Krabbe disease is an illness of genetic origin, resulting from a change in the DNA sequence of the galactocerebrosidase enzyme.¹ This change can have damaging effects on the enzyme’s function, which can have a deluge of downstream effects. In this article we will focus on evaluating the direct developments that result from this affliction, with a specific focus on respiratory complications. 

What is galactocerebrosidase?

Galactocerebrosidase, also known as galactosylceramidase, is β-hydrolase enzyme, abbreviated commonly to GALC It is a protein with 17 exons and 16 introns.² Typically, the enzyme can be found in small sacs in the lysosome, a part of cells used to destroy waste products and proteins. More specifically, it is present in the lysosomes of microglia, which are specialised cells that are responsible for removing waste and harmful products as part of the immune system that serves the brain.³

They are capable of surveying their local environment and carrying out the destruction of dying cells, waste, and pathogens as required. More than 130 different mutations can result in GALC can become mutated or absent.⁴ It then becomes non-functional, thus leading to the symptoms of Krabbe Disease.¹ However, not all of these mutations lead to the onset of disease at birth. There are different periods of onset, ranging from during the first year of life to the first few decades, depending on the specific mutation.⁴

The mutations for this enzyme can be found on chromosome 14.⁴ Though not all genetic changes are pathogenic, as some common polymorphisms (harmless variations in the DNA base sequence for a gene) do exist, the presence of these polymorphisms alongside pathogenic mutations is thought to contribute to the severity of the disease.² As this is an autosomal recessive disease, having one copy of the mutation is not enough to cause disease in an individual. Instead, a person with one mutation is a carrier for the disease and will not exhibit symptoms.¹

When two copies of mutations are inherited (one from each parent) then Krabbe disease will occur. Some research indicates that mutations in the N or C terminus of the gene results in the disease manifesting later in life (possibly after the age of 10) whereas mutations located in the central region of the gene often result in infant-onset, which is the case in approximately 90% of cases.^1,4

What is Krabbe disease?

Krabbe disease refers to the illness caused by the mutation of the GALC enzyme.¹ The enzyme in particular breaks down ester bonds using water (called hydrolysis), targeting two main lipid (fatty) molecules in particular. One is called galactosylceramide and the other is psychosine (also known as galactosylsphingosine).¹

Galactosylceramide is found all over the nervous system and is produced by the myelin-producing Schwann cells that cover the nerves. Myelin is a lipid substance that covers most motor neurones and some sensory neurones, thus allowing electrical impulses to travel more quickly so that we can act and react more quickly to the world around us.⁵ The hydrolysis of galactosylceramide permits the absorption of old myelin, thus permitting new, healthy myelin to form to protect the nerves and increase electrical transmission speeds. In Krabbe disease, due to the insufficiency of GALC, the galactosylcermaide cannot be efficiently removed, and as a result, old damaged myelin may not be removed.⁴

Therefore, new myelin may not form, slowly leading to the deterioration of a healthy nervous system. Though galactosylceramide is mainly found in Schwann cells, it is distributed throughout the nervous system with 12% of all white matter composed of it, so Krabbe disease can have a range of widespread effects all over the body where this product cannot be removed.⁶

Psychosine is also a primarily targeted by GALC. This is another lipid that results as a by-product of myelin manufacture. However, unlike galactosyloceramide, psychosine is toxic and can cause cell death by triggering apoptotic (death) pathways in surrounding cells.^4,7 Therefore, it is necessary for this to be removed soon after production in order to maintain a natural balance within the body. Ordinarily, the concentration of psychosine in healthy people remains below 0.71nmol/L, but this can significantly increase in patients with Krabbe disease to greater than 3mol/L.⁸

Due to its cytotoxic effects, it is understandable that the presence of this lipid in such high concentrations can cause an array of symptoms as a result of widespread cell death in various positions throughout the body. More specifically, it is the irreversible death of Schwann cells that can produce many symptoms of Krabbe disease because once the nerves are left exposed without new healthy myelin-forming, they are more susceptible to nerve damage and pathogenic contamination.^1,7 However, it is not only nerve cells to which psychosine can cause damage, but all cell types.⁷

With the inability to remove damaged myelin as well as the accumulation of active damage and cell death in many nervous tissues, nerves can become damaged and lead to the onset of relevant symptoms such as vision loss and muscle weakness.¹

Krabbe disease is also known as globoid leukodrystrophy disease.¹ This is because the microglia which are supposed to dispose of debris within the nervous system cannot function properly due to a lack of functioning GALC.¹ Therefore, multiple glia may try to merge together in order to compensate and try to remove the debris. The cells become larger, globular and multi-nucleated.¹ They tend to accumulate beside Scwahnn cells as they attempt to deal with the ongoing issues, thus causing more damage to their neighbouring cells and further aggravating the issue of myelin damage.

How is the respiratory system affected in the latter parts of the disease?

Once nerve damage begins to accumulate, the central nervous system can no longer efficiently pass on messages to other parts of the body, if at all. Some of the nerves which can become damaged are the glossopharyngeal and vagus nerves, which help you swallow and breathe.⁹ Consequently, the small epiglottis flap which covers the opening to the breathing tube (the trachea) and prevents food going into it doesn’t always work anymore.¹⁰

During swallowing, food can often make its way into the trachea, causing coughing fits and eventually frequent infections from food and drink making its way into the lungs.11 This can take its toll on the body, causing greater fatigue as the body tries to make enough energy to deal with multiple infections as well as accumulating nerve damage.¹¹

The phrenic nerve is the nerve which supplies the diaphragm, allowing it to rise and fall so your lungs can breathe in and out as the diaphragm rises and falls.¹² Once this nerve begins to become damaged due to the GALC insufficiency/ absence, breathing can become more and more difficult. Ventilators can help but as the condition is genetic, it would require a ventilator for the rest of your life as more and more nerve damage accumulates, causing pain, blindness and other nervous issues.^1,4,12

Eventually, when the nerve damage is too great, the lungs will no longer be able to breathe and oxygen inhalation will not naturally occur. Waste products from respiration such as carbon dioxide will also not be removed efficiently from the body, thus causing the blood to become more acidic.¹³ Although the body may try to compensate by making energy without oxygen (anaerobic respiration), this isn’t feasible in the long term due to toxic lactic acid by-product which can build up as a result.¹³ This causes even more cell damage. Ultimately, the body will not have energy to survive, and this is commonly the cause of death for most patients with Krabbe disease.¹¹

Summary

Krabbe disease is a rare autosomal recessive disease which affects the population. It occurs when the galactosylceramidase enzyme cannot function properly or at all, thus leading to psychosine build-up and the lack of galactosylceramide hydrolysis. Consequently, nerve damage develops and damaged myelin is unable to be removed and replaced, especially as Schwann cells begin to die. Nervous transduction is affected as the body becomes less able to pass messages quickly via myelinated neurones, and slowly nerve damage accumulates as symptoms become more obvious. Frequent infections may occur when food passes into the lungs if the body cannot control the epiglottis. Ultimately, weak muscle tone and nerve damage will result in the lungs no longer being able to inflate, and death may occur from oxygen deprivation.