July 19, 2006

Dear Health Care Provider,

The New York Newborn Screening Program will begin testing for Krabbe Disease on August 7, 2006.  This will have no effect on the collection and transport of the initial specimen to the Wadsworth Center. Likewise, there will be no changes in the other aspects of the program’s screening for 44 conditions.  However, this test will introduce several new actions into the program following identification of a screen-positive result.  Information on Krabbe Disease can be found in the enclosed fact sheet.

It is important that each Health Care Provider understand the new role he or she may be asked to play following identification of a screen-positive result for Krabbe Disease.  Because of the need for a rapid diagnosis and initiation of therapy for confirmed cases, special actions, tests, and consultations will be implemented as part of the diagnostic work-up for this condition.  An outline of this process is enclosed.  These procedures will apply only to Krabbe Disease; no changes will be made in the follow-up as currently practiced for all of the other conditions in the screening panel.

In brief, the enclosed protocol provides for analysis of a blood specimen at a designated laboratory in New York City and, if indicated, specialized diagnostic procedures at a hospital with the capability to perform the tests.  Follow-up staff from the screening program and Dr. Laura Helton, the new Medical Director for the Newborn Screening Program at Wadsworth Center, will direct these procedures and advise each of you of actions needed on your part.

Questions about this new screening protocol can be directed to our main telephone number:  (518) 473-7552.

Thank you for your continued support of the NYS Newborn Screening Program.

Sincerely,
Michele Caggana, Sc.D., FACMG
Director, Newborn Screening Program

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KRABBE DISEASE

(GLOBOID CELL LEUKODYSTROPHY; GLD; GCL; GLOBOID CELL LEUKOENCEPHALOPATHY; GALACTOSYLCERAMIDE BETA-GALACTOSIDASE DEFICIENCY; GALACTOCEREBROSIDASE DEFICIENCY; GALC DEFICIENCY)

Classification: Leukodystrophy

• Inheritance: Autosomal recessive
• Population Incidence: 1:100,000 people
• Ethnic Incidence: While pockets of Krabbe disease have been identified in insular populations, it is found in all races and ethnicities.
• Gene & Location: GALC gene at 14q24.3-34.1
• Common Mutation: A deletion of 30kb has been identified in roughly 50% of alleles, others are found repeated at lower frequencies. Many of the nearly 75 mutations identified are private. None have occurred in the regulatory region. Several polymorphisms in the gene are known to attenuate enzyme activity.
• OMIM # #245200 (descriptive entry of the phenotype, not a unique locus)  * 606890 (gene sequence is known)

• Symptom Onset: Most patients present in the first six months of life, though it has been diagnosed in older children and adults.
• Symptoms: Krabbe disease involves the white matter of the central and peripheral nervous systems. Early symptoms include feeding difficulties, gastroesophageal reflux, irritability, and clasped thumbs. Later 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.
• Physical Findings: There are usually no obvious congenital anomalies present at birth.
• Treatment: Supportive enzyme replacement or dietary treatment has not been effective. Hematopoetic stem cell from cord blood or bone marrow transplantation, preceded by myeloablative chemotherapy, prior to the onset of symptoms, has been successful.
• Natural History Without Treatment: In the infantile form, death usually occurs in the first two years of life. Later onset forms show slower development, regression and death. The genotype to phenotype correlation is not clear.
• Natural History With Treatment: Preliminary findings from transplantation have been positive, showing stabilization of symptoms, improved myelination, and improved cognition. Gross motor skills may still be affected.

Metabolic Information: Krabbe disease is caused by the complete deficiency of galactocerebrosidase, the lysosomal enzyme that breaks down galactosylceramide (a galactolipid and major component of myelin) and degrades psychosine and galactocerebroside (highly concentrated in myelin sheaths). Psychosine is a highly cytotoxic metabolite that results in destruction of oligodendroglia and Schwann cells.

Missing Enzyme & Location: Galactocerebrosidase metabolizes galactocerebroside to cerebroside and galactose. It is present in all organs except kidneys.

MS/MS Profile: Not applicable

Prenatal Testing: Possible using chorionic villi and/or amniocytes from amniotic fluid.

1. Wenger DA, Suzuki K, Suzuki Y, Suzuki K. Galactosylceramide lipidosis: globoid-cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. Vol. 3. New York: McGraw-Hill, 3669-94, 2001.
2. Escolar ML, Poe MD, Provenzale JM, Richards KC, Allison J, Wood S, Wenger DA, Pietryga D, Wall D, Champagne M, Morse R, Krivit W, Kurtzberg J. Outcomes of babies with infantile Krabbe Disease after umbilical cord blood transplantation. New England Journal of Medicine. 352(20):20-32, 2005.

Krabbe Disease Screening and Follow-up

Newborn Screening for Krabbe Disease

Krabbe disease is caused by the complete deficiency of the enzyme galactocerebrosidase.  It is considered a lysosomal storage disorder and a leukodystrophy involving both 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. Enzyme replacement and dietary treatment have not been effective.  Hematopoetic stem cell transplantation from umbilical cord blood (preceded by myeloablative chemotherapy) prior to the onset of symptoms has been shown to stabilize the disease, although gross motor skills may still be affected.  Unfortunately, infants who receive umbilical cord blood transplantation after the onset of symptoms continue to show declining physical and cognitive functions. 

Newborn screening for Krabbe disease provides the earliest window for population-based diagnosis and treatment. The screening will be accomplished at the New York Sate Department of Health, in the Wadsworth Center, using specimens already collected for other newborn screening tests.  There will be no change in the way the specimens are currently collected and shipped.  Wadsworth Center expects to refer up to 70 infants each year for further Krabbe testing - 0.03% screen-positives from the annually screened population of approximately 252,000 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 activity.  An infant with confirmed activity less than 8% of the daily mean is screen-positive.  Her/his physician is notified immediately and DNA analysis is initiated concurrently.  An infant with confirmed activity between 8% and 10% of the daily mean is indeterminate and DNA analysis is initiated.  An infant with confirmed activity greater than 10% of the daily mean is screen-negative and her/his physician is notified by report.

DNA Analysis
DNA analysis is initiated for any sample with enzyme activity less than 10% of the daily mean.  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 screen-positive and her/his physician is notified immediately.  If no mutations are found, sequence analysis is performed.  If sequence analysis demonstrates any mutation, the infant is screen-positive and her/his physician is notified immediately.  If no mutations are observed after sequence analysis and the activity is greater than 8% of the daily mean, the infant is screen-negative and her/his physician is notified by report. 

Stage Two: Primary Physician, Inherited Metabolic Disease Physician, Child Neurologist

Notification
The Newborn Screening Program staff reports screen-positive results to the pediatrician of record, the Inherited Metabolic Disease designee at the birth hospital, and the Inherited Metabolic Disease Treatment Center/Child Neurologist in the infant’s Health Service Area.  These individuals communicate and one of the physicians notifies the family of the positive screen for Krabbe disease.  The infant is then referred to the Inherited Metabolic Disease Treatment Center in her/his Health Service Area as soon as possible.

Evaluation
The infant is seen by the Inherited Metabolic Disease Specialist and/or the Child Neurologist.  The family is counseled and the infant is examined for early signs of Krabbe disease.  Blood is collected using a kit provided by Wadsworth Center.  Five to ten 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 Red Cross for HLA testing 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 the follow-up unit in Wadsworth Center. 

Stage Four: Child Neurologist

If the second tier laboratory finds enzyme activity, the infant does not have Krabbe disease.  If the second tier laboratory finds no enzyme activity, the infant is referred immediately to the Child Neurologist for a neurodiagnostic evaluation.  This evaluation includes a 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 will be closely monitored.   If the neurodiagnostic evaluation is consistent with infantile Krabbe disease, the infant is referred for consideration of an umbilical cord blood transplant. 

Currently, 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 are ready to accept patients with Krabbe from New York who may be in need of an umbilical cord blood transplant.  There are several centers in New York who have experience transplanting young infants, although none have transplanted a newborn with Krabbe disease.  These centers may be an option if a family in need of a transplant chooses not to go to Duke.