LEUKODYSTROPHY FACTS

Krabbe's Disease

(Globoid Cell Leukodystrophy)

 

 

 SUMMARY

 

Krabbe's disease is a lethal, demyelinating condition caused by a deficiency of galactosylceramidase (GALC) enzyme activity. This leads to accumulation of cerebroside and psychosine.

 

The most common form of Krabbe disease is the infantile form. These babies have mental and motor deterioration related to loss of myelin in the brain and peripheral nervous system. They usually die by two years of age. Less common are later onset forms of Krabbe disease that affect children and adults. It is likely that different mutations in the GALC gene cause this variability in onset and severity of symptoms. Sometimes differences may occur even among family members. Krabbe disease is inherited in an autosomal recessive pattern, two copies of non-working (GALC) genes must be present for symptoms to occur. Researchers are currently trying to develop methods of treatment.

 

General Nerve cells, or neurons, are one means by which cells and organs communicate. A neuron has a cell body which contains its nucleus. The long, thin process extending from the cell body is called an axon. Axons are the structures which transmit a signal from one neuron to another cell.

 

Myelin is the protective covering, or insulation, of the nerve cells in both the central (brain and spinal cord) and peripheral (all other body areas) nervous systems. Groups of myelinated axons appear white and are called the "white matter" of the brain. This is in contrast to the "gray matter" which are areas where the gray-colored cell bodies of the neurons are located. Myelin is a dynamic structure; it is formed, broken down and reformed over time as the nerve axons grow. Any problem in breaking down or forming myelin will affect the nervous system resulting in symptoms of Leukodystrophy. Symptoms include difficulties with walking, talking, seeing and thinking. These problems often worsen as an individual ages, since more and more of the myelin contains unusual components and is lost. Demyelination is the loss of myelin from nerves.

 

Galactosylceramide (cerebroside) is a type of fat, or lipid, and an important component of the myelin sheath. Psychosine is a lipid formed from breakdown of cerebroside and it is very toxic to cells. It is not usually present in the body in measurable amounts. Oligodendrocytes, the myelin synthesizing cells in the central nervous system, are killed when psychosine is not degraded as usual.

 

There are specialized proteins in the body, called enzymes, which are responsible for the breakdown of carbohydrates, fats and other proteins. Enzyme activity is a measure of how well the enzyme does its job. People with an enzyme deficiency have little or no enzyme activity. Lysosomes are substructures of the cell where many enzymes are stored and do their work. Lysosomes are the sites where the basic elements of degraded lipids, proteins and starches are recycled.

 

Galactosylceramidase (GALC) is a lysosomal enzyme found throughout the body's tissues and fluids. It is responsible for the breakdown of cerebroside and psychosine. GALC is the enzyme deficient in individuals with Krabbe disease. If GALC does not work correctly, cerebroside and psychosine will not be degraded as usual.

 

In Krabbe disease scavenger cells internalize cerebroside and become large lipid containing "globoid cells". The presence of globoid cells is a critical diagnostic feature of this condition, which is also known as globoid cell Leukodystrophy. When tissues from people with Krabbe disease are examined under the microscope these cells can be seen in white matter, as well as the kidney.

 

GALC deficiency can result from changes, or mutations, in genes causing production of a non-working enzyme. Symptoms of Krabbe disease are seen when a person inherits two non-working GALC genes (gene type GALC/GALC) causing a deficiency of GALC enzyme activity. The GALC gene that produces a working enzyme can be called GALC. The GALC gene is located on chromosome 14.

 

 CLINICAL

 

Several forms of Krabbe disease exist. These are classified by the age of onset of symptoms. There is no way to predict what form an individual will develop. The type and progression of symptoms varies for each person who has the condition. If more than one person in a family is diagnosed with Krabbe disease, they may not have the same form or express the same symptoms. The different forms of Krabbe disease are allelic. This means that the non-working gene (GALC) is found at the same DNA address as the working gene.

 

Infantile Krabbe disease [~90% of cases]

 

Symptoms usually start at two to six months of age. Development may be normal up to that time. An increased response to sensory stimuli (irritability, excessive crying), developmental delay or regression, difficulty in feeding, and seizures are common first symptoms. Children then have a more severe and rapid deterioration of mental and motor function. Hypertonia (increased muscle tone, stiffness) and problems with vision develop. Eventually children lose mental and motor function, some may become deaf and blind, cannot move or speak, and typically must be fed through a tube. The average age of death is 13 months  (ranging from 6 months to 5 years).

 

Many babies in this stage of Krabbe's disease are misdiagnosed.  It is common for parents of these babies to be told that their infant has colic, reflux, food/milk allergy, or even cerebral palsy.

 

Juvenile Krabbe disease [rare]

 

Onset of symptoms occurs between three and ten years of age. Loss of mental function and vision, paralysis on one side of the body, and difficulty in walking or other motor performance may be seen. Initially symptoms progress rapidly but then the rate of deterioration is much slower than for the infantile form. Symptoms may last five years or longer.

 

Adult Krabbe disease [rare]

 

Symptoms can appear as early as 10 years of age and as late as 45 years. These individuals may be learning disabled. Common first signs are loss of vision and deterioration in fine movements. Symptoms may last more than 20 years.

 

Pseudodeficiency of GALC [rare]

 

There are reports of healthy people with very low GALC activities. Even through their enzyme activity is low, they do not become symptomatic. This is called Pseudodeficiency of GALC. Neurological symptoms in these individuals may not be related to the Pseudodeficiency, but due to another cause. Many clinical and laboratory criteria must be used to determine whether a person has Krabbe disease or a Pseudodeficiency.

 

 WHAT CAUSES KRABBE'S DISEASE?

 

Krabbe disease is inherited in an autosomal recessive manner.  If both parents carry a disease-causing mutation in the GALC gene there is a 25% chance of having a Krabbe affected child with each conception, a 50% chance that each offspring will be a carrier and a 25% chance of having a child who does not carry a disease causing mutation.  This genetic disease is found in all ethnic groups.  The carrier rate in the general population is estimated to be 1 in 150.  Krabbe disease occurs in about 1 in 100,000 live births in the United States.  Diagnosis can easily be made by testing the white cells from a blood sample for GALC activity. 

 

 DIAGNOSIS AND ANALYSIS

 

Clinical symptoms

 

Krabbe disease is a condition which usually appears in the first year of life. The general progression of symptoms is irritability, increased muscle tone, and deterioration of motor and developmental function.

 

Cerebrospinal fluid (CSF) protein

 

The CSF fills the otherwise open spaces of the brain and spinal cord. CSF typically does not contain much protein. Elevated CSF protein is often seen in children with Krabbe disease whose symptoms begin before age three. Other individuals with Krabbe disease may or may not have increased protein in their CSF.

 

Electroencephalogram (EEG)

 

The EEG measures the electrical activity of the brain using flat, wire electrodes taped to the scalp. Individuals who have Krabbe disease may have normal EEG patterns at first, but they will eventually develop abnormal EEG patterns. Seizures are often associated with these types of EEG patterns.

 

Nerve conduction velocity studies

 

These are similar to an EEG but measure the amount of time it takes an artificial electrical stimulus to travel along the nerve. The stimulus is detected at a point further down the neuronal pathway. Nerve conduction velocities are often decreased in people with Krabbe disease. Other types of peripheral nerve function tests also show unusual patterns. Loss of myelin covering the peripheral nerve (demyelination) causes these findings. It takes more time for unmyelinated nerves to send electrical messages to and from the brain.

 

Computerized tomography (CT)

 

The CT scan is a series of X-ray pictures of adjacent slices of the brain. It allows visualization of the internal structures of the brain without having to do an invasive procedure like surgery. Results of a CT scan may be normal in the initial sages of Krabbe disease. As this condition progresses there will be characteristic changes in the white matter.

 

Magnetic resonance imaging (MRI)

 

Similar to a CT scan, MRI produces pictures of the inside of the brain without surgery. Instead of X-rays, a magnetic field is used to visualize the brain. MRI is more sensitive than the CT scan in detecting loss of or irregularities in the brain's white matter. Findings are like those seen with the CT scan. Individuals with Krabbe disease will eventually show white matter changes by MRI.

 

Histology

 

Histologic techniques use chemical stains to look at tissues under the microscope. Stained samples of Krabbe disease brain tissue show the presence of many globoid cells, demyelination and decreased numbers of myelin synthesizing cells (oligodendrocytes in the brain). Peripheral nerve tissue shows degeneration of axons and demyelination. Although no globoid cells are seen, small tubular structures, or inclusions, can be found in Schwann cells, the myelin synthesizing cells in the peripheral nervous system. These inclusions may be cerebroside deposits.

 

Biochemical enzyme assays

 

As previously mentioned, enzyme activity can be tested in the laboratory. The compound on which an enzyme acts is called a substrate. Cerebroside and psychosine are substrates for galactosylceramidase (GALC). Cells from skin (skin fibroblasts), amniocentesis samples (amniocytes), other tissues, or blood can be tested for GALC activity. The amount of cerebroside, or a similar man-made chemical, broken down by the GALC in these cells is measured.

 

In general the following results are found. Healthy people with two working GALC genes (GALC+/GALC+) have enzyme activities within a certain range. This represents 100% activity and is called the control range. Of note, the control range of GALC enzyme activity is very wide. A parent of a child with Krabbe disease, and others who carry one working GALC gene and one non-working gene (GALC+/GALC-), will have very little or no enzyme activity. So GALC is not available to break down cerebroside or psychosine. The accumulation of these lipids causes the demyelination, globoid cell formation and symptoms of Krabbe disease.

 

Because Krabbe disease is a genetic condition, healthy relatives of someone with Krabbe disease often wish to know their "carrier status", or if they carry one copy of a GALC- gene. Biochemical testing of their blood cells is the most common way of answering this question. If the person is a carrier, the enzyme activity seen in their cells is usually ~50% for the control range. However, carrier testing may be difficult due to the wide range for GALC activity seen in healthy people.

 

Prenatal diagnosis of Krabbe disease using a biochemical enzyme test is discussed below.

 

DNA testing

 

The instructions to make the components of our body are found in our DNA. These instructions are coded by four chemicals whose order, or sequence, along the DNA tells that cell how to make proteins.

 

The GALC+ gene has recently been isolated and the chemical code of the GALC+ gene determined. With additional research, direct analysis of DNA changes causing Krabbe disease my be found. This will lead to improved methods for diagnosis and carrier detection in the future.

 

 PRENATAL DIAGNOSIS

 

Prenatal diagnostic tests can look at certain features of a fetus before it is born.

 

A sample of the fetus' cells is usually obtained in one of two ways. Chorionic villus sampling (CVS) removes a small portion of the placenta; this is usually done in the 10th-11th weeks of pregnancy. A small amount of fluid that surrounds the fetus in the womb is removed by amniocentesis, usually done between 15-18 weeks of pregnancy.

 

Prenatal diagnosis can be performed on Chorionic villus or amniocentesis samples, and may be helpful to those who have a family history of Krabbe disease. For example, if two parents are each known to carry one non-working GALC gene, they have a 25% chance of having a child with Krabbe disease. They may wish to find out if their fetus has the condition. The GALC enzyme activity in the fetal cells is measured. If the activity is low, it is likely the fetus has Krabbe disease.

 

 TREATMENT

 

Drug therapy

 

Drug therapy has proved useful in controlling specific symptoms, such as seizures. This treatment, however, will not prevent loss of nervous system function.

 

Bone Marrow/Cord Blood Transplantation

 

Bone marrow is in the center part of our bones. It is where blood cells are made. Transplantation tries to replace marrow from a person with Krabbe disease with new bone marrow from a healthy person.

 

Cord blood, which is also called "placental blood," is the blood that remains in the umbilical cord and placenta following birth and after the cord is cut. Cord blood is routinely discarded with the placenta and umbilical cord.

 

Bone marrow is difficult to match between the donor and recipient because a "perfect match" is usually required. Cord blood immune cells, however, are less mature than in bone marrow and can be successfully used even when there is only a half-match. This means there is more opportunity for transplants between family members when cord blood is stored. Some studies have shown that overall survival rates for related transplants are more than double that of transplants from unrelated donors.

 

 

 

Dr. Joanne Kurtzberg

 

Pediatric Bone Marrow Transplant

 

2400 Pratt Street, Suite 1400

 

Durham, NC 27705

 

(919) 668-1100

 

Fax Telephone:

(919) 668-1183

 

What is Known About Cord Blood Transplants

 

With its more than 30-year history, bone marrow transplants are a well-established, life-saving treatment for a wide range of blood disorders such as leukemia and aplastic anemia, as well as selected immune system deficiencies and genetic disorders. While the history of cord blood transplants is less extensive, there is evidence to suggest that these transplants can cure diseases, too. But with cord blood there are more unknowns, and doctors and their patients must carefully evaluate the situation before deciding on the best treatment.

 

The following lists explain what is known and not known about cord blood transplants. While these lists are not exhaustive, they do include aspects of cord blood transplants that are critical in the decision-making process:

 

What We Know About Cord Blood Transplants

 

  • Cord blood contains sufficient numbers of stem cells for engraftment in most recipients weighing less than 50 kilograms (about 110 pounds).
  • Collection of cord blood poses no health risk to the mother or infant donor.
  • Because it is stored and available for use, cord blood is sometimes more readily available than a potential marrow or blood stem donor, who may be unavailable for donation when it is needed.
  • Cord blood is rarely contaminated by viruses often found in marrow, such as cytomegalovirus (CMV) and Epstein-Barr virus.
  • Cord blood can cause severe GVHD, but possibly less frequently than in bone marrow transplants.

 

What We Think We Know about Cord Blood Transplants Based on Clinical Data

 

  • Compared to bone marrow transplants, cord blood transplants may have a lower rate of acute GVHD, at least in cases where a related (sibling) donor is used.
  • It appears that the transplant process using cord blood (from the time a search is started to the time donor cells are ready for transplant) is shorter than that for marrow cell donation because the cord blood units are in storage and ready for use.

 

What We Don't Know about Cord Blood Transplants (because of lack of clinical evidence)

 

  • Whether cord blood is sufficient for engraftment in most adult recipients, although experience suggests that it may be sufficient for a significant proportion of these recipients.
  • Whether cord blood transplants pose a different risk of relapse (recurrence of an illness after a remission) compared to unrelated bone marrow transplants.
  • Whether targeted cord blood collection will be successful in reducing the current shortage of racial and ethnic minority donors, and thereby increasing the number of available transplants for patients in this group.

 

Gene Therapy

 

Gene therapy is a new method which attempts to provide working copies of genes to people with non-working copies. The DNA sequence of a working gene is placed into the person with an enzyme deficiency. Ideally, working enzyme would be made by the person's "new" cells and degrade whatever substance has been stored.

 

Although gene therapy cannot be used to treat Krabbe disease today, it may offer hope for the future. Clues for gene therapy in Krabbe disease may be obtained from clinical trials of gene therapy for other genetic conditions like cystic fibrosis. However, correcting an enzyme defect in the nervous tissue will be more complicated.