LEUKODYSTROPHY FACTS Krabbe Disease (Globoid Cell Leukodystrophy)

SUMMARY

Krabbe 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

Joanne Kurtzberg   

Pediatric Bone Marrow Transplant

2400 Pratt Street, Suite 1400

Durham, NC 27705

(919) 668-1100

Fax Telephone:
(919) 668-1183

Duke University Pediatric Bone Marrow Transplant

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

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

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

 

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.

 

List of Leukodystrophy (Place your cursor over the text and a description will appear)

Krabbe 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.
Adrenoleukodystrophy is a rare inherited metabolic disorder characterized by the loss of the fatty covering (myelin sheath) on nerve fibers within the brain (cerebral demyelination) and the progressive degeneration of the adrenal gland (adrenal atrophy). Adrenoleukodystrophy that is inherited as an X-linked genetic trait may begin in childhood or adulthood. However, Adrenoleukodystrophy that is inherited as an autosomal recessive genetic trait typically begins during infancy (neonatal period).
See Adrenoleukodystrophy
Aicardi Syndrome is an extremely rare congenital disorder in which the structure linking the two cerebral hemispheres of the brain (corpus callosum) fails to develop. The absence of the corpus callosum is associated with frequent seizures, marked abnormalities of the retina and choroid (the thin membrane that covers the retina) of the eyes, and/or mental retardation
Alexander Disease is an extremely rare, progressive, neurological disorder that usually becomes apparent during infancy or early childhood. However, less commonly, cases have been described in which symptom onset has occurred in later childhood or adolescence (juvenile onset) or, rarely, during the third to fifth decades of life (adult onset). Alexander Disease belongs to a group of rare disorders known as leukodystrophies, which are characterized by degenerative changes of the white matter of the brain. More specifically, in Alexander Disease there is a lack of normal amounts of the protective, fatty material (myelin) that forms an insulating wrapping (sheath) around certain nerve fibers (axons). Myelin enables the efficient transmission of nerve impulses and provides the "whitish" appearance of the so-called white matter of the brain. Alexander Disease is characterized by deficient myelin formation in infants, and sometimes in juvenile cases, that is most prominent in the front (i.e., frontal) lobes of the brain's two hemispheres (cerebrum). The disorder is also associated with the formation of abnormal, fibrous deposits known as "Rosenthal fibers" throughout certain regions of the brain and spinal cord (central nervous system [CNS]).
Most patients develop a progressive gait disorder, speech difficulty or even coma between 1 and 5 years of age. Early development is often normal. Onset of the disease can be spontaneous or after mild head trauma or a febrile illness. Head circumference is usually normal and the peripheral nerves are not affected. Motor difficulties are progressive, but prolonged periods of stability or even transient mild improvements lasting years are common. Swallowing is normal until very late in the course. Most patients develop seizures (epilepsy) late in the illness that is easy to control. Patients with later onset of disease have a slow progression, and often live in the second and third decades.
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a frequently overlooked cause of leukoencephalopathy leading to stroke and dementia in early middle age. Radiological signs of this cerebral non-artherosclerotic, non-amyloid angiopathy may be present from childhood at a presymptomatic stage of the disease so that it can come to the attention of the child neurologist. Migraine with or without aura begins in the fourth decade. Within the next decade, transient ischemic attacks and small strokes are evident. Mood disturbances and dementia follow, usually before age 60. Epilepsy has been described in a few cases.
Canavan's Leukodystrophy is a rare inherited neurological disorder characterized by spongy degeneration of the brain and spinal cord (central nervous system). Symptoms may include progressive mental decline accompanied by the loss of muscle tone, poor head control, an abnormally enlarged head (megalocephaly), and/or blindness. Canavan's Leukodystrophy is caused by a deficiency of the enzyme aspartoacylase. Symptoms appear in early infancy and usually progress rapidly.
CTX has an autosomal recessive pattern of inheritance. Patients with CTX may present first with cataracts or with mild mental retardation. A specific finding, which is missed unless it is looked for, is the presence of fatty tumors (called Xanthomas)in the tendons, most often in the Achilles tendon or heel cord. Later on, patients may develop seizures, emotional or psychiatric disturbances, and motor deficits. The diagnosis of CTX is important, since it is by far the most treatable of the leukodystrophies. There is a very favorable response to chenodeoxycholic acid, a medication that can be taken by mouth
Metachromatic Leukodystrophy (MLD), the most common form of leukodystrophy, is a rare inherited neurometabolic disorder affecting the white matter of the brain (leukoencephalopathy). It is characterized by the accumulation of a fatty substance known as sulfatide (a sphingolipid) in the brain and other areas of the body (i.e., liver, gall bladder, kidneys, and/or spleen). The fatty protective covering on the nerve fibers (myelin) is lost from areas of the central nervous system (CNS) due to the buildup of sulfatide. Symptoms of Metachromatic Leukodystrophy may include convulsions, seizures, personality changes, spasticity, progressive dementia, motor disturbances progressing to paralysis, and/or visual impairment leading to blindness
Adrenoleukodystrophy is a rare inherited metabolic disorder characterized by the loss of the fatty covering (myelin sheath) on nerve fibers within the brain (cerebral demyelination) and the progressive degeneration of the adrenal gland (adrenal atrophy). Adrenoleukodystrophy that is inherited as an X-linked genetic trait may begin in childhood or adulthood. However, Adrenoleukodystrophy that is inherited as an autosomal recessive genetic trait typically begins during infancy (neonatal period).
Females with leukodystrophy and ovarian dysgenesis in whom all other known causes of either leukodystrophy or ovarian malfunction have been ruled out. Usually present with difficulty walking (ataxia) or just mental retardation. So far all patients had progressive dementia and motor difficulties. They can become wheelchair bound.
Pelizaeus-Merzbacher brain sclerosis is a rare inherited disorder affecting the central nervous system that is associated with abnormalities of the white matter of the brain. Symptoms develop due to lack of the fatty covering of nerve cells (myelin sheath). Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, and/or brain stem. Symptoms may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, loss of motor abilities, and the progressive deterioration of intellectual function. The symptoms of Pelizaeus-Merzbacher brain sclerosis are usually slowly progressive.
Refsum Syndrome is a rare disorder of lipid metabolism inherited as a recessive trait. Symptoms may include a degenerative nerve disease (peripheral neuropathy), failure of muscle coordination (ataxia), retinitis pigmentosa (a progressive vision disorder), and bone and skin changes. This disorder is believed to be due to the absence of phytanic acid hydroxylase in the blood, an enzyme needed for the metabolism of phytanic acid (found in dairy products, beef, lamb and some seafoods). Refsum Syndrome is characterized by a marked accumulation of phytanic acid in the plasma and tissues. Prolonged treatment with a diet deficient in phytanic acid can be beneficial. This slowly progressive disorder is most common in children and young adults of Scandinavian heritage. Phytanic Acid is a derivative of phytol, a component of chlorophyll.
During the first few years of life, children with VLE usually have a normal or close to normal function. From the age of 4 to 5 years onwards, most children develop a slowly progressive cerebellar ataxia, followed by mild spasticity. Most patients become wheelchair dependent in the second decade. Because of the ataxia speech becomes unclear too. From the age of late primary school onwards, mental slowing is noted and learning problems develop, although mental capacities remain relatively better intact than motor capacities. Most children have infrequent epileptic seizures, which can be easily controlled with antiepileptic medication. There are more severe variants. In some children, early development is already seriously delayed. Some children never achieve independent walking or lose it within a few years. Sometimes, the epilepsy is more serious. However, there are also milder variants, in which independent walking is maintained for several decades. In some patients, mental capacities remain intact for a long time.
Zellweger Syndrome is a rare hereditary disorder affecting infants. It is characterized by reduction or absence of peroxisomes in the cells of the liver, kidneys, and brain. Unusual problems in prenatal development, an enlarged liver, high levels of iron and copper in the blood, and vision disturbances are among the major manifestations of Zellweger Syndrome.

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