Introduction

Pompe Disease is a genetic disease passed on in an autosomal recessive fashion, meaning both parents must pass on a faulty gene for symptoms to be exhibited in the child.1 Once this happens, children of a minimum of three months can begin to present symptoms such as respiratory issues or cardiac problems, which, without immediate treatment, can soon become terminal.¹ The following article will examine this genetic condition, focusing mainly on speech and language issues.

What causes Pompe disease?

When we eat food, our body’s cells take in glucose from the bloodstream to utilise it for respiration (making energy) to keep our cells alive. Because we eat so often, any excess glucose is linked together and becomes an insoluble storage molecule called glycogen.2 This mostly occurs either in the liver or skeletal muscles (muscles that line the skeleton to help us move e.g. biceps, triceps, quadriceps, and hamstrings). Whenever your body needs more glucose to make energy but there isn’t enough available from the bloodstream, for example, if you skipped breakfast or have been sleeping for quite a while, then your body can break down some glycogen to get enough glucose to make energy and keep you alive.²

Glycogen can be broken down in 2 ways: In lysosomes using the enzyme acid α-glucosidase or in the cytoplasm (cytosol) of cells in a 2-step enzymatic process which uses glycogen phosphorylase and glycogen debranching enzyme working in unison to break the α-1,4 and α-1,6 glycosidic bonds that hold the glycogen macromolecule together, thus releasing the glucose to be used for energy.^1,2

In Pompe disease, a faulty version of the gene for the enzyme α-glucosidase is inherited from both the mother and the father on chromosome 17, thus leading to a malfunctioning version of the enzyme being present, or a complete absence of it.³ The mother and father would presumably be fine as this is an autosomal recessive disorder; however, symptoms would be present only when 2 copies of the genes code for a dysfunctional enzyme in child.¹

Consequently, the acid α-glucosidase in Pompe disease is unable to break down glycogen in the lysosome, and the glycogen keeps building up there.¹ The lysosome is the main recycling centre of the cell, recycling intracellular and visiting extracellular polymers such as proteins, carbohydrates, and lipids into their monomer components like amino acids, sugars, and fatty acids.⁴ When the glycogen is no longer broken down in the lysosome, it starts to accumulate, slowly filling up the lysosome and preventing other materials from being digested there.

As a result, less glucose is broken down from glycogen so less is available for respiration, thus leading to a possible energy deficit if the cytoplasmic method of breaking down glycogen isn’t as efficient or active. The secondary effect of this disorder is the lysosome becomes gradually filled with glycogen over time, which is a large, insoluble macromolecule. As the lysosome becomes fuller, it may become less able to degrade other molecules within the cell, such as toxic or harmful byproducts of natural reactions which can lead to cell damage.¹ Eventually, the lysosome may burst from over-filling, thus causing digestive enzymes to be released into the cell and leading to the degradation of key proteins and lipids within the cell.⁵

How is speech affected in Pompe disease?

Pompe disease can start with symptoms from the first few months of life, with symptom onset depending on the type of mutation present.^1,6 In these cases, once the symptoms begin to develop, death can occur within a few months, especially without treatment. As children are often so young when symptoms develop, in most cases, they can speak to communicate what issue is occurring and what specifically hurts. As a result, the most common symptoms of Pompe’s disease which are noticed are respiratory issues or cardiac issues from an enlarged heart.1 Children will also have tongues that don’t move very much.7 This can make speaking difficult, and breathing as the tongue fills the space in their mouths, and, isn’t very motile.⁷

The lack of glucose availability from the glycogen is not being broken down and can lead to hypertonia in muscles, including in the diaphragm.^3,6 This means that although the nervous system is correctly sending messages from the brain telling the body to breathe in and out (possibly this is also interrupted if nerve cells also develop problems with their lysosomes from failed glycogen degradation)⁷, the diaphragm doesn’t have enough energy to keep contracting and relaxing repeatedly. As a result, it only breathes in and out very little, so the body constantly needs a large amount of oxygen. Eventually, especially if the lysosomes rupture and the diaphragm muscle fibres start to degrade due to the lysosomal enzymes, the ability to breathe will stop¹ which can lead to death.

Before death occurs, the body may try to compensate for insufficient levels of oxygen, so reaching the cells in the body. The heart may pump faster and more strongly with each beat so the same blood can reach the lungs more frequently, passing smaller but more frequent amounts of oxygen to the cells, thus allowing more oxygen to be taken in for respiration.^3,6 However, overworking the heart in this way will take its toll, and the heart muscle will adapt, becoming larger to pump more blood faster in a more efficient manner. If lysosomes burst and digest key cardiac proteins, this can result in parts of the heart being unable to contract and the body may try to generate more cardiac muscle to compensate.^3,5 This positive feedback cycle will continue, eventually resulting in the heart and respiratory system failing from a lack of oxygen too, leading to death without intervention.

The hypnotic tongue can also contribute to the respiratory complications demonstrated in Pompe’s disease because it can fill the mouth, making it more difficult to breathe, especially in more difficult circumstances when it is harder for the diaphragm and intercostal muscles to contract and breathe in oxyge.⁷ This condition can occur from Pompe’s disease, too; especially due to an excess of engorged lysosomes in both the hypoglossal nerve and the tongue muscle itself.⁷ Specifically, tongue involvement in Pompe’s disease is characteristic of late-onset Pompe’s disease, and their results are due to a partially dysfunctional acid α-glucosidase.⁷

Another classic feature of respiratory and speech issues caused by Pompe’s disease is tracheomalacia or tracheobronchomalacia.⁸ This is when the trachea (breathing tube) is malformed and much narrower than usual in some Pompe patients. As less air passes through the narrower breathing tube, the speech volume and clarity can become more difficult to understand, especially with tongue issues involved.⁸ Research indicates that this too is caused by the excess of over-occupied lysosomes, with animal models suggesting that the airways in these patients are less responsive to bronchoconstrictive medication and there is less calcium-induced contraction in the smooth muscle of airways, presumably due to the same issues as in other muscles observed.⁸

What interventions are available for Pompe disease?

Intravenous enzymes can be given to alleviate the issues. These include Alglucosidase-α or Avalglucosidas-α.¹ They can aid in maintaining normal heart function by reducing glycogen build-up, and improving muscle tone so you can move your muscles, breathe, and move your tongue to speak more easily.¹

In emergency cases when the onset of symptoms is very swift or noticed late, a ventilator may help to maintain the respiratory system. Emergency thoracotomies may also be performed to widen the trachea and maintain the airway to enable the body to keep breathing.^1,8

Additionally, antibiotics may be given to combat any infections which may result from a lack of respiratory function in the airways. Speech and language therapy can help ameliorate speech in late-onset Pompe’s disease, though this won’t be a permanent solution. Humidified air can help ease the airways and improve breathing, especially with tracheomalacia; however, this isn’t a permanent solution.⁸ Currently, gene therapy solutions that aim to replace the faulty enzyme genes within Pompe patients are being researched, though this is still in the experimental phase.⁹

Summary

Pompe Disease is a genetic condition in which both parents pass on a mutated form of the gene. This leads to a mutation in the enzyme acid α-glucosidase, thus preventing the breakdown of the storage molecule glycogen. Consequently, glycogen begins to accumulate within the body’s tissues without them being able to use it; so causing damage and muscle wasting, which can eventually be fatal without treatment.