Second-tier test for confirming a diagnosis of Krabbe disease
Carrier testing for individuals with a family history of Krabbe disease in the absence of known mutations in the family
If skin biopsy is received, fibroblast culture for genetic test will be added and charged separately.
See Newborn Screen Follow-up for Infantile Krabbe Disease in Special Instructions.
For more information, see Newborn Screening Act Sheet Krabbe Disease: Decreased Galactocerebrosidase in Special Instructions.
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 unknown. Molecular tests form the basis of confirmatory or carrier testing.
This assay includes DNA sequencing of all 17 exons within the GALC gene as well as evaluation for the common 30-kb deletion spanning intron 10 through the end of the gene. This deletion accounts for a significant proportion of disease alleles that contribute to infantile Krabbe disease. While enzyme activity is not predictive of age of onset, there are known genotype-phenotype correlations. 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.
All detected alterations are evaluated according to American College of Medical Genetics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
This analysis does not exclude a diagnosis of atypical Krabbe disease due to saposin A deficiency.
A small percentage of individuals who are carriers or have a diagnosis of Krabbe disease may have a mutation that is not identifiable by this method (eg, large genomic deletions, promoter mutations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of Krabbe disease.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
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.
1. Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424
2. Wenger DA: Krabbe Disease (Most recent review March 2011). Available at www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=krabbe
3. Luzi P, Rafi MA, Wenger DA: Structure and organization of the human galactocerebrosidase (GALC) gene. Genomics 1995;26:407-409
4. 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
5. 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
