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Newborn Screening for Krabbe Disease

Archived Information and Updates

Archived Information and Updates

Contact Us

Contact Us

  • Mailing Address:
    Newborn Screening Program
    NYS Department of Health
    Wadsworth Center
    Empire State Plaza
    P.O. Box 509
    Albany, NY 12201-0509
  • Phone: (518) 473-7552
  • Email: nbsinfo@health.state.ny.us

Krabbe disease is caused by the complete deficiency of the enzyme galactocerebrosidase. It is considered both a lysosomal storage disorder and a leukodystrophy involving the central and peripheral nervous systems. Krabbe disease generally presents in the first six months of life, though it has been diagnosed in older children and adults. There are usually no obvious congenital anomalies present at birth. Early symptoms of the infantile form include feeding difficulties, gastroesophageal reflux, irritability and clasped thumbs. Late symptoms include hypertonicity followed by hypotonicity, flaccidity, deafness and blindness. In the infantile form, there is rapid mental deterioration, which usually leads to death before the age of two. Dietary treatment has not been effective at either reversing the symptoms or halting their progression. Currently, no enzyme replacement therapy is available. Hematopoetic stem cell transplantation from umbilical cord blood following myeloablative chemotherapy prior to the onset of symptoms has been shown to stabilize the disease, although gross motor skills may still be affected. Unfortunately, symptomatic infants receiving umbilical cord blood transplantation continue to show declining cognitive and physical functions.

Newborn screening for Krabbe disease provides the earliest window for population-based diagnosis and treatment. The screening is accomplished at the New York State Department of Health, in the Wadsworth Center, using specimens already collected for other newborn screening tests. There is no change in the way the specimens are currently collected and shipped. Wadsworth Center expects to refer approximately 50 infants each year for further Krabbe disease testing - 0.02% screen-positives from the annually screened population of about 250,000 infants. The screening protocol is designed to minimize screen positive results while preventing an infant with Krabbe from being missed. The items below briefly outline the screening and follow-up process:

Stage One: Wadsworth Center, Newborn Screening Program

Mass Spectrometry
A 3 millimeter "punch" is taken from the bloodspot card and transferred to the Krabbe testing laboratory. Mass spectrometry is used to test the sample for galactocerebrosidase (GALC) activity. An infant with GALC activity greater than 12% of the daily mean is considered to be screen-negative and her/his primary care physician is notified by written report per the normal NBS protocol. DNA analysis is initiated for any sample with confirmed enzyme activity less than 12% of the daily mean.

DNA Analysis
The specimen is tested for three polymorphisms and five common mutations using a rapid assay. If one or more mutations are found and confirmed, the infant is considered to be screen-positive and a physician is notified immediately. If no mutations are found, sequence analysis is performed. If sequence analysis demonstrates any mutation, the infant is considered to be screen-positive and a physician is notified immediately. If no mutations and only polymorphisms are observed after sequence analysis, the infant is considered to be screen-negative and her/his primary care physician is notified by written report of the findings by the normal NBS protocol.

Stage Two: Child Neurologist, Inherited Metabolic Disease Physician

Notification
The Newborn Screening Program staff reports screen-positive results to the Child Neurologist and the Inherited Metabolic Disease Specialist at the Treatment Center nearest the infant's home. The Inherited Metabolic Disease Specialist notifies the family of the positive screen for Krabbe disease. The infant is then given an appointment for evaluation at the Inherited Metabolic Disease Treatment Center as soon as possible.

Evaluation
The infant is seen by the Inherited Metabolic Disease Specialist and the Child Neurologist. The family is counseled about Krabbe disease and the infant is examined for early signs. Blood is collected using a kit provided by Wadsworth Center. Five milliliters of blood is drawn and sent to the second tier laboratory. In addition, two bloodspot cards are collected; one card is sent to the American Red Cross for Human Leukocyte Antigen (HLA) typing and one card is returned to Wadsworth Center for identity testing and confirmation of the previous result.

Stage Three: Second Tier Laboratory


The second tier laboratory tests the specimen for galactocerebrosidase activity. The results are reported back to the ordering physician and Wadsworth Center.

 

Stage Four: Child Neurologist

If the second tier laboratory finds enzyme activity, the infant is at low risk for Krabbe disease and resumes routine care.

If the second tier laboratory finds borderline enzyme activity, the infant is at moderate risk for Krabbe disease and is closely monitored by the Child Neurologist.

If the second tier laboratory finds no enzyme activity, the infant is at high risk for Krabbe disease. The Child Neurologist and Inherited Metabolic Disease Specialist coordinate an immediate inpatient neurodiagnostic evaluation to determine whether signs of infantile Krabbe disease are present. This evaluation includes a detailed neurologic exam, lumbar puncture, MRI, nerve conduction studies, visual evoked response and brain stem auditory evoked response. If the neurodiagnostic evaluation is not consistent with infantile Krabbe disease, the infant is closely monitored by the Child Neurologist. If the neurodiagnostic evaluation is consistent with infantile Krabbe disease, the infant is referred for consideration of an umbilical cord blood transplant.

The transplant center with the most experience with neonatal Krabbe disease is Duke University Medical Center in Durham, North Carolina. The transplant physicians at Duke will accept patients with Krabbe from New York who may be in need of an umbilical cord blood transplant. There are also several centers in New York with experience transplanting young infants, although none have transplanted a newborn with Krabbe disease. These centers may be options if a family in need of a transplant chooses not to go to Duke.