Test Id : PSY

If the patient has abnormal newborn screening result for Krabbe disease, immediate action should be taken. Refer to the appropriate American College of Medical Genetics and Genomics Newborn Screening ACT Sheet.(1,2)

The following are available:

-Newborn Screen Follow-up for Krabbe Disease: Galactocerebrosidase

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

This test is recommended for newborns or infants who have not had previous psychosine testing. This test is not intended to be used as a monitoring test for individuals with Krabbe disease who are treated or for children or adults at risk of developing Krabbe disease. For patients older than infancy, order PSYR / Psychosine, Whole Blood.

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

Container/Tube:

Preferred: Card-Blood Spot Collection (Filter Paper)

Acceptable: PerkinElmer 226 filter paper, Munktell filter paper, Whatman protein Saver 903 paper, local newborn screening card, or blood collected in tubes containing EDTA (preferred) or heparin and dried on filter paper

Specimen Volume: 2 Blood spots

Collection Instructions:

1. Completely fill at least 2 circles on the filter paper card (approximately 100 microliters blood per circle).

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

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

4. Do not stack wet specimens.

5. Keep specimen dry.

Additional Information:

1. For collection instructions, see Blood Spot Collection Instructions

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

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

• Biochemical Genetics Patient Information
• Blood Spot Collection Card-Spanish Instructions
• Blood Spot Collection Card-Chinese Instructions
• Newborn Screen Follow-up for Krabbe Disease: Galactocerebrosidase
• Newborn Screen Follow-up for Krabbe Disease: Galactocerebrosidase and Psychosine
• Blood Spot Collection Instructions

1. Biochemical Genetics Patient Information (T602)

2. If not ordering electronically, complete, print, and send a Biochemical Genetics Test Request (T798) with the specimen.

1 Blood spot

Aids in the biochemical detection of Krabbe disease and saposin A cofactor deficiency

Second-tier testing or follow up testing after an abnormal newborn screening result in an infant for Krabbe disease

This test is not capable of identifying carriers of Krabbe disease.

This test is not intended for long-term monitoring of individuals being treated for Krabbe disease or for older children or adult patients at risk to develop Krabbe disease.

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive lysosomal storage disorder caused by an enzyme deficiency of galactocerebrosidase (GALC).

Although Krabbe disease is clinically variable, the most common and severe form of the disorder is early infantile onset that presents with rapid neurological regression and results in early death.

This test is a second-tier assay for infants who have abnormal newborn screening results with reduced GALC activity and can detect patients with infantile or late infantile Krabbe disease or saposin A cofactor deficiency.

If the patient has abnormal newborn screening result for Krabbe disease, immediate action should be taken. Refer to the appropriate American College of Medical Genetics and Genomics Newborn Screening ACT Sheet.(1,2)

The following are available:

-Newborn Screen Follow-up for Krabbe Disease: Galactocerebrosidase

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

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive lysosomal storage disorder caused by an enzyme deficiency of galactocerebrosidase (GALC). GALC facilitates the lysosomal degradation of psychosine (galactosylsphingosine) and 3 other substrates, galactosylceramide, lactosylceramide, and lactosylsphingosine. Krabbe disease is caused by variants in the GALC gene, and it has an estimated frequency of 1 in 100,000 births.

The clinical course of Krabbe disease can be variable, even within the same family. Eighty-five percent to 90% of patients present before the first year of life with central nervous system impairment, including increasing irritability, developmental delay, and sensitivity to stimuli. Rapid neurodegeneration, including white matter disease follows, with death usually occurring by 2 years of age. Late onset forms of the disease affect 10% to15% of individuals and are characterized by ataxia, vision loss, weakness, and psychomotor regression, typically presenting from age 6 months to the seventh decade of life.

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 early, prior to onset of neurologic damage.

Psychosine is 1 of 4 substrates degraded by GALC and is a neurotoxin at elevated concentrations. It has been shown to be elevated in patients with active Krabbe disease or with saposin A cofactor deficiency and, therefore, may be a useful biomarker for the presence of disease or disease progression.

Reduced or absent GALC in leukocytes (GALCW / Galactocerebrosidase, Leukocytes) or dried blood spots (PLSD / Lysosomal and Peroxisomal Storage Disorders Screen, Blood Spot) along with elevated psychosine levels can indicate a diagnosis of Krabbe disease. Molecular sequencing of the GALC gene (KRABZ / Krabbe Disease, Full Gene Analysis and Large [30 kb] Deletion, Varies) allows for detection of the disease-causing variants in affected patients and carrier detection in family members.

Individuals with a disease phenotype similar to Krabbe disease may have saposin A cofactor deficiency. Saposin A cofactor deficiency also results in elevated psychosine levels. Testing for this condition via molecular analysis of the PSAP gene is useful in those with elevated psychosine and normal to reduced GALC activity with normal molecular genetic GALC sequencing.

Normal <2 nmol/L

An interpretive report will be provided.

An elevation of psychosine is indicative of symptomatic Krabbe disease or symptomatic saposin A cofactor deficiency.

When abnormal results are detected, a detailed interpretation is given, including an overview of the results and of their significance, a correlation to available clinical information, elements of differential diagnosis, recommendations for additional biochemical testing and in vitro confirmatory studies (enzyme assay, molecular analysis), and a phone number to reach one of the laboratory directors in case the referring physician has additional questions.

Normal psychosine levels may be seen in patients (from childhood to adulthood) who are not yet symptomatic or have later onset Krabbe disease or saposin A cofactor deficiency.

Receiver operating characteristic curve analysis of 220 controls and 6 patients affected with Krabbe disease yielded an area under the curve of 1.0, permitting the selection of a cutoff value yielding a positive predictive value and negative predictive value of 1.0.

1. Newborn Screening ACT Sheet [Decreased galactocerebrosidase, elevated psychosine] Krabbe Disease (infantile form). American College of Medical Genetics and Genomics; 2021. Updated May 2022. Accessed June 10, 2024. Available at www.acmg.net/PDFLibrary/Krabbe-Infantile.pdf

2. Newborn Screening ACT Sheet [Decreased galactocerebrosidase, mildly elevated psychosine] Krabbe Disease (late-onset form). American College of Medical Genetics and Genomics; 2021. Updated May 2022. Accessed June 10, 2024. Available www.acmg.net/PDFLibrary/Krabbe-Later-Onset.pdf

3. Orsini JJ, Morrissey MA, Slavin LN, et al. Implementation of newborn screening for Krabbe disease: population study and cutoff determination. Clin Biochem. 2009;42(9):877-884. doi:10.1016/j.clinbiochem.2009.01.022

4. Svennerholm L, Vanier MT, Mansson JE. Krabbe disease: A galactosylsphingosine (psychosine) lipidosis. J Lipid Res. 1980;21(1):53-64

5. Enns GM, Steiner RD, Cowan TM. Lysosomal disorders. In: Sarafoglou K, Hoffman G, Roth KS, eds. Pediatric Endocrinology and Inborn Errors of Metabolism. McGraw-Hill Medical; 2009:744

6. Turgeon CT, Orsini JJ, Sanders KA, et al. Measurement of psychosine in dried blood spots--a possible improvement to newborn screening programs for Krabbe disease. J Inherit Metab Dis. 2015;38(5):923-929. doi:10.1007/s10545-015-9822-z

7. Wenger DA, Escolar ML, Luzi P, Rafi MA: Krabbe disease (globoid cell leukodystrophy). In: Valle D, Antonarakis S, Ballabio A, Beaudet AL, Mitchell GA, eds. The Online Metabolic and Molecular Bases of Inherited Disease. McGraw-Hill; 2019. Accessed August 30, 2023. Available at https://ommbid.mhmedical.com/content.aspx?sectionid=225546481&bookid=2709

8. Guenzel AJ, Turgeon CT, Nickander KK, et al. The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease. Genet Med. 2020;22(6):1108-1118. doi:10.1038/s41436-020-0764-y

9. Thompson-Stone R, Ream MA, Gelb M, et al. Consensus recommendations for the classification and long-term follow up of infants who screen positive for Krabbe disease. Mol Genet Metab. 2021;134(1-2):53-59. doi:10.1016/j.ymgme.2021.03.016

Internal standard is added to a dried blood spot. The extract is evaporated and reconstituted prior to injection onto a liquid chromatography tandem mass spectrometry (LC-MS/MS). Following separation of the structural isomers glucopsychosine and psychosine (PSY) by liquid chromatography, their concentrations are measured by MS/MS analysis in the multiple reaction monitoring positive mode to follow the precursor to product species transitions for PSY. The ratio of the extracted peak area of PSY to internal standard as determined by LC-MS/MS is used to calculate the concentration of PSY in the sample.(Unpublished Mayo method)

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

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