Krabbe Disease, Known Mutation
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 (GALC, galactosylceramide beta-galactosidase). GALC is encoded by the GALC gene located on 14q31. Krabbe disease occurs in approximately 1 in 100,000 live births with a carrier frequency of about 1 in 150 in the general population. Deficiency of GALC activity leads to an accumulation of galactosylceramide in globoid cells (multinucleated macrophages) causing severe demyelination throughout the brain. The toxic metabolite galactosylsphingosine (psychosine), an apoptotic compound, accumulates in oligodendrocytes and Schwann cells and contributes to disease pathogenicity.
Severely affected individuals typically present between 3 to 6 months of age with increasing irritability and sensitivity to stimuli. Rapid neurodegeneration follows with death usually occurring by age 13 months. There are later onset forms of the disease that are characterized by ataxia, vision loss, weakness, and psychomotor regression. The clinical course of Krabbe disease can be variable even within the same family. Treatment is mostly supportive, although hematopoietic stem cell transplantation has shown some success if treatment begins before neurologic damage has occurred.
The recommended first-tier test for Krabbe disease is LDSBS / Lysosomal Disorders Screen, Blood Spot, CBGC / Galactosylceramide Beta-Galactosidase, Leukocytes, or CBGT / Galactosylceramide Beta-Galactosidase, Fibroblasts. Individuals with GALC activity below the reference range for these assays are more likely to have mutations in the GALC gene that are identifiable by molecular genetic testing. The above tests are not reliable for detection of carriers of Krabbe disease. Molecular genetic testing (this test) is the recommended test for individuals with a family history of Krabbe disease in which the mutations in the family are known. The recommended molecular test if mutations in the family are not known is GALCS / Krabbe Disease, Full Gene Analysis and Large (30 kb) Deletion, PCR.
This assay tests for specific mutations previously identified in a family member and, therefore, may also be used for diagnosing individuals with a suspected diagnosis of Krabbe disease when mutations in the family are known. While enzyme activity is not predictive of age of onset, there are known genotype-phenotype correlations. The common 30-kb deletion spanning intron 10 through the end of the gene accounts for a significant proportion of disease alleles that contribute to infantile Krabbe disease. Individuals who are homozygous for the deletion, or compound heterozygous for the deletion and a second GALC mutation (with the exception of late-onset mutations), are predicted to have infantile Krabbe disease. The c.857G->A (p.Gly286Asp) mutation, on the other hand, is only associated with a late-onset phenotype.
Carrier testing of individuals with a family history of Krabbe disease when a mutation has been identified in an affected family member
Diagnostic confirmation of Krabbe disease when familial mutations have been previously identified
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
The identification of a disease-causing mutation in an affected family member is necessary before testing can be offered for other family members. If a familial mutation has not been previously identified, order GALCS / Krabbe Disease, Full Gene Analysis and Large (30 kb) Deletion, PCR.
Analysis is performed for the familial mutations provided only. This assay does not rule-out the presence of other mutations within this gene or within other genes that may be associated with metabolic disease.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
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.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Wenger DA: Krabbe Disease (Most recent review March 2011). Available at http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=krabbe
2. Luzi P, Rafi MA, Wenger DA: Structure and organization of the human galactocerebrosidase (GALC) gene. Genomics 1995;26:407-409
3. Luzi P, Rafi MA, Wenger DA: Characterization of the large deletion in the GALC gene found in patients with Krabbe disease. Hum Mol Genet 1995;4(12):2335-2338
4. Spiegel R, Bach G, Sury V, et al: A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: report of saposin A deficiency in humans. Molec Genet Metab 2005,84:160-166