Krabbe Disease Newborn Screening

Newborn screening for Krabbe disease is crucial because it allows for early diagnosis and treatment of this genetic disorder before symptoms appear. Early diagnosis and intervention can help significantly improving the child’s quality of life and chances of survival. Unfortunately, many states do not screen for Krabbe disease, but KrabbeConnect is working with states to get the test added to their testing panels.

What is Newborn Screening?

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).

Which states currently screen newborns for Krabbe disease?

New York was the first state to begin newborn screening for Krabbe disease in 2006 and since inception, has identified 5 infants with early infantile Krabbe disease.

Currently there are 11 states screening for Krabbe disease. Please take a look at the chart below to see which states screen for Krabbe disease. Information provided in the chart shows the number of babies screened annually, how many infants have been identified with either the EIKD (Early Infantile Krabbe Disease), LOKD (Late Infantile Krabbe Disease), and if the states provide second tier testing which measures 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.

Adding a condition to the RUSP takes time however, if the U.S. Secretary of Health, as advised by the ACHDNC, adds Krabbe disease to the RUSP, other states across the U.S. will follow suit. You can see a list of states that align their newborn screening panel with RUSP here.

How is Krabbe Disease Screened?

States screening for Krabbe disease do so by measuring the activity 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 (also known as galactosylceramideA galactolipid that is an important component of the normal turnover of myelin in nerve fibers. When there is an enzyme deficiency, excess galactosylceramide and psychosine (both galactolipids) store 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.

Information about Psychosine

Psychosine accumulates in the blood when the enzymeA protein needed by the body to break down certain substances by causing a biochemical reaction within the cells. In Krabbe disease, galactocerebrosidase is the deficient enzyme.  Words that end in 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.

What More Should I Know about Krabbe Disease Newborn Screening?

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 mutationsThis is an older word used to describe a change in a specific gene leading to disease.  As not all mutations are bad, the word mutation has been replaced with the term “pathogenic variant” that d in the GALC geneThe GALC gene is located on chromosome 14. This gene provides instructions for making the enzyme galactocerebrosidase. This enzyme breaks down certain fats called galactolipids. Galactocerebrosidase 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 transplantA medical procedure whereby diseased bone marrow is replaced with healthy bone marrow. Often times, the patients’ bone marrow will be destroyed by high doses of certain chemotherapies and/or radiati in the 4th week of life.

References:

1. 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.
2. 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.
3. 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.