Krabbe disease is a rare inherited disorder where an enzyme normally responsible for processing lipids (fats) in the brain and nervous system is deficient or completely absent. This causes a build-up of these lipids in the brain. They are neurodegenerative and cause damage to brain cells, particularly the white matter. Krabbe disease progresses rapidly and is fatal. It can occur at any age, first presenting at around 6 months, or can begin to present any time after this and into adulthood. The age when symptoms begin can affect the type and severity of symptoms, and the main symptoms are affecting mental and motor ability.

Treatment is focused on slowing the progression of the disease, and to counteract symptoms as they arise, and supporting the patient in maintaining as much normal function as possible.

What is krabbe disease?

Krabbe disease is a rare, inherited disease in which the affected individual has a genetic mutation that causes the absence or dysfunction of an enzyme (galactocerebrosidase) that is important in breaking down lipids (fats) in the brain and central nervous system. Without the functioning enzyme, lipids build up and cause damage to the cells of the brain, leading to neurodegeneration that is a characteristic of Krabbe disease.¹ 

Once symptoms begin, Krabbe disease progresses rapidly, manifesting many neurological and physical issues, eventually leading to death. There is no cure for Krabbe disease because it is caused by a genetic mutation, and once brain cells are damaged, there is no way for them to be repaired.

Cause of krabbe disease

Krabbe disease is an inherited condition and is passed genetically to any offspring in a recessive manner, meaning that two copies (one from each parent) of the mutated gene are needed for the disorder to be expressed. This means that both parents must be carriers for the disorder, resulting in a 1 in 4 chance a child would be born with the defective gene that causes Krabbe disease, a 50% chance of being a carrier of a faulty gene and a 25% chance of having no defective copies of the gene. There is no difference depending on whether the child is male or female.

The mutation occurs in a specific area of the DNA called the GALC gene. This is the area of DNA that has the instructions to make a specific enzyme called galactocerebrosidase. This enzyme is important in the proper function and structure of the brain as it is involved in the breakdown of galactosylceramide, a component of the myelin sheaths that protect nerve cells and ensure proper nerve conduction. The proper function of the GALC protein is important in the destruction of old myelin sheaths and the creation of new ones. This maintains proper signaling and the structure of nerves in the brain to widen the nervous system.

The GALC enzyme is also important in breaking down lipids (fatty molecules) that are a by-product of myelin formation. The action of the GALC enzyme is important as these lipids are toxic, and when they build up, they destroy the myelin sheaths around nerve cells.²

Symptoms of krabbe disease

The age at which symptoms develop has a large impact on the severity of the symptoms;  life expectancy is also affected. The younger the onset of symptoms, the more severe and quicker the symptoms progress.

Infantile Krabbe disease is often defined in different stages:

Stage 1- Normal growth up to roughly 6 months of age; symptoms begin with irritability, vomiting, restlessness, difficulty feeding and failure to thrive. This may be accompanied by an increased sensitivity to touch, noise and light, which may cause spasms.

Stage 2- Symptoms progress and generally include visual difficulties, optic atrophy, abnormal posturing (due to spasms causing a posture change) and seizure-like episodes (different from epilepsy and cannot be treated with anticonvulsants).

Stage 3- This is the most severe stage, blindness, deafness, further abnormal posture (decerebrate posturing), reduced mobility and potentially no voluntary movement. This is usually fatal by age 2.

Late-onset infantile Krabbe disease:

Symptoms present between 13 and 36 months of age tend to be irritability, vision changes, and abnormal gait (walking). As it progresses, there would be seizures,  some difficulties breathing and body temperature instability. The average age of death is 6 years old.

Juvenile onset Krabbe disease:

Common symptoms are vision changes, tremors, gait abnormality and attention deficit hyperactivity disorder (ADHD).Rrate of progression can vary, but it will eventually become more severe, with death occurring within 10 years of symptom onset.

Late-onset Krabbe disease:

Symptoms begin with a burning sensation in the extremities, changes in mood and behavior, Ataxia (clumsy movement), vision and hearing issues leading to blindness/deafness, seizures and spasticity (abnormal muscle tightness). Often, those late-onset diseases will result in physical and mental deterioration.

This would also lead to death, though the progression may not be as rapid.³ 

Diagnosis

Infantile Krabbe disease is the most common, and a diagnosis is generally confirmed by testing for activity of the GALC enzyme; a test of the GALC gene can be done to confirm a variant that causes Krabbe disease, and both these tests can be done in tandem to ensure a correct diagnosis.⁴ 

Treatment and management of krabbe disease

Krabbe disease is incurable, and treatment is generally reserved for those that are asymptomatic (show no symptoms) or are minimally symptomatic, as they would respond best to treatment as opposed to those at a more advanced stage.

The main form of treatment is hematopoietic stem cell transplants(HSCT). These are derived from bone marrow or umbilical cord blood. These cells are undifferentiated, meaning they have the potential to turn into any cell in the human body. Transplanting with these stem cells is done with the hope that they will become the type of cells that are prevented from being damaged, increase the life expectancy, and delay worse symptoms. With these stem cells coming from healthy donors, they can produce the GALC enzyme, although this is at low levels.⁵ 

Supportive treatment is often used once symptoms manifest; these are methods that seek to ease symptoms in the hope that the remaining time can be as comfortable as possible. The treatments are:

• Muscle relaxants for spasms
• Anticonvulsants for seizures
• Physical therapy to aid movement and lessen deterioration.
• Tube feeding for proper nutrition if swallowing is affected.

These therapies are not perfect but are the best methods for attempting to improve the quality of life for those living with Krabbe disease.

Summary

Krabbe disease is a genetic disorder where the gene that codes for a specific enzyme is affected, and so the enzyme is defective or completely absent. This results in the build-up of lipids (fatty molecules) in the brain; these are toxic and cause the degradation of nerve cells. 

Krabbe disease can manifest from 4-6 months of age up until adulthood. The age of onset affects the severity of symptoms and speed of progression. When onset occurs at an early age, progression is very fast, and death can occur within 18 months. In adulthood, symptoms are often both physical and mental, causing a gradual decline in health and independence.

Treatment is mainly used in those that have not yet developed symptoms, as these people respond best to this through hematopoietic stem cell transplant. These cells, from a healthy donor, can release small levels of the enzyme that an affected person is lacking and help the nerve cells that would be damaged by a build-up of lipids.

Most treatment focuses on supporting those who have developed symptoms, ensuring they have as good a quality of life as possible in the time they have left. This is done by combatting symptoms, focusing on stopping seizures and spasms, and aiding feeding and physical therapy to retain as much muscle control and strength as possible.