Diagnosis of Krabbe disease
Genetics Test Information Provides information that may help with selection of the correct test or proper submission of the test request
Diagnostic testing for patients with clinical signs and symptoms suspicious for Krabbe disease.
Included in the diagnostic workup for infants following a positive newborn screen result for Krabbe disease.
This test is not intended for carrier detection.
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder caused by a deficiency of galactocerebrosidase. A deficiency of this enzyme leads to an accumulation of galactosylceramide causing severe demyelination throughout the brain. Krabbe disease is primarily caused by mutations in the GALC gene, and it has an estimated frequency of 1 in 100,000 births. Although rare, a few infants with an early onset Krabbe disease phenotype due to deficiency of saposin A (SAP-A) have been found. Saposin-A is a sphingolipid activator protein that assists galactocerebrosidase in its action on galactosylceramide.
Severely affected individuals typically present between 3 to 6 months of age with increasing irritability and sensitivity to stimuli. Rapid neurodegeneration including white matter disease follows with death usually occurring by age 2. A small subset of individuals have later onset forms of the disease that are characterized by ataxia, vision loss, weakness, and psychomotor regression presenting anywhere from age 6 months to the seventh decade of life. The clinical course of Krabbe disease can be variable, even within the same family.
Newborn screening for Krabbe disease has recently been implemented in some states. The early (presymptomatic) identification and subsequent testing of infants at risk for Krabbe disease may be helpful in reducing the morbidity and mortality associated with this disease. While treatment is mostly supportive, hematopoietic stem cell transplantation has shown some success if performed prior to onset of neurologic damage.
Reduced or absent galactocerebrosidase in leukocytes or fibroblasts (CBGT / Galactocerebrosidase, Fibroblasts) can indicate a diagnosis of Krabbe disease, however a number of polymorphisms in the GALC gene have been identified that result in reduced galactocerebrosidase activity in vitro, but by themselves do not cause disease. Molecular sequencing of the GALC gene (KRABZ / Krabbe Disease, Full Gene Analysis and Large [30 kb] Deletion, PCR) allows for detection of the disease-causing mutations in affected patients and carrier detection in family members.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
> or =1.20 nmol/h/mg protein
Values below the reference range are consistent with a diagnosis of Krabbe disease.
The upper limit of normal may change with the specific activity of the substrate. Elevated values have no known clinical significance.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Because of the wide range of enzymatic activities observed in carriers and noncarriers, this test is not recommended for carrier detection.
Pseudodeficiency of galactocerebrosidase causes reduced enzymatic activity, but does not cause disease.
A Krabbe disease phenotype can also be caused by the absence of a physiologically active sphingolipid activator protein, saposin A (SAP-A)
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Wenger DA: Krabbe Disease. Available at: http://www.ncbi.nlm.nih.gov/books/NBK1238/ Last updated March 31, 2011. Reviewed January 29, 2016
2. Wenger DA, Escolar ML, Luzi P, Rafi MA: Krabbe disease (Globoid Cell Leukodystrophy). In: The Online Metabolic and Molecular Bases of Inherited Disease. Edited by D Valle, AL Beaudet, B Vogelstein. New York, NY, McGraw-Hill. 2014. http://ommbid.mhmedical.com/content.aspx?bookid=971&Sectionid=62644214. Accessed January 29, 20163. Graziano AC, Cardile V: History, genetic, and recent advances on Krabbe disease. Gene 2015 Jan 15;555(1):2-13 4. Wenger DA, Luzi P, Rafi MA: Lysosomal storage diseases: heterogenous group of disorders. Bioimpacts 2013;3(4):145-147