Leukodystrophy, Krabbe's

Leukodystrophy, Krabbe's

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Leukodystrophy, Krabbe's is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

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

Disorder Subdivisions

  • None

General Discussion

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 mental retardation, paralysis, blindness, deafness and paralysis of certain facial muscles (pseudobulbar palsy). Krabbe's Leukodystrophy is inherited as an autosomal recessive trait.

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).

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.

Affected Populations

About 1 in 40,000 newborn babies in the United States is affected with Krabbe's Leukodystrophy. Males are affected as often as females.

Standard Therapies

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.



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.

Investigational Therapies

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: prpl@cc.nih.gov



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.

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

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building

176 Nantwich Road

Crewe, CW2 6BG

United Kingdom

Tel: 4408452412173

Fax: 4408452412174

Email: enquiries@climb.org.uk

Internet: http://www.CLIMB.org.uk



Kennedy Krieger Institute

707 North Broadway

Baltimore, MD 21205

Tel: (443)923-9200

Fax: (443)923-9405

Tel: (800)873-3377

TDD: (443)923-9400

Email: info@kennedykrieger.org

Internet: http://www.kennedykrieger.org



The Arc

1825 K Street NW, Suite 1200

Washington, DC 20006

Tel: (202)534-3700

Fax: (202)534-3731

Tel: (800)433-5255

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



United Leukodystrophy Foundation

224 N. 2nd St.

Suite 2

DeKalb, IL 60115

Tel: (815)748-3211

Tel: (800)728-5483

Email: office@ulf.org

Internet: http://www.ulf.org/



ELA - European Association Against Leukodystrophies

2, rue Mi-les-Vignes

54521

Laxou Cedex, 61024

France

Tel: 33383309334

Fax: 33383300068

Email: ela@ela-asso.com

Internet: http://www.ela-asso.com



NIH/National Institute of Neurological Disorders and Stroke

P.O. Box 5801

Bethesda, MD 20824

Tel: (301)496-5751

Fax: (301)402-2186

Tel: (800)352-9424

TDD: (301)468-5981

Internet: http://www.ninds.nih.gov/



Hunter's Hope Foundation, Inc.

PO Box 643

6368 West Quaker Street

Orchard Park, NY 14127

Tel: (716)667-1200

Fax: (716)667-1212

Tel: (877)984-4673

Email: info@huntershope.org

Internet: http://www.huntershope.org



Australian Leukodystrophy Support Group, Inc.

Nerve Centre

54 Railway Road

Blackburn, VIC 3130

Australia

Tel: 61395847070

Tel: 1800141400

Email: mail@alds.org.au

Internet: http://www.alds.org.au



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Madisons Foundation

PO Box 241956

Los Angeles, CA 90024

Tel: (310)264-0826

Fax: (310)264-4766

Email: getinfo@madisonsfoundation.org

Internet: http://www.madisonsfoundation.org



Hide & Seek Foundation for Lysosomal Disease Research

6475 East Pacific Coast Highway Suite 466

Long Beach, CA 90803

Tel: (877)621-1122

Fax: (866)215-8850

Email: info@hideandseek.org

Internet: http://www.hideandseek.org



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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