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Test Catalog

Test ID: KRABZ    
Krabbe Disease, Full Gene Analysis and Large (30 kb) Deletion, Varies

Useful For Suggests clinical disorders or settings where the test may be helpful

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 sequence variants in the family

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

Testing includes full gene sequencing of the GALC gene.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

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 GALCW / Galactocerebrosidase, Leukocytes.

Individuals with GALC activity below the reference range for these assays are more likely to have variants in the GALC gene that are identifiable by molecular genetic testing. The above test is not reliable for detection of carriers of Krabbe disease. Additionally, measurement of the psychosine biomarker can aid in diagnosis and ongoing therapeutic monitoring (PSY / Psychosine, Blood Spot).

 

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 alteration (with the exception of late-onset variants) are predicted to have infantile Krabbe disease. The c.857G->A (p.Gly286Asp) alteration, on the other hand, is only associated with a late-onset phenotype.

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.

Interpretation Provides information to assist in interpretation of the test results

All detected alterations are evaluated according to American College of Medical Genetics and Genomics (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

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 variant that is not identifiable by this method (eg, large genomic deletions, promoter alterations). The absence of a variant, 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 alterations 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 the interpretation of results may occur if information given is inaccurate or incomplete.

Clinical Reference Recommendations for in-depth reading of a clinical nature

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. Orsini JJ, Escolar ML, Wasserstein MP, Caggana M: Krabbe disease. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews [Internet]. University of Washington, Seattle; 2000. Updated October 11, 2018. Accessed June 30, 2020. Available at ncbi.nlm.nih.gov/books/NBK1238/

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

Special Instructions Library of PDFs including pertinent information and forms related to the test