Overview

Krabbe’s disease (global cell leukodystrophy, galactocerebrosidase deficiency) is a rare, inherited disorder in which the metabolism of lipids is altered, resulting in the destruction of the nervous system and the brain. It’s caused by a mutation in the GALC gene that encodes the enzyme galactocerebrosidase which is responsible for facilitating the breakdown of psychosine - a type of lipid compound found in cells of the nervous system. As a result, toxic psychosine accumulates within the cells of the nervous system, ultimately leading to neuronal degeneration. Whilst Krabbe’s disease is relatively uncommon, it is fatal.¹ 

Causes 

Krabbe’s disease is a disorder, inherited in an autosomal recessive pattern. Both parents must carry the mutation for the disease to manifest in the offspring. The mutation in question is on the GALC gene (which is located on chromosome 14). This gene encodes for the enzyme galactocerebrosidase. A mutated version of the gene halts the normal function of this enzyme, leading to Krabbe’s disease pathophysiology. Galactocerebrosidase is involved in the metabolism (breakdown) of psychosine (lipids involved in nervous system function). Abnormal enzyme function therefore results in a build-up of psychosine and other lipids within the cells of the nervous system (such as the neurons). The accumulation of these compounds is toxic to the cells - abnormal levels of psychosine destroy oligodendrocytes - key cells involved in the production of myelin. Myelin is an integral part of the neuronal function - it helps carry signals across the neuron to neighbouring ones and therefore is implied in brain activity. Lack of myelin disrupts neuronal activity and leads to observed symptoms.¹

This disorder is very rare - in the United States it’s estimated that only 1 in 100,000 births will develop Krabbe’s. Males are more affected than females and some ethnic groups show higher prevalence (ex. those of Scandinavian descent).² 

Symptoms

Often the symptoms vary from individual to individual. The typical onset is during the infant years. The severity of symptoms depends on the age of onset - the earlier the disease begins to present, the more severe and life-threatening it can be. 

During infant years typical symptoms of disease presentation include:

• Restlessness (issues with sleep/wake cycle)
• Irritability (infants may cry excessively) 
• Gastrointestinal issues (unexplained nausea, vomiting)
• Difficulties with feeding (infants may have trouble with suckling, which may lead to weight loss).
• The infant may also become hypersensitive to - touch, light and noise. 

As the disease progresses, the infant may begin to develop: 

• Vision difficulties (due to optic atrophy) 
• Seizures (that do not respond to anti-convulsants)
• Peripheral neuropathies (which manifest through muscle weakness, pain, numbness and difficulty moving limbs).²

The most severe symptoms in infant years include complete blindness, deafness, and decerebrate posturing (abnormal, rigid body posture, indicative of brain damage).³

When the disease is present in later childhood years, symptoms include: 

• Irritability
• Visual difficulties
• Abnormal gait
• Motor skills regression 
• Ataxia (loss of coordination and balance)
• Seizures
• Attention deficit hyperactivity disorder

As older kids have less debilitating symptoms, they often have longer survival prognosis (reaching up to 10 years survival post-diagnosis).⁴

Diagnosis

Inclination for the development of Krabbe’s disease can be picked up during newborn screening. Measures of GALC enzyme activity in newborn blood can suggest potential abnormalities in its function and prompt further testing, which can include measuring levels of psychosine (cytotoxic myelin by-product).⁴ Together these measures can aid medical professionals in diagnosing Krabbe’s disease in a newborn. However, these tests do not indicate when the symptoms of the disease will start to manifest - and therefore the development of more throughput methods is required. 

Imaging techniques are also used to diagnose and monitor Krabbe’s disease. Computer tomography (CT) scans of the brain can help identify abnormally dense regions, which would be indicative of myelination issues from lipid metabolism issues. Magnetic resonance imaging (MRI) can pinpoint brain lesions associated with disease progression, the location of which can correlate to a specific symptom.⁴

Krabbe’s patient then requires close monitoring from medical professionals to track disease progression. 

Genetic testing is another method of identifying the likelihood of Krabbe’s diagnosis and this can be performed pre-conception.⁴ Interested parents can undergo molecular genetic analysis of their genomes to identify whether they are carriers of GALC mutation. This information can help inform future parents of potential risks and aid with decisions in family planning. 

Treatment

Currently, no specific treatment for Krabbe’s disease exists. Common fast onset, severity of symptoms and the young age of patients make it difficult to develop a fast-acting and global treatment that would counteract genetically encoded enzyme deficiency. 

However, methods such as hematopoietic stem cell transplant (HSCT) have been employed in cases of Krabbe’s and showed promising results. HSCT works by populating the brains of patients with healthy cells that carry functional GALC activity.⁴ This method helped slow down the progression of the disease. However, HSCT can only show promising results when performed before symptom manifestation/in very early phases and therefore is not a viable option for other patients. 

More research is being done to develop treatment options for Krabbe’s patients. Currently, bone marrow transplantation and gene therapy are being clinically trialled and hopefully in the near future will become a treatment option for Krabbe’s disease patients. 

Summary

In conclusion, Krabbe’s disease is a rare but severe and life-threatening condition that mainly affects infants and young children. It is caused by a mutation in the GALC gene, which encodes for the enzyme galactocerebrosidase. This enzyme is responsible for the breakdown of toxic products in the nervous system such as psychosine. The inability to remove these products results in abnormal function of oligodendrocytes which produce myelin - an integral product in neuronal function. As a result, signals are not able to propagate through the nervous system, resulting in atrophy and degeneration. These abnormalities are manifested in the symptoms Krabbe’s patients experience. 

Symptoms of Krabbe’s disease vary in severity, which depends on the age of onset. Typically, the earlier the symptoms manifest, the faster the disease progresses which greatly reduces the life expectancy. 

Whilst diagnosis and treatment options exist, these often are not throughout and are not available for every case of Krabbe’s. Further research is required to better identify and treat patients of this disease, focusing on not just improving viability but also quality of life.