Krabbe (KRAH-buh) disease | inherited disorder

DEFINITION

Krabbe (KRAH-buh) disease is an inherited disorder that destroys the protective coating (myelin) of nerve cells in the brain and throughout the nervous system.

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

There's no cure for Krabbe disease, and treatment focuses on supportive care. However, stem cell transplants have shown some success in infants who are treated before the onset of symptoms and in some older children and adults.

Krabbe disease affects about 1 in 100,000 people in the United States. It is also known as globoid cell leukodystrophy.

SYMPTOMS

In most cases, the signs and symptoms of Krabbe disease appear during the first few months of life. They begin gradually and progressively worsen.

Infants

Common signs and symptoms early in the course of the disease include the following:

• Feeding difficulties
• Unexplained crying
• Extreme irritability
• Fever with no sign of infection
• Declines in alertness
• Delays in typical developmental milestones
• Muscle spasms
• Loss of head control
• Frequent vomiting

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

• Seizures
• Loss of developmental abilities
• Progressive loss of hearing and sight
• Rigid, constricted muscles
• Stiff, fixed posture
• Progressive loss of ability to swallow and breathe

Older children and adults

When Krabbe disease develops later in childhood or during adulthood, signs and symptoms can vary widely. They may include:

• Progressive loss of vision
• Difficulty walking (ataxia)
• Decline in thinking skills
• Loss of manual dexterity
• Muscles weakness

As a general rule, the younger the age that Krabbe disease occurs, the faster the disease progresses and the more likely it is to result in death.

Some people diagnosed during adolescence or adulthood may have less severe symptoms, with muscle weakness as a primary condition. They may have no impairment of their thinking skills.

When to see a doctor

The early signs and symptoms of Krabbe disease in infancy can indicate any number of diseases or developmental problems. Therefore, it's important to get a prompt and accurate diagnosis if your child is experiencing any signs or symptoms of the disease.

Signs and symptoms most often associated with older children and adults also are not specific to Krabbe disease and require a timely diagnosis.

CAUSES

Krabbe disease is caused when a person inherits two copies of an altered (mutated) gene — one copy from each parent.

A gene provides a kind of blueprint for producing proteins. If there is an error in this blueprint, then the protein product may not work properly. In the case of Krabbe disease, two mutated copies of a particular gene result in little or no production of an enzyme called galactocerebrosidase (GALC).

Enzymes, such as GALC, are responsible for breaking down certain substances in a cell's recycling center (lysosome). In Krabbe disease, the short supply of GALC enzymes results in the accumulation of certain types of fats called galactolipids.

Damage to nerve cells

Galactolipids normally exist in cells that produce and maintain the protective coating of nerve cells (myelin). However, an abundance of galactolipids has a toxic effect. Some galactolipids trigger myelin-forming cells to self-destruct.

Other galactolipids are taken up by specialized debris-eating cells in the nervous system called microglia. The process of cleaning up excessive galactolipids transforms these normally helpful cells into abnormal, toxic cells called globoid cells, which promote myelin-damaging inflammation.

The subsequent loss of myelin (demyelination) prevents nerve cells from sending and receiving messages.

RISK FACTORS

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

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

• A 25 percent chance of inheriting two mutated copies, which would result in the disease
• A 50 percent chance of inheriting only one mutated copy, which would result in the child being a carrier of the mutation but would not result in the disease itself
• A 25 percent chance of inheriting two normal copies of the gene

Genetic testing

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

• If one or both parents are likely carriers of a GALC gene mutation because of a known family history of Krabbe disease, a couple may want to have tests to understand the risks in their own family.
• If one child is diagnosed with Krabbe disease, a family may consider genetic tests to identify other children who could develop the disease later in life.
• If the parents are known carriers, they may request a prenatal genetic test to determine if their child is likely to develop the disease.
• Known carriers, who are using in vitro fertilization, may request a genetic test with fertilized eggs before implantation.

Genetic testing should be carefully considered. Ask your doctor about genetic counseling services that can help you understand the benefits, limits and implications of genetic testing.

COMPLICATIONS

A number of complications — including infections and respiratory difficulties — can develop in children with advanced Krabbe disease. In the later stages of the disease, children become incapacitated, are confined to their beds and eventually lapse into a vegetative state.

Most children who develop Krabbe disease in infancy die before the age of 2, most often from respiratory failure or complications of immobility and markedly decreased 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.

PREPARING FOR YOUR APPOINTMENT

In some cases, Krabbe disease is diagnosed in newborns with screening tests before symptoms appear. Conversations with your child's doctor and a specialist in nervous system disorders (neurologist) would begin as soon as a diagnosis is confirmed. In most cases, however, the onset of symptoms triggers an exploration of possible causes.

Well-baby visits

It's important to take your child to all regularly scheduled well-baby visits and annual appointments during childhood. These visits are an opportunity for your child's doctor to monitor your child's development in key areas, including:

• Growth
• Muscle tone
• Muscle strength
• Coordination
• Posture
• Age-appropriate motor skills
• Sensory abilities — vision, hearing and touch

Questions you should be prepared to answer during regular checkups might include the following:

• What concerns do you have about your child's growth or development?
• How well does he or she eat?
• How does your child respond to touch?
• Is your child reaching certain milestones in development, such as rolling over, pushing up, sitting up, crawling, walking or speaking?

Preparing for other doctor visits

If you're seeing your doctor because of the recent onset of symptoms, you'll likely start by seeing your general practitioner or your child's pediatrician. After an initial evaluation, your doctor may refer you to a neurologist.

Be prepared to answer the following questions about your symptoms or on your child's behalf:

• What signs or symptoms have you noticed? When did they begin?
• Have these signs or symptoms changed over time?
• Do you notice any changes in your child's attentiveness?
• Has your child had a fever?
• Have you noticed unusual or excessive irritability?
• Have you noticed changes in eating habits?

Questions especially for older children or adults may include:

• Has your child experienced any changes in school performance?
• Have you experienced difficulty with normal tasks or job-related work?
• Are you or is your child being treated for any other medical conditions?
• Have you or your child recently begun a new medication?

TESTS AND DIAGNOSIS

Your doctor will conduct a general physical exam and assess signs and symptoms that may indicate a neurological disease. A diagnosis of Krabbe disease is based on a series of tests, which may include the following.

Laboratory tests

A blood sample and small skin sample (biopsy) will be sent to a laboratory to assess the level of GALC enzyme activity. Very low or no GALC activity level may indicate Krabbe disease.

Although the results help a doctor make a diagnosis, they don't provide evidence of how quickly the disease may progress. For example, very low GALC activity doesn't always mean that the condition will advance rapidly.

Imaging tests

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

• Magnetic resonance imaging (MRI), a technology that uses radio waves and a magnetic field to produce detailed 3-D images
• Computerized tomography (CT), a specialized X-ray technology that produces 2-D images

Nerve conduction study

A nerve conduction study assesses the rate at which nerves conduct a signal — essentially how quickly can they send a message. A special device measures the time it takes an electrical impulse to travel from one point on the body to another. When myelin is impaired, nerve conduction is slower.

Genetic testing

A genetic test may be done with a blood sample to confirm a diagnosis. There are variant forms of the mutated gene that results in Krabbe disease. The particular type of mutation may provide some clues regarding the expected course of the disease.

Newborn screening

In some states, a screening test for Krabbe disease is part of a standard set of assessments for newborns. The initial screening test measures GALC enzyme activity. If the enzyme activity is found to be low, follow-up GALC tests and genetic tests are conducted.

The use of newborn screening tests is relatively new. Researchers are still working to understand how best to use these tests, how well the tests lead to an accurate diagnosis and how well they predict the course of the disease.

TREATMENTS AND DRUGS

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

• Anticonvulsant medications to manage seizures
• Drugs to ease muscle spasticity and irritability
• Physical therapy to minimize deterioration of muscle tone
• Nutritional support, such as the use of a tube to deliver fluids and nutrients directly into the stomach (gastric tube)

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

• Physical therapy to minimize deterioration of muscle tone
• Occupational therapy to achieve as much independence as possible with daily activities

Stem cell transplantation

Hematopoietic stem cells are specialized cells that can develop into all of the different types of blood cells in the body. These stem cells are also the source of microglia, specialized debris-eating cells that take up residence in the nervous system. In Krabbe disease, microglia are transformed into toxic globoid cells.

In stem cell transplantation, donor stem cells are delivered into the recipient's bloodstream through a tube called a central venous catheter. The donor stem cells help the body produce healthy microglia that can populate the nervous system and deliver functioning GALC enzymes. This treatment may help restore some degree of normal myelin production and maintenance.

This therapy may improve outcomes in infants if treatment begins before the onset of symptoms — that is, when a diagnosis results from a newborn screening test.

Presymptomatic infants receiving a stem cell transplant have had slower disease progression, but these children still experience significant difficulties with speech, walking and other motor skills.

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

Sources for hematopoietic stem cells include:

• Umbilical cord blood
• Donor bone marrow
• Donor circulating (peripheral) blood stem cells

LIFESTYLE AND HOME REMEDIES

Krabbe (KRAH-buh) disease is an inherited disorder that destroys the protective coating (myelin) of nerve cells in the brain and throughout the nervous system.

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

There's no cure for Krabbe disease, and treatment focuses on supportive care. However, stem cell transplants have shown some success in infants who are treated before the onset of symptoms and in some older children and adults.

Krabbe disease affects about 1 in 100,000 people in the United States. It is also known as globoid cell leukodystrophy.