Krabbe disease is inherited in an autosomal recessive pattern. Normally a person has two functional GALC genes. In people with Krabbe disease, both genes have a mutation and there is a deficiency of the critical enzyme activity. Each parent of a newborn with Krabbe disease typically has one functional and one mutated gene and is considered a carrier. When both parents are carriers, the chance of a newborn inheriting two mutated genes is 25%.
Carriers of Krabbe disease do not typically have symptoms.
Infantile Krabbe disease generally presents in the first six months of life. 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.
Late infantile Krabbe disease presents between 6 months and 3 years. The symptoms and progression are similar to the infantile group. Juvenile Krabbe disease presents between 3 and 8 years of age and has similar symptoms to the infantile forms, but a slower progression.
Adult onset Krabbe is extremely variable with symptoms ranging from weakness to significant decline in intellectual abilities.
- Incidence: The overall incidence is reported to be approximately 1 in 100,000. However, the incidence in New York State has been found to be approximately 1 in 300,000.
- New York State Method of Screening (First Tier): Screening for Krabbe disease is accomplished by measuring galactocerebrosidase activity using mass spectrometry. An infant with confirmed GALC activity that is less than or equal to 12% of the daily mean that has one or more mutations (see below) in the GALC gene is considered to be screen positive. For these infants, a physician is notified immediately by telephone. An infant with confirmed activity greater than 12% of the daily mean is considered to be screen-negative.
- Second Tier Screening: DNA analysis is initiated for any sample with enzyme activity less than 12% of the daily mean. The specimen is tested for three polymorphisms and five common mutations using a rapid assay, and sequence analysis is performed. If one or more mutations are found and confirmed, the infant is considered to be screen-positive as indicated above and a physician is notified immediately. If no mutations are found, but known polymorphisms are detected, a report will be issued that indicates which polymorphisms were detected. Infants with polymorphisms only are not considered to be at risk for Krabbe disease and are not referred for a follow-up diagnostic work-up.
- Testing can be affected by: Improper storage of the blood specimen including extreme heat, which may cause lower GALC enzyme activity. In addition, low white cell counts may cause enzyme activity to be below our 12% of daily mean cutoff and lead to false positive results.
- Interpretation/reporting of data: Results are reported as within acceptable limits or as a referral. Prompt consultation with a specialist is required for a referral. We also report “Polymorphisms Only”. For this report, the GALC enzyme activity is at or below 12% of the daily mean and only polymorphisms (benign changes) were detected in the DNA. These infants are considered screen negative and no follow-up testing is required, but the identification of polymorphisms is reported as part of the newborn screen result.
- Referral to Specialty Care Center: Patients with an abnormal newborn screen for Krabbe disease are referred to an Inherited Metabolic Disorder Specialty Care Center for evaluation by a biochemical geneticist trained in the diagnosis and treatment of Krabbe disease.
Diagnostic testing includes measuring the galactocerebrosidase enzyme activity of the white blood cells isolated from the blood sample taken at the follow-up visit. Enzyme testing is performed at the Jefferson Medical College, in Philadelphia, Pennsylvania. If the GALC enzyme activity measured at this laboratory are greater than or equal to 0.3 nmol/mg/hr, then the infant is not at risk for Krabbe disease. However, if there is borderline activity, the child may be at risk for Krabbe disease and she/he will require further diagnostic testing and clinical evaluation in order to determine if the child has Krabbe disease. In this case the child will be closely monitored by the Child Neurologist.
If there is very low 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 treatment.
The only treatment available is hematopoetic stem cell transplantation (HSCT) from umbilical cord blood following myeloablative chemotherapy prior to the onset of symptoms.
HSCT 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.
Krabbe disease is an inherited metabolic disorder 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.