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
- Pennsylvania (Opt-In)
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.
The Experts in NBS for Krabbe Disease
Below is a list of individuals devoted to newborn screening for Krabbe disease. Their scientific discoveries and related studies continue to improve the timeliness of diagnosis for expedited treatment. Given the difficulty in diagnosing Krabbe disease, KrabbeConnect believes it’s important to make you aware of the brilliant individuals involved with NBS for Krabbe disease. It’s our goal to one day, have Krabbe disease be part of the RUSP.
Professor Michael H. Gelb
Professor Michael Gelb is the Boris and Barbara L. Weinstein Endowed Chair in Chemistry in the Departments of Chemistry and Biochemistry at the University of Washington in Seattle. Professor Gelb’s laboratory developed the technology that brought newborn screening (NBS) for Krabbe disease to the forefront and led to New York being the first to begin statewide NBS for Krabbe disease in 2006. Since the initial inception, Gelb has worked closely with Dr. Dietrich Matern, at the Mayo Clinic in MN, and Dr. Joseph Orsini, at the Wadsworth Center in NY, to develop methods to improve screening, diagnostic challenges, and prognostic testing for Krabbe disease. This team continues to monitor newborn screening and post-screening data to further define the best approach to newborn screening and follow-up for Krabbe disease. This work will provide the foundation for a successful nomination of Krabbe disease to the RUSP. To learn more about Michael Gelb, visit his Laboratory or feel free to reach out to him by email at email@example.com.
Joseph Orsini, Ph.D.
Dr. Joseph Orsini is the Deputy Director for the New York Newborn Screening Program. Dr. Orsini’s laboratory was the first to implement newborn screening for Krabbe disease (KD), applying the research method of Dr. Michael Gelb’s laboratory, to high throughput screening. Dr. Orsini worked with Genzyme (currently Sanofi)in developing a test that could screen for psychosine, the enzyme that is deficient in Krabbe disease patients. Studies have revealed that psychosine is noticeable elevated in newborns when assessing infantile KD. Furthermore, additional studies indicate that second tier testing for psychosine can significantly reduce the incidence rate of false positive in KD. Currently, Dr. Joseph Orsini works with Professor Michael Gelb, Dr. Dietrich Matern, the New York State Krabbe Consortium, and the Krabbe Disease Task Force to redefine who’s at risk for late onset KD. This ongoing work in newborn screening for Krabbe disease will provide the scientific platform for a successful nomination of Krabbe disease to the RUSP. To learn more about Joseph Orsini, visit his Laboratory or feel free to reach out to him by email at firstname.lastname@example.org
- 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.