Although Krabbe disease is a rare neurological disease, it affects 1 in 100,000 children in Europe and manifests with serious and often fatal symptoms. The disease presents early in life and exhibits rapid disease progression. Therefore, understanding the diagnosis, treatment and management options for Krabbe disease is essential.

In this article, we will briefly describe Krabbe disease, its stages, and the corresponding symptoms. Current diagnostic and treatment options will then be explained, followed by the various management strategies available to individuals with Krabbe disease. Lastly, new potential treatment options will be discussed to ensure a comprehensive understanding of Krabbe disease, its diagnosis and its treatment pathway.

Introduction

Krabbe disease is a rare neurological disorder that can be inherited within families. It is estimated to be found in 1 of 100,000 and 1 of 250,000 children in Europe and the United States respectively. It is a type of leukodystrophy disease, which results from the loss of myelin, the protective layer around nerve cells.

Krabbe disease is heritable as individuals can inherit faulty copies of the GALC gene from their parents. This gene is responsible for the healthy function of the galactocerebrosidase enzyme which is an essential part of myelin in nerve cells. Faulty copies of GALC therefore lead to loss of the protective myelin layer in nerve cells of Krabbe disease patients. Furthermore, the inheritance pattern is autosomal recessive, which means that both parents of Krabbe disease patients must be carriers of a faulty GALC gene copy.

Loss of myelin is detrimental to the transmission of nerve signals in patients with Krabbe disease. This destroys healthy cells and forms large abnormal cells (globoid cells) in the brain, manifesting in the neurological symptoms of Krabbe disease, such as intellectual disability, paralysis, and deafness.

Symptoms of Krabbe disease

Up to 90% of Krabbe disease patients are diagnosed in early life, from about 1 – 7 months of age. This is known as the infantile form of Krabbe disease, which is commonly described in three main stages:¹

Stage 1 -  refers to the initial onset of symptoms which include:

• Restlessness
• Muscle weakness (hypotonia)
• Irritability and difficulty feeding
• Vomiting
• Increased sensitivity to touch, noise, or bright lights

Stage 2 - is diagnosed as symptoms progress into:

• Vision loss
• Muscle contractions in the neck, trunk and limbs which cause an abnormal posture
• Seizure-like episodes
• Delays in development or loss of previously established developmental milestones

Stage 3 - describes the full severity of the disease when the following symptoms are observed:

• Loss of sight
• Loss of hearing
• Abnormal posture: Often observed is the holding of straight arms and legs, while head and neck are arched back
• Decreased mobility

Contrastingly, late-onset Krabbe disease is normally diagnosed after 1 year of age. The symptoms are similar to the infantile form, following similar disease progression and increasing symptom severity.² While the infantile form is normally fatal by age 2, late-onset Krabbe disease cases are normally more varied and some patients live up to 10 years after initial diagnosis.³

Diagnosis of Krabbe disease

Rapid diagnosis of Krabbe disease is essential given its severe and rapidly progressing symptoms. Additionally, the efficacy of some Krabbe disease treatments is observed to be time-sensitive and hence efficient diagnosis can significantly improve patient outcomes.

Diagnosing the infantile form of Krabbe disease is generally more straightforward given more severe symptoms. However, late-onset cases vary in progression and severity, complicating diagnosis.

Many states in the US currently screen for Krabbe disease in their standard newborn screening protocol. The test measures the levels of GALC enzyme activity in newborns, with low activity levels supporting further testing for potential Krabbe disease.⁴

Further testing can measure psychosine levels in the blood or sequence the GALC gene to identify disease-causing errors. Measuring psychosine levels is a popular method given that genetic sequencing is unavailable in every clinic. It is an essential step as GALC levels can be low for various reasons and a positive psychosine result drastically increases the sensitivity of a Krabbe disease diagnosis.⁴

Once aKrabbe disease is suspected using the above diagnostic tests, a thorough health assessment is necessary to confirm the diagnosis and uncover symptoms related to the disease.

A neurological assessment is conducted through magnetic resonance imaging (MRI) and electroencephalography (EEG). While an MRI detects brain lesions associated with Krabbe disease, an EEG highlights any abnormal electrical brain signalling. A lower conduction velocity of nerves is detected in most infantile forms and 1 in 5 late-onset Krabbe disease cases. A lumbar puncture may also be used to test cerebrospinal fluid (CSF) protein levels confirming infantile-form Krabbe disease. Moreover, the examination of a Krabbe patient’s vision and hearing is important to determine the extent of eye and ear function.⁴

Lastly, molecular genetic testing should be conducted on parents and other family members who may be carriers of the causal GALC gene variant. This will inform genetic counselling of the disease and advise the family about their Krabbe disease risk in future pregnancies. This is important given that in utero genetic testing can identify pregnancies affected by Krabbe disease in mothers with a family history, increasing the likelihood of early treatment intervention to maximise outcomes.

Current treatment and Management of Krabbe disease

Currently, there is still no curative treatment for Krabbe disease. Given the progressive and severe neurodegenerative symptoms of the disease, the disease is usually fatal within the decade of symptom onset.

Hematopoietic stem cell transplant (HSCT) is the main treatment available for Krabbe disease which slows down neurodegeneration.  In this treatment, stem cells from a healthy donor are used to replace the stem cells found in the Krabbe disease patient. These donor cells have healthy function and result in normal GALC enzyme function, unlike the original stem cells of the individual with Krabbe disease.

HSCT normally takes the form of an umbilical cord blood transplant in children with Krabbe disease. This slows disease progression and is observed to be more effective before the onset of Krabbe disease symptoms, highlighting the importance of early diagnosis. While some studies have shown that HSCT can momentarily halt neurodegeneration, the treatment remains non-curative and efficacy varies based on the time of HSCT. Most patients experience difficulties with walking and speech by the end of the first decade of life regardless of HSCT.⁵

It is important to note that HSCT is not recommended to all Krabbe patients and its efficacy is greatly dependent on each individual’s case. Therefore, it is essential to consult a healthcare professional when exploring this treatment option.

Additionally, management strategies can support individuals with Krabbe disease through their symptoms to achieve a better quality of life. Examples of common management strategies include:

• Medication to reduce muscle spasms and seizures
• Physical and occupational therapy to manage motor decline
• Speech therapy
• Tube feeding if swallowing is affected

Future treatment options for Krabbe Disease

Since Krabbe disease is caused by errors in only one gene (GALC), it has the potential to be treated with gene therapy approaches. Currently, there are preliminary clinical trials which test for the efficacy of gene therapies in Krabbe disease. Results from these trials will dictate whether such therapies hold promise in the cure of Krabbe disease.⁶

Summary

In conclusion, Krabbe disease is a rare, neurodegenerative disease caused by the inheritance of a faulty GALC gene. It normally presents in the first two years of life and presents with rapid progression and serious symptoms.

The current diagnosis of Krabbe disease is achieved by an initial test for GALC activity followed by psychosine testing. Low GALC activity and high psychosine concentrations are indicators of Krabbe disease and warrant further neurological, sensory, motor and genetic assessments in these patients.

While there is currently no curative treatment for Krabbe disease, HSCT can slow disease progression if administered before the onset of symptoms. However, most patients still deteriorate even with HSCT and therefore management strategies of Krabbe disease are critical in maintaining patients’ quality of life. Gene therapies are being explored in Krabbe disease, although the work is still in initial stages and further clinical trial results will need to be obtained to support its development.