Krabbe’s disease is an inherited disease that affects the nerves of the nervous system. It affects about 1 in 100 people and most often affects babies. It is caused by the malfunction of an enzyme that results in damage to the myelin sheath.

Definition

Krabbe disease is an inherited disorder that destroys the sheath that surrounds the nerve cells (myelin) of the central (brain and spinal cord) and peripheral nervous system.

In most cases, the signs and symptoms of Krabbe disease develop in babies before the age of 6 months, usually resulting in death by the age of 2 years. When it develops in older children and adults, the course of the disease can vary widely.

There is no cure for Krabbe disease, and treatment is focused on supportive care. However, stem cell transplant methods have shown some success in infants who are treated before symptoms start and in some older children and adults.

Krabbe disease affects approximately 1 in 100 people. The infantile form accounts for 000% of cases in populations of northern Europe. It is also known as globoid cell leukodystrophy.

Causes of Krabbe’s disease

Krabbe disease is caused by a mutation in a particular gene (GALC) that produces a specific enzyme (galactocerebrosidase). The absence of this enzyme caused by the mutation leads to the accumulation of products (galactolipids) which will destroy the oligodendrocytes – cells which are at the origin of the formation of myelin. The subsequent loss of myelin (a phenomenon called demyelination) prevents nerve cells from sending and receiving messages.

Who is most affected?

The gene mutation associated with Krabbe disease only causes the disease if the patient has both mutated copies of the gene inherited from the parents. A disease resulting from two mutated copies is called an autosomal recessive disorder.

If each parent has a mutated copy of the gene, the risk to a child would be as follows:

• A 25% risk of inheriting two mutated copies, which would lead to the disease.
• A 50% risk of inheriting from a single mutated copy. The child is then a carrier of the mutation but does not develop the disease.
• A 25% risk of inheriting two normal copies of the gene.

Diagnosis of Krabbe disease

In some cases, Krabbe disease is diagnosed in newborns with screening tests before symptoms appear. However, in most cases, the onset of symptoms is triggered first before a test, with subsequent exploration of possible causes.

Laboratory tests

A blood sample and a biopsy (small sample of skin) are sent to a lab to assess the level of activity of the GALC enzyme. A very low level or zero activity level may reflect the presence of Krabbe disease.

Although the results help a doctor make a diagnosis, they do not provide evidence of how quickly the disease can progress. For example, very low GALC activity does not necessarily mean that the disease will progress quickly.

Electroencephalogram (EEG)

An abnormal EEG can reinforce the hypothesis of a disease.

Imaging tests

Your doctor may order one or more imaging tests that can detect loss of myelin in affected areas of the brain. These tests include:

• Magnetic Resonance Imaging, a technology that uses radio waves and a magnetic field to produce detailed 3-D images.
• Computerized tomography, a specialized radiology technology that produces two-dimensional images.
• The study of nerve conduction, which measures how quickly nerves can send a message. When the myelin that surrounds the nerves is impaired, nerve conduction is slower.

Genetic test

A genetic test can be done with a blood sample to confirm a diagnosis.

Genetic testing to assess the risk of having a child with Krabbe disease may be considered in certain situations:

• If the parents are known carriers, they can order prenatal genetic testing to determine if their child is likely to develop the disease.
• Whether one or both parents are likely carriers of a GALC gene mutation due to a known family history of Krabbe disease.
• If a child is diagnosed with Krabbe disease, a family may consider genetic testing to identify their other children who might develop the disease later in life.
• Known carriers, who use in vitro fertilization, may request genetic testing before implantation.

Newborn screening

In some states, a test for Krabbe disease is part of a standard set of assessments for newborns. The initial screening test measures the activity of the GALC enzyme. If the activity of the enzyme is low, follow-up GALC tests and genetic tests are done. The use of screening tests in newborns is relatively new.

Evolution et complications possible

A number of complications – including infections and breathing difficulties – can develop in children with advanced Krabbe disease. In the later stages of the disease, children become disabled, stay in their beds, and end up in a vegetative state.

Most children who develop Krabbe disease in childhood die before the age of 2, most often from respiratory failure or complications from complete loss of mobility and marked decrease in muscle tone. Children who develop the disease later in childhood may have a somewhat longer life expectancy, usually between two and seven years after diagnosis.

The first signs and symptoms of Krabbe disease in early childhood can resemble several illnesses or developmental issues. Therefore, it is important to get a quick and accurate diagnosis if your child has any signs or symptoms of the disease.

The signs and symptoms most commonly associated with older children and adults are not specific to Krabbe disease and require timely diagnosis.

The questions the doctor will ask about the symptoms are as follows:

• What signs or symptoms have you noticed? When did they start?
• Have these signs or symptoms changed over time?
• Have you observed any changes in your child’s attention?
• Has your child had a fever?
• Have you noticed unusual or excessive irritability?
• Have you noticed any changes in eating habits?

Questions, especially for older children or adults, may be:

• Has your child experienced any changes in their academic performance?
• Did you have difficulty with normal tasks or work-related tasks?
• Is your child being treated for any other medical problem?
• Has your child recently started a new treatment?

In most cases, the signs and symptoms of Krabbe disease appear in the first few months after birth. They start gradually and gradually get worse.

The signs and symptoms common at the onset of the disease (between two and six months of life) are as follows:

• Feeding difficulties
• Unexplained screams
• Extreme irritability
• Fever without signs of infection
• Decreased vigilance
• Delays in development stages
• Muscle spasms
• Poor head control
• Frequent vomiting

As the disease progresses, the signs and symptoms become more severe. They may include:

• Abnormal development
• Progressive loss of hearing and sight
• Rigid and tight muscles
• Gradual loss of the ability to swallow and breathe

When Krabbe’s disease develops later in childhood (1 to 8 years) or into adulthood (after 8 years), signs and symptoms can vary widely and include:

• Progressive vision loss with or without peripheral neuropathy
• Difficulty walking (ataxia)
• Paresthesia with burning sensation
• Loss of hand dexterity
• Muscular weakness

As a general rule, the earlier the age of onset of Krabbe disease, the faster the disease progresses.

Some people diagnosed during adolescence or adulthood may have less severe symptoms, with muscle weakness being a primary condition. They may not have any alteration in their cognitive abilities.

It is important to have the child follow up in order to monitor his development, in particular:

• his growth
• His muscle tone
• His muscle strength
• Its coordination
• His posture
• Their sensory capacities (vision, hearing and touch)
• His diet

For infants who have already developed symptoms of Krabbe disease, there is currently no treatment that can alter the course of the disease. Treatment therefore focuses on managing symptoms and providing supportive care.

Interventions include:

• anticonvulsant drugs to manage seizures;
• drugs to relieve muscle spasticity and irritability;
• physiotherapy to minimize the deterioration of muscle tone;
• supply of nutrients, for example by using a gastric tube to deliver fluids and nutrients directly into the stomach.

Interventions for older children or adults with milder forms of the disease may include:

• physiotherapy to minimize the deterioration of muscle tone;
• occupational therapy to achieve as much independence as possible with daily activities;
• transplantation of hematopoietic stem cells which can maintain myelin by producing GALC enzymes. They come from umbilical cord blood, donor bone marrow or circulating blood stem cells.

This therapy may improve results in infants if treatment is started before symptoms start, that is, when a diagnosis is made after a newborn screen is tested. Infants who do not yet have symptoms and receive a stem cell transplant have a slower progression of the disease. However, they still have significant difficulty with speaking, walking and other motor skills.

Older children and adults with mild symptoms may also benefit from this treatment.