Krabbe Disease

Overview

Krabbe Disease is a rare, inherited condition that affects 1 in 250,000 live births in the United States. This condition affects the nerve cells and results in neurological issues such as intellectual disability, paralysis, and deafness. Krabbe Disease typically affects babies under the age of 1 yet can also affect older children and adults. As a degenerative condition, symptoms progressively get more severe over time.

Synonyms

Krabbe Disease is known by many terms and may be referred to as such by medical professionals and other online resources. Below is a list of synonyms for this condition:

• Galactocerebrosidase (GALC) Deficiency
• Galactocerebroside Beta-Galactosidase Deficiency
• Galactosylceramidase Deficiency
• Galactosylceramide Lipidosis
• Globoid Cell Leukoencephalopathy
• Leukodystrophy, Globoid Cell
• Sphingolipidosis, Krabbe's Type

Children with Krabbe Disease

Signs and Symptoms

Krabbe Disease is a degenerative condition. This means that over time, symptoms become more severe and eventually lead to death in the affected person. Although typically affecting infants, Krabbe Disease symptoms may not begin until later in life. Because of this, Krabbe Disease is often categorized according to when symptoms begin.

Juvenile/ Infantile Krabbe Disease

This form of Krabbe Disease is the most common, affecting 90% of cases. Here, symptoms begin prior to 18 months of age and is generally fatal by age 2 without treatment intervention. On average, these children tend to grow, develop, and hit milestones as expected until around 4-6 months of age. At this point, the symptoms follow 3 stages.

Stage 1:

• Restlessness and irritability
• Vomiting
• Difficulty nursing and bottle feeding
• Failure to thrive
• Fevers
• Muscle weakness
• Hypersensitive to touch, noise, and bright light leading to muscle spasms

Stage 2:

• Vision changes (optic atrophy)
• Backbend from neck to heel (opisthotonic posturing)
• Seizure-like episodes
• Slowed mental and physical development
• Regression of developmental milestones

Stage 3:

• Hearing loss
• Vision loss
• Decreased mobility
• Abnormal body posture (decerebrate posturing)

Adult/ Late-Onset Krabbe Disease

Krabbe Disease beginning after 18 months of age is quite variable, with each affected person experiencing a different course of symptoms with variable severity. Below is a list of symptoms that may occur throughout the life of a person with Krabbe Disease:

• Progressive loss of mental function
• Deterioration of motor skills
• Muscle weakness and inability to stretch (Hypertonia)
• Myoclonic seizures (uncontrollable, fast muscle movements)
• Spasticity (involuntary muscle movement)
• Fever
• Blindness
• Difficulty swallowing
• Deafness

Prognosis

Death from Krabbe Disease typically results from breathing difficulties. The healthcare team can help to make this process as comfortable as possible through the use of palliative care services.

How Krabbe Disease Affects the Body

Metabolism Overview

Metabolism refers to how we process proteins, the building blocks our bodies use to function. Enzymes are a type of protein that build up and break down other proteins. Our DNA, organized into units called genes, can be thought of as an instruction manual for protein function. Sometimes, differences in DNA prevents proteins from working properly, leading to conditions such as Krabbe Disease.

Nerve cell with myelin sheath visible.

Neurology Overview

Nerve cells can be thought of as cables that carrier electrical signals between your brain and your body. These signals allow us to…

• Experience sensations such as touch, taste, sight, smell, and sound
• Consciously move our muscles to allow for activities such as walking, running and sitting up straight
• Subconsciously work muscles in our body needed for activities such as breathing, digesting foods, and sweating

These nerves are protected by a layer of insulation called myelin. Myelin allows the electrical signals to move quickly and efficiently along the nerve from the brain to the body and back.

What Specifically Causes Krabbe Disease Symptoms?

Krabbe Disease is caused by a difference in a gene called GALC. In typical bodies, this gene creates an enzyme called galacrocerebrosidase. Galacrocerebrosidase is responsible for creating a protein product called Galactocerebroside. Galactocerebroside is an important part of the myelin and allows it to function properly.

When the GALC gene is not working properly, galacrocerebrosidase does not work properly. This leads to a buildup of harmful toxins in the body and breaks down the myelin, preventing signals from moving effectively between the brain and the body.

This myelin breakdown results in the neurological symptoms associated with Krabbe Disease such as intellectual disability, deafness, and blindness.

Recessive inheritance pattern showing the likelihood of having an affected child when both parents are carriers.

Inheritance

Humans have two copies of every gene, one from their biological mother and one from their biological father. Certain genes, such as GALC, can continue functioning normally when only one gene is altered. However, when both copies of this gene are altered, signs and symptoms of a disease are experienced. These conditions are called “recessive” and often do not show up in every generation of a family. People with one altered cope of a gene and one typical copy of a gene are referred to as “carriers”. Carriers of a GALC difference show no signs or symptoms of Krabbe Disease. When both biological parents of a child are carriers of a recessive altered gene, they have a 25% risk of having a child with the condition, Krabbe Disease in this case. Additionally, they have a 50% chance of having a child who is also a carrier for the condition. Finally, there is a 25% chance that the child inherited both parents’ typical genes and is not a carrier of the condition. These chances are the same for each pregnancy. This inheritance pattern can be viewed in the image to the left.

If you are concerned about the chance of passing on Krabbe Disease to your children, talk to a health care provider about genetic counselling and assisted reproductive technologies.

Diagnosis

Prenatal

Prenatal diagnosis is not available to the general population for Krabbe Disease unlike other conditions such as Down Syndrome. If you have a family history of Krabbe Disease and are concerned about your chance of having an affected pregnancy, diagnostic testing can be arranged. A test called an amniocentesis can be can be completed after 18 weeks gestation. Through the use of a needle through the abdomen, a small amount of the baby's DNA is captured and analyzed to look for differences in the GALC gene.

Newborn Screening

Newborn screening for Krabbe Disease may be offered depending on your location. Here, a heel prick at birth is analyzed too look for activity of the Galactosylceramidase enzyme. If abnormal activity is seen, a genetic test will be ordered to confirm a Krabbe Disagnosis.

Childhood

For later-onset forms of Krabbe Disease, a diagnosis can be made by analyzing Galactosylceramidase activity, such as in newborn screening, or through the use of an MRI to look for brain differences associated with the disorder.

Management

There is no cure for Krabbe Disease. Typically, management plans are supportive, focusing on increasing the quality of life and avoiding complications. Below is a list of common treatment aspects:

• Muscle relaxant medication for spasms
• Anticonvulant drugs for seizures
• Physical therapy to increase mobility
• Occupational therapy
• Tube feeding if swallowing is affected.

Haematopoietic Stem Cell Transplantation (HSCT)

When a diagnosis is made before symptoms become severe, a HSCT may be able to meaningfully prolong life and increasing its quality. Haematopoietic stem cells (HSC) are immature cells that are can develop into all types of blood cells. This procedure required a donor to provide healthy HSC to the affected person. These cells then mature within the recipient and replace their poorly functioning cells with cells with proper enzyme function.

Patient Resources

Patient Resources and SUpport Groups

KrabbeConnect

• KrabbeConnect strives to be the source of comprehensive information and access to resources for patients with Krabbe disease through the cooperative planning, implementation, analysis and reporting of controlled clinical trials, as well as observational studies and educational activities within the Krabbe community.

Hunter's Hope

• Hunter's Hope is a nonprofit organization created by the family of an affected child commited to giving hope through education, awareness, research, and family care.

It is common for affected families to feel a sense of isolation after receiving a rare disease diagnosis. Many find comfort in reading about the stories of other individuals affected by a similar condition, or in joining online support groups. These can be found within the resources listed above.

Genetic Counselling

Genetic counsellors can help patients understand their diagnosis, their chance of having an affected child, and testing options. Consider speaking to a genetic counsellor near you to learn more about how Krabbe Disease may affect your or your family.

Canada: Canadian Association of Genetic Counsellors

United States: National Society of Genetic Counselors