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

Useful For

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

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
FIBR Fibroblast Culture Yes No
CRYOB Cryopreserve for Biochem Studies No No

Testing Algorithm

If a skin biopsy is received, fibroblast culture and cryopreservation for biochemical studies will be added at an additional charge.

 

The following are available in Special Instructions:

-Newborn Screen Follow-up for Krabbe Disease: Galactocerebrosidase

-Newborn Screen Follow-up for Krabbe Disease: Galactocerebrosidase and Psychosine

-Newborn Screen Follow-up for Krabbe Disease: Galactocerebrosidase, Psychosine, and GALC 30kb Deletion

-Newborn Screening Act Sheet Krabbe Disease: Decreased Galactocerebrosidase

Method Name

Polymerase Chain Reaction (PCR) followed by DNA Sequencing

Reporting Name

Krabbe Disease, Full Gene Analysis

Specimen Type

Varies


Advisory Information


The recommended first-tier test for Krabbe disease is GALCW / Galactocerebrosidase, Leukocytes, however this test is not reliable for detection of carriers.

 

For ongoing therapeutic monitoring for patients with Krabbe disease or for second tier newborn screening, order PSY / Psychosine, Blood Spot.



Shipping Instructions


Specimen preferred to arrive within 96 hours of collection.



Specimen Required


Patient Preparation: A previous bone marrow transplant from an allogenic donor will interfere with testing. Call 800-533-1710 for instructions for testing patients who have received a bone marrow transplant.

 

Submit only 1 of the following specimens:

 

Specimen Type: Whole blood

Container/Tube:

Preferred: Lavender top (EDTA) or yellow top (ACD)

Acceptable: Any anticoagulant

Specimen Volume: 3 mL

Collection Instructions:

1. Invert several times to mix blood.

2. Send specimen in original tube.

Specimen Stability Information: Ambient (preferred)/Refrigerated

 

Specimen Type: Cultured fibroblasts

Container/Tube: T-75 or T-25 flask

Specimen Volume: 1 Full T-75 or 2 full T-25 flasks

Specimen Stability Information: Ambient (preferred)/Refrigerated <24 hours

 

Specimen Type: Skin biopsy

Supplies: Fibroblast Biopsy Transport Media (T115)

Container/Tube: Sterile container with any standard cell culture media (eg, minimal essential media, RPMI 1640). The solution should be supplemented with 1% penicillin and streptomycin.

Specimen Volume: 4-mm punch

Specimen Stability Information: Refrigerated (preferred)/Ambient

 

Acceptable:

Specimen Type: Blood spot

Supplies: Card - Blood Spot Collection (Filter Paper) (T493)

Container/Tube:

Preferred: Collection card (Whatman Protein Saver 903 Paper)

Acceptable: Ahlstrom 226 filter paper or Blood Spot Collection Card

Specimen Volume: 2 to 5 Blood spots

Collection Instructions:

1. An alternative blood collection option for a patient older than 1 year of age is finger stick.

2. Let blood dry on the filter paper at ambient temperature in a horizontal position for 3 hours.

3. Do not expose specimen to heat or direct sunlight.

4. Do not stack wet specimens.

5. Keep specimen dry.

Specimen Stability Information: Ambient (preferred)/Refrigerated

Additional Information:

1. For collection instructions, see Blood Spot Collection Instructions in Special Instructions.

2. For collection instructions in Spanish, see Blood Spot Collection Card-Spanish Instructions (T777) in Special Instructions.

3. For collection instructions in Chinese, see Blood Spot Collection Card-Chinese Instructions (T800) in Special Instructions.


Specimen Minimum Volume

Blood: 1 mL
Blood Spots: 3

Specimen Stability Information

Specimen Type Temperature Time Special Container
Varies Varies

Clinical Information

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

An interpretive report will be provided.

Interpretation

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.

Clinical Reference

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

Day(s) and Time(s) Performed

Varies

Analytic Time

14 days

CPT Code Information

81406 GALC (galactosylceramidase) (eg, Krabbe disease), full gene sequence

88233-Tissue culture, skin or solid tissue biopsy (if appropriate)

88240-Cryopreservation (if appropriate)

LOINC Code Information

Test ID Test Order Name Order LOINC Value
KRABZ Krabbe Disease, Full Gene Analysis 87738-1

 

Result ID Test Result Name Result LOINC Value
53505 Result Summary 50397-9
53506 Result 82939-0
53507 Interpretation 69047-9
53508 Additional Information 48767-8
53509 Specimen 31208-2
53510 Source 31208-2
53511 Released By 18771-6

Test Classification

This test was developed and its performance characteristics determined by Mayo Clinic in a manner consistent with CLIA requirements. This test has not been cleared or approved by the U.S. Food and Drug Administration.

Forms

1. New York Clients-Informed consent is required. Document on the request form or electronic order that a copy is on file. The following documents are available in Special Instructions:

-Informed Consent for Genetic Testing (T576)

-Informed Consent for Genetic Testing-Spanish (T826)

2. Molecular Genetics: Biochemical Disorders Patient Information (T527) in Special Instructions

3. If not ordering electronically, complete, print, and send an Inborn Errors of Metabolism Test Request (T798) with the specimen.