Krabbe disease (also called globoid cell leukodystrophy) is a severe neurological condition. It is part of a group of disorders known as leukodystrophies, which result from the loss of myelin (demyelination) in the nervous system. Myelin is the protective covering around nerve cells that ensures the rapid transmission of nerve signals. Krabbe disease is also characterized by abnormal cells in the brain called globoid cells, which are large cells that usually have more than one nucleus.

The most common form of Krabbe disease, called the infantile form, usually begins before the age of 1. Initial signs and symptoms typically include irritability, muscle weakness, feeding difficulties, episodes of fever without any sign of infection, stiff posture, and delayed mental and physical development. As the disease progresses, muscles continue to weaken, affecting the infant's ability to move, chew, swallow, and breathe. Affected infants also experience vision loss and seizures. Because of the severity of the condition, individuals with the infantile form of Krabbe disease rarely survive beyond the age of 2.

Less commonly, Krabbe disease begins in childhood, adolescence, or adulthood (late-onset forms). Vision problems and walking difficulties are the most common initial symptoms in these forms of the disorder, however, signs and symptoms vary considerably among affected individuals. Individuals with late-onset Krabbe disease may survive many years after the condition begins.

Mutations in the GALC gene cause Krabbe disease. This gene provides instructions for making an enzyme called galactosylceramidase, which breaks down certain fats called galactolipids. One galactolipid broken down by galactosylceramidase, called galactosylceramide, is an important component of myelin. Breakdown of galactosylceramide is part of the normal turnover of myelin that occurs throughout life. Another galactolipid, called psychosine, which is formed during the production of myelin, is toxic if not broken down by galactosylceramidase.

GALC gene mutations severely reduce the activity of the galactosylceramidase enzyme. As a result, galactosylceramide and psychosine cannot be broken down. Excess galactosylceramide accumulates in certain cells, forming globoid cells. The accumulation of these galactolipids causes damage to myelin-forming cells, which impairs the formation of myelin and leads to demyelination in the nervous system. Without myelin, nerves in the brain and other parts of the body cannot transmit signals properly, leading to the signs and symptoms of Krabbe disease.

Normal Function

The GALC gene provides instructions for making an enzyme called galactosylceramidase. Through a process called hydrolysis, this enzyme uses water molecules to break down certain fats called galactolipids, which are found primarily in the nervous system and kidneys.

Within cells, galactosylceramidase is found in enzyme-filled sacs called lysosomes where it hydrolyzes specific galactolipids, including galactosylceramide and psychosine. Galactosylceramide is an important component of myelin, the protective covering around certain nerve cells that ensures the rapid transmission of nerve impulses. Its breakdown by galactosylceramidase is part of the normal turnover of myelin that occurs throughout life. Psychosine, which is toxic to cells, forms during the production of myelin and is quickly broken down by galactosylceramidase. Under normal conditions, tissues contain very little psychosine.

Health Conditions Related to Genetic Changes

Krabbe disease

More than 200 GALC gene mutations that cause Krabbe disease have been identified. Krabbe disease is a brain disorder that usually begins in infancy (infantile Krabbe disease) and causes movement and eating problems, impaired development, and seizures. The most common mutation in affected individuals of European ancestry (often called 30-kb del) deletes a large segment of the GALC gene. Other mutations insert additional DNA building blocks (nucleotides) into the GALC gene, delete a small number of nucleotides from the gene, or replace single nucleotides with incorrect nucleotides.

These GALC gene mutations severely reduce or eliminate the activity of the galactosylceramidase enzyme. As a result, galactosylceramide and psychosine cannot be broken down. The accumulation of these galactolipids causes damage to myelin-forming cells, which impairs the formation of myelin and leads to the loss of myelin (demyelination) in the nervous system. Without myelin, nerves in the brain and other parts of the body cannot transmit signals properly, leading to the signs and symptoms of Krabbe disease.

Some individuals develop symptoms of Krabbe disease in childhood, adolescence, or adulthood (late-onset Krabbe disease). It is thought that these individuals have a mutation that allows some activity of the galactosylceramidase enzyme, which delays onset of the condition. The severity of the condition may also be affected by the presence of additional common variations (polymorphisms) in the GALC gene that affect the activity of the galactosylceramidase enzyme.

Other Names for This Gene

• galactocerebrosidase
• galactosylceramide beta-galactosidase
• GALC_HUMAN
• GALCERase

Genomic Location

Krabbe disease is a genetic condition. Babies inherit it from their biological (birth) parents.

• Krabbe disease is an autosomal recessive condition. Babies inherit the condition when each parent passes down a nonworking GALC gene to their baby. Only babies with two nonworking GALC genes—one from the mom and one from the dad—have this condition.
  • People with one working copy and one nonworking copy of the GALC gene are called carriers.
  • Carriers do not have or develop the condition. However, they may pass down a nonworking copy of the gene to their children.
  • If two parents are carriers of a nonworking copy of the GALC gene, they have a 1 in 4 chance of having a child with Krabbe disease.
  • Carriers for Krabbe disease often do not know they are carriers before having a child with the condition. In most cases, families have no history of the condition until the birth of a child with Krabbe disease.
  • Parents who already have a child with Krabbe disease still have a 1 in 4 chance of having another child with Krabbe disease. This 1 in 4 chance stays the same for all future children.
• Genetic counselors and medical geneticists can help families learn about this condition and the chance of having children with it.

Signs of Krabbe disease can appear in the first few months after birth, particularly in the early infantile-onset form. The later-onset form of Krabbe disease may not appear until later in infancy, childhood, adolescence, or adulthood.

Signs of the condition may include the following:

• Irritability
• Muscle weakness
• Stiffness and muscle spasms
• Feeding problems
• Fevers
• Seizures
• Loss of motor milestones (milestone regression)
• Vision loss

Newborn screening for Krabbe disease requires collecting a small amount of blood from your baby’s heel.

Screening measures how much GALC enzyme is in your baby’s blood. Babies with a low level of this enzyme might have Krabbe disease.

In some cases, screening measures how much of the galactolipid psychosine is in your baby’s blood. Babies with a high level of psychosine might have Krabbe disease.

Screening may also look at the gene that causes Krabbe disease. Babies found to have changes in the Krabbe disease gene may have Krabbe disease.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for Krabbe disease is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need the following tests after an out-of-range screening result:

• Blood or urine tests
• DNA testing using a blood or cheek swab sample
• Measurement of certain proteins in the spinal fluid (a CSF total protein test)
• Magnetic resonance imaging (MRI)
• Tests of your baby's nerve function (nerve conduction velocity test)

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly.

False-positive newborn screening results for this condition may happen. Some babies with positive newborn screening results for Krabbe disease have “pseudodeficiency.” Pseudodeficiency means that a baby’s enzyme levels are low on the screening but are normal in their body. These babies do not have and will never develop Krabbe disease. In very rare cases, babies may have positive newborn screening result for Krabbe disease, but actually have a different disease called Saposin A deficiency.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of treatment is to try to address the health problems caused by this condition.

Treatments may include the following:

• Stem cell transplant (SCT)
• Specific treatments to address health problems like:
  • Reflux
  • Feeding problems
  • Spasticity
  • Respiratory problems
• Gene Therapy and other research clinical trials may also be available.

Children who receive early and ongoing treatment for Krabbe disease may live longer and have fewer health issues.

In the United States, Krabbe disease affects about 1 in 100,000 individuals. A higher incidence (6 cases per 1,000 people) has been reported in a few isolated communities in Israel.