Overview

Krabbe disease is a rare genetic condition affecting a small proportion of the population, often diagnosed after a person’s vision is impacted.¹ The disease progression can be swift, so early diagnosis and a clear understanding of the disease are vital. This paves the way for better disease management and an improved health outcome for the patient as this disorder has no cure yet.  

This article focuses on Krabbe disease, highlighting disease progression as it concerns vision.. 

The genetic causes of krabbe disease

Krabbe disease is inherited from both parents or caused by a spontaneous genetic change (mutation) during pregnancy. As it is an autosomal recessive disease, one copy of the faulty gene must be inherited from each of your parents for the disease to manifest.¹ 

There are more than 130 different mutations that can account for this disease, all found on chromosome 14.² These mutations all affect an enzyme-galactocerebrosidase (GALC). responsible for breaking down specific fats (lipids) – mostly found in the nervous system and kidneys.² These mutations can either cause the GALC enzyme to stop functioning completely or it can affect its action, thus preventing it from adequately using water to break down its two main fatty acid targets.¹ This can have devastating consequences on the body which can sometimes be fatal. 

The type of mutation can influence the onset of the condition, with mutations located at the chromosome’s ends demonstrating disease onset later in life whereas more central mutations can lead to symptom onset in infancy.² However, specific mutations cannot currently be used to predict the age of disease onset, and some changes to the gene can be harmless (thus not causing Krabbe disease).² 

The specific fatty lipids the GALC enzyme targets are called galactolipids. There are 2 specific ones the GALC enzyme targets, breaking them down through the use of water.¹

They are: 

• Galactosylceramide 
• Psychosine/galactosyl sphingosine

These are both responsible for causing Krabbe disease in different ways, but first, we will look a little more closely at the structure of the nervous system in order to figure out how the accumulation of these 2 lipids causes this disease.

How is the nervous system normally structured?

The central nervous system is composed of the brain and the spinal cord.³ Receptors in our skin, eyes, nose, and other parts of the body detect changes (such as movement, change in colour or smell). These trigger sensory neurons. These  are long, thin nerve cells that are connected, passing the message from one nerve cell to the other across tiny gaps (called synapses) to the central nervous system.³ 

If an automatic response is needed, for example for a reflex reaction such as when the knee is hit,  the message reaches the relay neurons in the spinal cord. Then motor neurons carry out the information of the correct automatic response to the desired muscles in the knee (stimulating the knee to jerk). 

If an automatic response isn’t required, for example when someone asks you to give them an object which receptors in your ears can hear, the sensory neurons carry the information via nerve cells to the brain where they convey the information to relay neurones.³

The relay neurons within the brain decide which response is most appropriate and then pass on the information to motor neurons (for example those stimulating your hands to grab the object and your body to turn) to allow you to carry out the effect. 

Because the information has to travel quite a distance, once your body has made the correct decision, it is wise to carry it out quickly for the sake of efficiency. Therefore, motor neurons are surrounded by special cells called Schwann cells. These produce a lipid (fatty) coating around the motor cells that acts like insulation and protects the motor nerve cells from damage, thus permitting them to function for longer.³ 

The insulation spans every few cells so the message from motor nerve cells doesn’t have to pass from cell to cell: instead, it can jump between gaps in the insulation every few cells to convey the message to the correct organs or muscles even faster. This can be particularly useful in vision when the receptors receive lots of information quickly. Research has shown that a visual response can occur within 0.15 seconds.⁴ If this were not the case, we would not be able to see very clearly, especially not in moving vehicles where the sights change multiple times within a second or so.

How is the nervous system affected by krabbe disease?

Krabbe disease affects the nervous system by:

• Disrupting the formation of new myelin( the covering of nerves) due to lack of breakdown of the fatty acid, galactosylceramide
• Death of Schwann cells(cells that facilitate the production of new myelin) due to the accumulation of fatty acid, psychosis
• Malfunction of the oligodendrocytes and microglia in the central nervous system

In Krabbe disease, the GALC enzyme doesn’t work properly or there isn’t enough of it to carry out its normal function.² Galactosylceramide is an important component of myelin, the destruction of which leads to the breakdown of old myelin, thus allowing the formation of healthy new myelin. Research has shown that new myelin can grow in 3-6 months after any damage.⁵ 

The GALC enzyme also acts to break down psychosine (also known as galactosyl sphingosine).¹ This is a byproduct that results from the formation of myelin and is toxic to Schwann cells, causing them to die. Normally in a healthy nervous system, the GALC enzyme can break this down using water, so there is normally less than 0.71 nmol/L in a healthy individual.⁶ 

After macrophages and microglia remove any damaged myelin, Schwann cells can transition into their repair state, facilitating the regeneration of new myelin sheaths. However, in Krabbe disease, more than 3 nmol/L of psychosine is sometimes present, causing multiple Schwann cells as well as other cell types to die irreversibly.1,6 This can affect myelin production. 

The equivalent of Schwann cells from the peripheral nervous system (PNS), are the oligodendrocytes in the central nervous system (CNS), which are similar but not identical. One oligodendrocyte can produce myelin for many nerve cells in the CNS, while Schwann cells typically myelinate only one axon in the PNS. Research has shown that when these oligodendrocytes survive in conditions where they should undergo apoptosis (cell death), they can begin to malfunction, and produce abnormal myelination. This can result in myelin being deposited inappropriately on certain parts of neurons, affecting the transmission of electrical signals and leading to dysfunction in muscle control and organs.⁷ 

Although it is not properly why or how this happens, the similarity of the oligodendrocytes to the Schwann cells may suggest that a similar effect may take place in Krabbe disease. The accumulation of psychosine causes Schwann cell dysfunction, which could further contribute to nerve damage even before Schwann cell death.⁸ 

The microglia are cells that work within the central nervous system to remove damage and debris as part of the immune system. They are the cells which are supposed to contain the GALC enzyme, and in Krabbe disease, they cannot function properly.¹ As a result, they attempt to make up for the deficiency of GALC, becoming multinucleated and globular in shape.¹ The globoid cells are abnormal and accumulate next to Schwann cells, causing more damage to myelin as they do so and thus exacerbating the problem.¹ They are the reason that Krabbe disease is also called globoid leukodystrophy disease.²

How does krabbe disease affect vision?

The effect of the disease on vision results from the effect on the function of myelin and motor neurons in the optic nerve, the nerve responsible for vision. Sometimes the optic nerve and ganglion cells can also begin to die due to the excessive build-up of psychosine, leading to a reduction in vision.^9,1,10 

The front of the eye is not affected, as the eye is able to detect messages with its photoreceptors, but it cannot transmit them to the brain. Due to the optic nerve damage, the transmission to the brain is affected and the brain will not be able to register images properly, if at all.¹ 

This affects about 7% of Krabbe patients, with some experiencing blurred, unfocussed vision, oscillopsia (makes still things look like they are moving) or strabismus (one eye turned away from the central line of vision).¹⁰

Onset within the first year of life can cause difficulty in feeding, irritability, unexplained fevers, noise hypersensitivity, blindness, spasms of the lower limbs and loss of head control. The effects of the psychosine can be far-reaching, as well as the damage caused to the motor neurons and their abnormal, or compromised myelination. 

Other symptoms associated with later-onset disease include:

• Seizures
• Visual impairment/ blindness
• Lack of motor control
• Burning sensations in the limbs
• Loss of previously possessed skills
• Delayed development
• Muscle spasms

Currently, no cure exists, with infancy onset in approximately 90% of cases leading to more severe symptoms.¹ 

Sometimes gene therapy may be offered in infancy cases, though it is not always effective. 

Summary

Krabbe disease, characterised by the mutation of the GALC enzyme, leads to cell death and the inability to remove old myelin and form new ones. The immune cells which are responsible for removing the debris in the central nervous system, microglia, are supposed to contain this crucial GALC enzyme and when they are unable to function properly they become multinucleated and globular. They accumulate near damaged myelin and cause further damage. This damage also affects the optic nerve, the nerve responsible for vision, resulting in visual problems. Currently, there is no cure for Krabbe disease.