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. Some 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 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 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 do not cause disease. Molecular sequencing of the GALC gene (KRABZ / Krabbe Disease, Full Gene Analysis and Large [30 kb] Deletion, PCR) is necessary for differentiating polymorphisms from disease-causing mutations in affected patients and for carrier detection in family members.
Diagnosis of Krabbe disease
Values below the reference range are consistent with a diagnosis of Krabbe disease.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
This test is not recommended for carrier detection because of the wide range of enzymatic activities observed in carriers and noncarriers.
Pseudodeficiency of galactocerebrosidase causes reduced enzymatic activity, but does not cause disease.
A Krabbe disease phenotype can also be caused in very rare cases by the absence of a physiologically active sphingolipid activator protein, saposin A (SAP-A).
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
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Wenger DA: Krabbe Disease. 2000 Jun 19 (Updated 2011 Mar 31). Edited by RA Pagon, MP Adam, HH Ardinger, GeneReviews. Seattle, WA: University of Washington, Seattle; 1993-2017. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1238/. Accessed March 27, 2017
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, et al. New York, NY: McGraw-Hill; 2014. http://ommbid.mhmedical.com/content.aspx?bookid=971§ionid=62644214. Accessed March 27, 20173. Graziano AC, Cardile V: History, genetic, and recent advances on Krabbe disease. Gene 2015 Jan 15;555(1):2-13 4. Orsini JJ, Kay DM, Saavedra-Matiz CA, et al: Newborn screening for Krabbe disease in New York State: the first eight years' experience. Genet Med 2016 Mar;18(3):239-248