What is Krabbe Disease?
Krabbe disease is a condition that leads to severe damage in the nervous system. It’s caused by a faulty gene on chromosome 14. This gene is supposed to produce an enzyme called galactosylceramide beta hydrolase, which is crucial for breaking down certain fats in the central and peripheral nervous systems. If this enzyme is not working correctly, these fats build up in the nervous system and lead to tissue damage.
This disease is also called globoid cell leukodystrophy. This name comes from the specific type of cells, called globoid cells, which are often found in the brain during a biopsy. They indicate degeneration in the white matter, which is a part of the brain responsible for transmitting signals from one part to another.
There are four different ways that Krabbe disease usually appears, and these are classified based on when symptoms show up. However, there’s some debate among experts about the age ranges for each category. The categories are:
– Early infantile type: symptoms begin showing from birth to 13 months
– Late infantile type: symptoms start between 13 to 36 months of age
– Juvenile type: symptoms present from 3 to 16 years old
– Adult type: symptoms start in individuals older than 16 years.
What Causes Krabbe Disease?
Krabbe disease happens when there’s a problem in the gene that provides the instructions for an enzyme called galactosylceramide beta hydrolase (GALC). This problem comes from what we call a “loss of function gene mutation”. It’s a bit like having a broken tool in a toolkit – if the tool (or enzyme, in our case) isn’t working properly, it can’t do its job, leading to problems in the body.
There are about 200 different ways this gene can be mutated, and some of these are associated with more severe disease. Large mutations, where a chunk of the gene (like 30 kilobases, or ‘kb’ for short) is deleted or changed, tend to be associated with more severe symptoms.
We’ve found that a 30kb gene deletion is fairly common, in fact. It accounts for 40-45% of cases of the severe, infantile form of Krabbe disease in Northern Europe, and 35% of cases in Mexican patients.
In patients who develop Krabbe disease during childhood or adulthood, about half have either this 30kb gene deletion or other mutations that reduce the activity of the GALC enzyme. This just means that the enzyme isn’t working as well as it should be, leading to the development of the disease.
Risk Factors and Frequency for Krabbe Disease
Krabbe disease is a rare genetic condition that develops rapidly and can be fatal. How often it occurs can greatly differ depending on the population. For example, in Europe, it’s estimated that 1 out of every 100,000 babies are born with the disease. In the United States, that number is believed to be around 1 out of every 250,000 babies, although some estimates bring it closer to the figures found in Europe.
In Israel’s Druze community, however, the disease is considerably more common due to marriages between close relatives, occurring in as many as 6 out of every 1000 babies.
- Among the four types of Krabbe disease, the infantile subtype is the most common, making up 85 to 90% of cases.
- Unfortunately, this subtype is also the most severe, with a mortality rate as high as 90% in the first two years of life.
- The late-onset subtype, while still serious, offers a better chance of survival. After symptoms begin, life expectancy is typically 5 to 7 years.
Signs and Symptoms of Krabbe Disease
There are various stages and forms of a certain disease, each with different symptoms and varying degrees of severity. Everything depends on when symptoms first appear.
In one form of the disease, symptoms appear when the child is still an infant. This variant progresses rapidly and is typically fatal by age 2. Symptoms generally appear between 4 to 6 months of age and include restlessness, irritability, vomiting, feeding difficulty, and failure to thrive. As the disease progresses:
- Stage 1: The child might be overly sensitive to bright lights, loud noises, or touch, and can develop muscle spasms.
- Stage 2: The child might start having trouble seeing, experience seizures that are not responsive to traditional seizure medications, and adopt a peculiar, rigid body posture.
- Stage 3: The disease becomes more severe. The child might lose their ability to see or hear and stop being able to control their movements.
In the late infantile form of the disease, symptoms typically appear between 13 to 36 months of age. Initial symptoms can include irritability, visual difficulties, and abnormal walking. As the disease progresses, the symptoms worsen and may include seizures, episodes of irregular breathing and uncontrolled body temperature. Usually, children with this form of disease do not live past six years of age.
In the juvenile form of the disease, children develop issues with their vision, gait abnormalities, and attention deficit hyperactivity disorder (ADHD). Even though the rate at which the disease progresses can vary, children with the juvenile form of the disease usually pass away within ten years of diagnosis.
In the late-onset form of the disease, patients experience tingling or numbness in the extremities, mood changes, difficulty walking, muscle stiffness, vision loss, seizures, hearing loss, and psychomotor retardation. Sometimes, these patients can also have muscle weakness or curvature of the spine. Some patients may experience physical symptoms without intellectual disability, while others may deteriorate both mentally and physically.
Testing for Krabbe Disease
In many parts of the U.S., newborns get a routine check for Krabbe disease. This involves testing the activity of a particular enzyme called GALC in their white blood cells or skin cells. If the activity is less than 5% of the normal range, it confirms the diagnosis of Krabbe disease. However, this test doesn’t show how severe the disease might be. As this method isn’t always accurate, additional tests can be applied to identify true positive cases. These may include measuring the levels of a substance called psychosine in the blood, or testing specifically for mutations in the GALC gene. High psychosine levels suggest infantile Krabbe’s disease. Given that not all laboratories can identify all GALC gene mutations, and there are several variations of unknown significance, measuring psychosine levels tends to be a more practical and reliable method.
Imaging techniques like CT scans and MRI scans are also used to inspect the brain for signs of Krabbe disease. Initial CT scans may show areas in the brain where myelin, a fatty substance that surrounds and protects nerve fibers, have been lost. Later scans may show areas of thinning in brain tissue due to shrinkage. MRI imaging is particularly useful in detecting specific abnormalities or lesions in the brain associated with Krabbe disease.
A test known as Magnetic Resonance Spectroscopy may be used, looking at specific areas of the brain and measuring certain compound levels. This can help to understand the disease progression, particularly for adult patients.
Moreover, an EEG (Electroencephalography) test may show signs of abnormal brain activities, which are common in Krabbe disease. The child may also need an evaluation by an ear and eye specialist to assess any loss of hearing or vision.
Genetic testing is fundamental, as it not only identifies carriers within a family but also identifies pregnancies at risk. In some cases, the type of mutation identified by genetic testing can help predict the expected symptoms and disease severity.
A ‘lumbar puncture’ or ‘spinal tap’ can also provide important information. This test, which involves collecting a fluid from the spine, may show abnormalities in the protein levels in babies with Krabbe Disease.
Tests like Electromyography and Nerve Conduction Studies that look at the nerves’ electrical activity also offer helpful insights, especially revealing slowed nerve responses, a common characteristic in Krabbe disease.
Lastly, a brain biopsy, surgery to remove a small piece of the brain for testing, can confirm a Krabbe disease diagnosis by showing the loss of myelin, the protective tissue around the nerves, and the presence of certain abnormal cells.
Treatment Options for Krabbe Disease
At present, options are limited for treating symptom-free or mildly symptomatic patients affected by the infantile form of Krabbe disease, a rare genetic disorder that affects the nervous system.
One treatment option is Hematopoietic Stem Cell Transplant (HSCT). This involves transplanting blood-forming cells from a healthy donor to the patient. These cells help the patient’s brain generate microglia, cells that support brain health and demonstrate strong GALC enzyme activity. GALC is an enzyme missing or present in low amounts in people with Krabbe disease. HSCT works best when performed before symptoms appear, and it can help slow down the disease’s progression. Some research shows it can stop the decline of cognitive (thinking, comprehension, learning) and motor (movement, coordination) abilities in the patient.
HSCT is associated with certain risks, largely due to the chemotherapy the patient receives to prevent rejection of the transplanted cells. Efforts are ongoing to make this treatment safer and reduce its side effects.
Cord Blood Stem Cell Transfusion is another potential treatment. This involves transferring stem cells taken from the umbilical cord blood of an unrelated donor to the patient. However, it has been found beneficial only for patients who are treated before symptoms appear.
As we wait for more effective treatment options for Krabbe disease to be developed, supportive care can be provided to help manage the disease’s symptoms. This may include:
– Muscle relaxants to ease spasms
– Anticonvulsants, which can sometimes help manage seizures
– Physiotherapy to enhance movement
– Occupational therapy to improve motor skills in children
– Speech therapy to aid swallowing and communication
– Tube feedings to ensure adequate nutrition if swallowing becomes difficult
What else can Krabbe Disease be?
When diagnosing Krabbe disease in infants, the possibilities include a wide range of other conditions that affect the brain and nervous system. These also show up as developmental delays and unusual white patches on brain scans:
- Alexander disease
- Canavan disease
- GM2 gangliosidoses
- Metachromatic leukodystrophy
- Sphingomyelinase deficiency
Even though it might be tricky to differentiate Krabbe disease from these conditions, doctors can confirm it using specific metabolism and genetic tests.
What to expect with Krabbe Disease
Infantile Krabbe disease typically reduces a patient’s average lifespan to about 13 months. Patients who develop the disease later in infancy usually pass away within two years of the disease beginning. There are variations in how the disease progresses and the impact it has on lifespan for those who develop the disease during childhood or as adults.
An treatment option known as hematopoietic stem cell transplantation (HSCT) – which involves replacing diseased or damaged stem cells in the bone marrow with healthy ones – can significantly improve short-term survival rates for individuals who are treated during the early newborn period before they start showing symptoms.
Possible Complications When Diagnosed with Krabbe Disease
This disease is often deadly. Most babies diagnosed with the disease sadly do not survive past two years of age. Children diagnosed even somewhat later usually succumb within two years of showing symptoms, and teenagers typically have around ten years post-diagnosis. The disease also brings numerous complications that come with their own challenges that the patient must face, such as:
- Hearing loss
- Loss of sight
- Stiffness in body posture
- Mental decline
- Increased risk of infections due to accidentally sucking food or liquid into the lungs
- Difficulty breathing resulting from weakened muscles
Preventing Krabbe Disease
Krabbe disease is a debilitating condition that is caused by genetics. It is crucial for both patients and caregivers to understand its nature. It’s also important that they are aware of potential complications that may arise, the likely course of the disease, and why starting treatment as early as possible can help. They should also know that a medical team will be working closely with them to achieve the best possible health outcome. Simple genetic tests are available for parents of children with Krabbe disease. This helps them understand if future pregnancies may also be affected. Knowing this, they can also discuss different options to prevent having another child with the disease.
