Guenzel AJ, Turgeon CT, Nickander KK, White AL, Peck DS, Pino GB, Studinski AL, Prasad VK, Kurtzberg J, Escolar ML, Lasio MLD, Pellegrino JE, Sakonju A, Hickey RE, Shallow NM, Ream MA, Orsini JJ, Gelb MH, Raymond K, Gavrilov DK, Oglesbee D, Rinaldo P, Tortorelli S, Matern D Genetics in medicine : official journal of the American College of Medical Genetics. 2020 Feb 24. doi: 10.1038/s41436-020-0764-y.
Abstract
Purpose
Newborn screening (NBS) for Krabbe disease (KD) is performed by measurement of galactocerebrosidaseA specific enzyme that receives its instructions from the GALC gene. When the GALC gene isn’t working properly, the enzyme, galactocerebrosidase, is unable to break down certain fats called galactol (GALC) activity as the primary test. This revealed that GALC activity has poor specificity for KD. PsychosineDue to the enzyme deficiency in Krabbe disease, psychosine accumulates in the nervous system of affected individuals. Psychosine, a galactolipid, is a cytotoxic type of lipid, that has destructive pr (PSY) was proposed as a disease marker useful to reduce the false positive rate for NBS and for disease monitoring. We report a highly sensitive PSY assay that allows identification of KD patients with minimal PSY elevations.
Methods
PSY was extracted from dried blood spots or erythrocytes with methanol containing d5-PSY as internal standard, and measured by liquid chromatography-tandem mass spectrometry.
Results
Analysis of PSY in samples from controls (N = 209), GALC pseudodeficiency carriers (N = 55), GALC pathogenic variantA variant is anychange in the DNA sequence away from what is considered normal or typical. A change that does not have medical consequences is described as benign, while disease-causing variants are carriers (N = 27), patients with infantile KD (N = 26), and patients with late-onset KD (N = 11) allowed for the development of an effective laboratory screening and diagnostic algorithm. Additional longitudinal measurements were used to track therapeutic efficacy of hematopoietic stem cell transplantion (HSCTHematopoietic stem cell transplantation (HSCT), a type of transplantation using multipotent hematopoietic stem cells typically derived from bone marrow, peripheral blood, or that from umbilical cord b).
Conclusion
This study supports PSY quantitation as a critical component of NBS for KD. It helps to differentiate infantile from later onset KD variants, as well as from GALC variant and pseudodeficiency carriers. Additionally, this study provides further data that PSY measurement can be useful to monitor KD progression before and after treatment.