immune system’s reaction to rhGAA in order to enhance the effectiveness of Enzyme Replacement Therapy (ERT) and determine the threshold of the body’s immune system’s tolerance to this treatment option.

In the research by Moreland, et al., (2011), it was noted that the rate at which GAA is converted from its 76-kDa form to its 70-kDa form was influenced by the type of amino acid that existed in the 201 position of the acid-α-glucosidase. This has an effect in affecting maturation of GAA which consequently increases the glycogen affinity and hence the rate at which Pompes disease progresses in affected animals. The researchers were able to determine that the differences observed in the rate of GAA maturation among various mammalian groups can be attributed to the sequencing of GAA and not the environment of the lysosomal protease. This has resulted in a renewed belief in the development of better rhGAA which will be quickly processed intracellularly.

Researchers have also been working on finding ways of reducing the side effects that arise from the immune system’s reaction to Enzyme Replacement Therapy (ERT). The researchers have noted that T cell epitopes play a significant part in development and operation of humoral and cell mediated responses in the adaptive immune system. The findings from the study on mapping T helper cells reaction to GAA provides an important in facilitating further studies aimed at evaluating and enhancing gene and protein therapies, and creation of protocols on immune tolerance. The study notes that pathogenic antibodies formation reduces efficiency of gene and protein therapies, increases toxicity and results in potentially fatal anaphylactic reactions in the body. The researchers are continuing to evaluate the importance of CD4+T cell epitopes in measurement and mechanistic works of the immune system’s reactions to rhGAA and development of immune tolerance protocols.

Current Treatment Options

Various treatment options for the disease have been considered and their effectiveness and possible side effects analyzed. In the past, bone marrow transplant was considered as a treatment option in human beings but was dropped due to its inefficiency. The current treatment options available for Pompes disease are gene therapy, Enzyme Replacement Therapy (ERT), and Transcription Factor EB (TFEB).

Gene Therapy

The general considerations applied in the gene therapy is the fact that the 1057delTA mutations of the acid-α-glucosidase gene which causes inadequate transcription of the GAA gene or expression of a highly altered mRNA GAA protein. Since inadequate acid-α-glucosidase activity causes accumulation of glycogen and results in damaging effects to the muscle cells, it can be seen that correcting the 1057delTA mutation in cells of affected animals offers a good chance for curing Pompes disease (Chen &Amalfitano, 2000). In one gene therapy treatment option, viral vectors are used to take the acid-α-glucosidase gene into fibroblasts and myoblasts directly obtained from individuals or animals affected by Pompes disease. The myoblasts are then infected extracellularly by the viral vector and then implanted into muscle cells of affected animals. This result in an increased number of GAA proteins which are able to target lysosomes and lower the amount of glycogen accumulated in the genetically modified cells. The treated cells also end up being able to secrete the GAA enzyme which enables cross-correction of myoblasts that have not yet been targeted for transduction by the viral vector.

Enzyme Replacement Therapy (ERT)

The general consideration applied in the Enzyme Replacement Therapy is the fact that there are cell-surface receptors which are able to facilitate transfer of lysosomal enzymes to affected tissues. Recombinant human acid-α-glucosidase (rhGAA) can be used as a method of treating the disease. In this case, the rhGAA precursor form is incubated with fibroblasts obtained from animals suffering with Pompes disease. The consequent uptake of the enzyme results in glycogen levels and activity of GAA being normalized in the fibroblasts of the affected animals. The extent of the ERT using rhGAA depends on the dosage administered to the sick animals. However, it has previously been noted that side adverse side effects of high dosage limit efficacy of treating Pompes disease using ERT. Researchers in the field are continuing to seek ways of determining the threshold of dosage that can be administered while ensuring that this treatment option remains effective. Inefficient mechanisms to deliver drugs to lysosomes at specific tissues that are targeted in the ERT also present challenges to its efficiency.

Transcription Factor EB (TFEB)

Transcription Factor EB (TFEB) helps in solving the challenge of delivering drugs to targeted tissues that is experienced in ERT. TFEB uses the capabilities of lysosomes to discharge their contents into extracellular spaces thereby clearing stored materials (Spampanato & Feeney, et al, 2013). TFEB helps in reducing the quantity of lysosomes filled with glycogen and therefore is efficient in treating Pompes disease. TFEB glycogen regulation in various cells involves the mTORC 1 and ERK kinases.

Exploration of Future Therapeutics

There is need to determine whether glycogen removal in the treated animal ends up improving their muscle function and the duration of the derived therapeutic effects. The efficiency of myoblast therapy in animals also needs to be illustrated. Research in future therapeutics seeks to find ways of minimizing adverse immune system reactions which limit the efficiency of various treatment measures that are currently being used in treating the disease.


Pompes disease presents various social and ethical concerns in research conducted on human beings. For instance, is application of genetic engineering and testing on human subjects acceptable socially and ethically? Would human subjects continue to live normally as human beings or would they have their lives changed if manipulation of their genetic coding is altered? Genetic testing in human populations continues to be a subject that evokes mixed emotions since it is believed that manipulation of genes has the potential of resulting in adverse unforeseeable consequences. However, it has been noted that genetic manipulation offers the best solution in treating the disease. A treatment option such as gene therapy has been noted to have considerable success against Pompes disease even though certain challenges in efficacy continue to persist.

It can be seen that due to the social and ethical concerns presented with genetic testing, many experiments are conducted on animals (mainly, Pompesmice. In the Brahman cattle, genetic testing can be applied without eliciting such reactions as would happen if human subjects were considered. The main challenge that arises in treating affected cattle comes from the fact that Pompes disease is highly debilitating, progresses rapidly, damages organs of affected animals, and is realized late in many cases. This means that the available treatment options may have limited chances of helping affected animals since the time needed to repair damaged organs and muscle cells may be too long. In spite of this, it remains crucial for research into enhancing the effectiveness of the available treatment options because of the financial impacts the loss of affected animals presents to the owners of Brahman cattle.


Even though Pompes disease poses a high mortality rate, genetic engineering and various therapeutic options provide suitable treatment solutions to it even though they are currently not as effective as they need to be. The knowledge in genetics has been vital in understanding more about the significance of the disease particularly the impact of mutations on the acid-α-glucosidaseon glycogen hydrolysis. Gene therapy, Enzyme Replacement Therapy and lately, Transcription Factor EB (TFEB) can be used to treat the disease to varying levels of success. Currently, the Transcription Factor EB (TFEB) method has been seen as the best option of treating the disease and more research is being conducted in TFEB. This is because it has been noted that it has the potential of overcoming the challenge of delivering drugs to the targeted tissues as experienced in the ERT treatment option.


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