What is NBS?
All babies in developed countries are screened for several conditions shortly after birth. Approximately 24-48 after a baby is born in the United States, the heel is pricked by a nurse to collect a small sample of blood. Afterwards, the nurse puts a series of blood drops onto a filter paper to create several “dried blood spots.” Next, the newborn screening card is sent to the state laboratory for analysis. Most states screen for the majority of conditions included on the Recommended Uniform Screening Panel (RUSP).
Is Krabbe Disease on the RUSP?
Krabbe disease is not on the RUSP; however, grassroot efforts by patient advocacy groups have successfully added Krabbe disease to their newborn screening program. New York was the first state to begin screening for Krabbe disease in 2006 and since inception, has identified 5 infants with early infantile Krabbe disease. The states currently screening for Krabbe disease are as follows:
- New York
- New Jersey
- Georgia (Begins screening September 20, 2021)
How is Krabbe Disease Screened?
States screening for Krabbe disease do so by measuring the activity of galactocerebrosidase (also known as galactosylceramide beta-galactosidase and GALC) in the dried blood spots collected from NBS. All Krabbe patients have very low GALC activity. When the GALC activity level is below the norm, screening laboratories perform additional tests on the dried blood spot samples to assess the patient’s risk of developing Krabbe disease. Most newborns who have an initial GALC activity value below the newborn screening cutoff will not develop Krabbe disease, as was shown in the NY Pilot Study1. State laboratories institute cutoffs with the initial screening at a relatively high value to minimize the risk of missing a baby with Krabbe disease.
What More Should I Know?
Following the initial test of the dried blood spots for Krabbe disease state laboratories conduct different analyses to confirm the disease. Some state laboratories look for mutations in the GALC gene to determine the genotype in newborns who initially test positive with the enzyme test. Other newborn screening laboratories determine the concentration of psychosine in the dried blood spot, as this metabolite serves as a useful biomarker for prediction of Krabbe disease.
Currently, data from New York and a few other states, reveals that the initial GALC enzymatic activity with GALC genotype is less reliable compared to the initial GALC enzymatic activity with psychosine level when attempting to confirm a diagnosis of Krabbe disease. Recent data from the Kentucky NBS laboratory supports this comparison as only 1 out of 110,000 babies screened in KY required a follow-up2. This newborn was then confirmed to have infantile Krabbe disease and received a bone marrow transplant in the 4th week of life.
A Little More Information about Psychosine
Psychosine accumulates in the blood when the enzyme GALC is deficient. The accumulation of Psychosine is thought to be toxic to neurons. This metabolite is measured only if there’s an abnormal level of GALC from the initial enzyme test. Drs. Michael H. Gelb (Univ. of Washington), Dietrich Matern (Mayo Clinic, Rochester, MN), and Joseph Orsini (Wadsworth Center, Albany, NY) have worked over the past few years to ensure that psychosine measurements are consistent among the few laboratories offering the psychosine test. Recently, Dr. Gelb has improved the traditional laboratory tests when measuring GALC enzymatic activity in blood, (not dried blood spots) to minimize the likelihood of a false-positive Krabbe disease diagnosis3. Dietrich Matern is currently working on validating this new GALC assay for universal diagnosis and prognosis.
- Newborn screening for Krabbe disease in New York State: the first eight years' experience. Orsini JJ, Kay DM, Saavedra-Matiz CA, Wenger DA, Duffner PK, Erbe RW, Biski C, Martin M, Krein LM, Nichols M, Kurtzberg J, Escolar ML, Adams DJ, Arnold GL, Iglesias A, Galvin-Parton P, Kronn DF, Kwon JM, Levy PA, Pellegrino JE, Shur N, Wasserstein MP, CagganaM; New York State Krabbe Disease Consortium. Genet Med. 2016 Mar;18(3):239-48. doi: 10.1038/gim.2015.211. Epub 2016 Jan 21.
- Precision newborn screening for lysosomal disorders. Minter Baerg MM, Stoway SD, Hart J, Mott L, Peck DS, Nett SL, Eckerman JS, Lacey JM, Turgeon CT, Gavrilov D, Oglesbee D, Raymond K, Tortorelli S, Matern D, Mørkrid L, Rinaldo P. Genet Med. 2017 Nov 9. doi: 10.1038/gim.2017.194.
- Lymphocyte Galactocerebrosidase Activity by LC-MS/MS for Post-Newborn Screening Evaluation of Krabbe Disease. Liao HC, Spacil Z, Ghomashchi F, Escolar ML, Kurtzberg J, Orsini JJ, Turecek F, Scott CR, GelbMH. Clin Chem. 2017 Aug;63(8):1363-1369. doi: 10.1373/clinchem.2016.264952.