Leukodystrophy, Krabbe’s

Disease Overview

Krabbe’s Leukodystrophy is a rare inherited lipid storage disorder caused by a deficiency of the enzyme galactocerebrosidase (GALC), which is necessary for the breakdown (metabolism) of the sphingolipids galactosylceremide and psychosine. Failure to break down these sphingolipids results in degeneration of the myelin sheath surrounding nerves in the brain (demyelination). Characteristic globoid cells appear in affected areas of the brain. This metabolic disorder is characterized by progressive neurological dysfunction such as intellectual disability, paralysis, blindness, deafness and paralysis of certain facial muscles (pseudobulbar palsy). Krabbe’s Leukodystrophy is inherited as an autosomal recessive trait.

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Synonyms

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

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Signs & Symptoms

Onset of Krabbe’s Leukodystrophy in the predominant infantile form (90% of cases) occurs between one and seven months of age. A late-onset form of the disorder occurs at 18 months or a later age, including adolescence and adulthood.

The specific symptoms and severity of Krabbe’s Leukodystrophy vary from case to case. Infants affected by Krabbe’s Leukodystrophy may be fretful and excessively irritable (hyperirritability). Vomiting, unexplained fevers, and partial unconsciousness are additional possible symptoms. The lower extremities may have spastic contractions. Seizures characterized by alternating contraction and relaxation (clonic), or by continuous tension (tonic), may also occur. Affected infants are hypersensitive to various stimuli such as sounds.

Mental and physical development may be slow. Regression of previously acquired skills may occur in some cases. Because of degeneration of certain parts of the brain, the legs are sometimes rigidly extended at the hip and knee; the arms may be rotated at the shoulder and extended at the elbow; and the ankles, toes and fingers may be flexed (decerebrate rigidity). Blindness caused by brain cortex degeneration may also occur. Individuals with Krabbe’s Leukodystrophy may also have difficulty swallowing (dysphagia) and peripheral neuropathy, a condition characterized by muscle weakness; pain; numbness; redness; and/or burning or tingling sensations in the affected areas, especially the arms and legs (extremities). Krabbe’s Leukodystrophy often progresses to cause life-threatening complications.

In the juvenile and adult forms of Krabbe’s Leukodystrophy, the initial symptom may be impaired control of voluntary movements and progressive rigidity of muscles in the legs (spastic paraparesis). Affected individuals with these forms of the disorder may also experience progressive vision loss and disease affecting multiple nerves (polyneuropathy).

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Causes

Krabbe’s Leukodystrophy is a hereditary disorder transferred to offspring through recessive genes. It is caused by a deficiency of the enzyme galactoside beta-galactosidase (galactosyl ceramidase). This enzyme is needed for the metabolism of galactocerebroside (galactosyl ceramide), a component of the fatty sheath around the nerves (myelin). The demyelination of the nerve cells in the large hemispheres of the brain (and in the brain stem) causes the neurological symptoms of Krabbe’s Leukodystrophy.

Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother. In recessive disorders, the condition does not appear unless a person inherits the same defective gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk of transmitting the disease to the children of a couple, both of whom are carriers for a recessive disorder, is 25 percent. Fifty percent of their children risk being carriers of the disease, but generally will not show symptoms of the disorder. Twenty-five percent of their children may receive both normal genes, one from each parent, and will be genetically normal (for that particular trait). The risk is the same for each pregnancy.

Investigators have determined that Krabbe’s Leukodystrophy may be caused by disruption or changes (mutations) of the human galactocerebrosidase (GALC) gene located on the long arm (q) of chromosome 14 (14q31). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered. For example, “chromosome 14q31” refers to band 31 on the long arm of chromosome 14.

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Affected populations

About 1 in 100,000 newborn babies in the United States is affected with Krabbe’s Leukodystrophy. Males are affected as often as females.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Krabbe’s Leukodystrophy. Comparisons may be useful for a differential diagnosis:

Adrenoleukodystrophy (ALD, or Schilder’s Disease) is one of many different leukodystrophies. The disorder may appear in two distinct genetic forms: sex-linked and Neonatal ALD. Both are characterized by destruction of the lipid sheaths surrounding the nerves (demyelination) in the brain. However, they differ in the mode of inheritance, severity and type of symptoms. All types of ALD are characterized by an accumulation of Very Long Chain Fatty Acids (VLCFA), which is a type of fat molecule that accumulates in the body’s tissues, especially in the adrenal gland and the white matter of the brain. An accumulation of lymph and plasma cells around the blood vessels in the central nervous system may also occur. (For more information on this disorder, choose “adrenoleukodystrophy” as your search term in the Rare Disease Database).

Canavan’s Leukodystrophy (Spongy Degeneration of the Brain) is a form of leukodystrophy that causes the white matter of the brain to be replaced by microscopic fluid-filled spaces. This disorder, a hereditary disease in children, is characterized by structural abnormalities and deterioration of motor, sensory, and intellectual functions. It seems to affect persons of Eastern European Jewish ancestry most frequently. The disorder is progressive and degenerative. Symptoms may include progressive mental decline accompanied by the loss of muscle tone, poor head control, an abnormally enlarged head (megalocephaly), and/or blindness. (For more information on this disorder, choose “Canavan’s Leukodystrophy” as your search term in the Rare Disease Database.)

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. Metachromatic Leukodystrophy is inherited as an autosomal recessive trait. (For more information on this disorder, choose “Metachromatic Leukodystrophy” as your search term in the Rare Disease Database).

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). In infants and young children affected by Alexander Disease, associated symptoms and findings include a failure to grow and gain weight at the expected rate (failure to thrive); delays in the development of certain physical, mental, and behavioral skills that are typically acquired at particular stages (psychomotor retardation); and progressive enlargement of the head (macrocephaly). Additional features typically include sudden episodes of uncontrolled electrical activity in the brain (seizures); abnormally increased muscle stiffness and restriction of movement (spasticity); and progressive neurological deterioration. In some cases, there is hydrocephalus. In most cases, Alexander Disease appears to occur randomly for unknown reasons (sporadically), with no family history of the disease. In an extremely small number of cases, it is thought that the disorder may have affected more than one family member. (For more information on this disorder, choose “Alexander” as your search term in the Rare Disease Database).

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Diagnosis

Krabbe's Leukodystrophy can be diagnosed by testing the activity of the enzyme galactocerebrosidase (galactosylceramidase) in fibroblast cells obtained from an infant or from a fetus by amniocentesis.

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Standard Therapies

Treatment

There is no specific treatment for Krabbe's Leukodystrophy. Treatment is symptomatic and supportive. Genetic counseling may be helpful for families of children affected by this illness.

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Clinical Trials and Studies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: [email protected]

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

The New England Journal of Medicine reported in May 2005 that the transplantation of umbilical-cord blood from unrelated donors, a procedure performed prior to symptoms developing in newborns diagnosed on the basis of family history, has shown enough promise to continue further investigation of this treatment.

Current research is directed toward the identification and cloning of genes, and defining the specific gene abnormality responsible for the leukodystrophy. Bone marrow transplantation is being researched as a possible treatment for Krabbe’s Leukodystrophy patients. This involves extracting cross-matched bone marrow from a healthy donor and injecting it into an affected individual. The healthy bone marrow cells enter the general circulation and migrate through the blood to marrow cavities in the patient’s bones. The new marrow cells begin to grow and produce new white blood cells and platelets. This procedure involves risks that must be balanced against possible benefits. It is used experimentally in the most severe cases of this disorder.

Researchers are investigating hematopoietic stem cell transplantation as a potential therapy for individuals with Krabbe’s Leukodystrophy. In the study, seven infants received stem cell transplant (six with cells from unrelated umbilical cord blood; one with matched sibling bone marrow). All seven infants have responded well to the treatment. However, more research is necessary to determine the long-term safety and effectiveness of this treatment option for individuals with Krabbe’s Leukodystrophy.

Researchers are studying the use of low-dose morphine to help control marked irritability often associated with Krabbe disease. Initial results demonstrated that low-dose morphine treatment resulted in improvement of irritability. More research is necessary to determine the long-term safety and effectiveness of this potential treatment for irritability associated with Krabbe disease.

Resources

Krabbe Disease: Externally-Led Patient-Focused Drug Development Meeting

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References

REVIEW ARTICLES

Wenger DA, et al., Krabbe disease: genetic aspects and progress toward therapy. Mol Genet Metab. 2000;70:1-9.

Krivit W, et al., Bone marrow transplantation for globoid cell leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy, and Hurler syndrome. Curr Opin Hematol. 1999;6:377-82.

JOURNAL ARTICLES

Tullu MS, et al. Krabbe disease-A clinical profile. Indian Pediatr. 2000;37:939-46.

Krivit W, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med. 1998;338:1119-26.

Schiffman R, Brady RO. New prospects for the treatment of lysosomal storage diseases. Drugs. 2002;62:733-42.

Stewart WA, et al., Irritability in Krabbe disease: dramatic response to low-dose morphine. Pediatr Neurol. 2001;25:344-5.

Wenger DA, et al. Krabbe disease: genetic aspects and progress toward therapy. Mol Genet Metab. 2000;70:1-9.

Krivit W, et al. Hematopoietic stem-cell transplantation in globoid-cell leukodystrophy. N Engl J Med. 1998;338:1119-26.

Kukita Y, et al. Characterization of the GALC gene in three Japanese patients with adult-onset Krabbe disease. Genet Test. 1997-98;1:217-23.

Turazzini M, et al. Adult onset Krabbe’s leukodystrophy: a report of 2 cases. Acta Neurol Scand. 1997;96:413-15.

De Gasperi R, et al. Molecular heterogeneity of late-onset forms of globoid-cell leukodystrophy. Am J Hum Genet. 1996;59:1233-42.

Cannizzaro LA, et al. Regional mapping of the human galactocerebrosidase gene (GALC) to 14q31 by in situ hybridization. Cytogenet Cell Genet. 1994;66:244-45.

Morell P, A correlative synopsis of the leukodystrophies. Neuropediatrics. 1984;15:62-5.

Zeigler M, et al., Prenatal diagnosis of Krabbe disease using a fluorescent derivative of galactosylceramide. Clinica Chimica Acta. 1984;:313-8

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Programs & Resources

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• Patient Organizations

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