Clinical Information

Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive disorder caused by a deficiency of galactocerebrosidase leading to an accumulation of galactosylceramide and severe demyelination throughout the brain. Krabbe disease is primarily caused by variants in the GALC gene, and it has an estimated frequency of 1 in 100,000 births.

The clinical course of Krabbe disease can be variable, even within the same family. Eighty-five percent to 90% of patients present before the first year of life with central nervous system impairment including increasing irritability, developmental delay, and sensitivity to stimuli. Rapid neurodegeneration including white matter disease is followed by death usually by age 2. Late onset forms of the disease affect 10% to15% of individuals and are characterized by ataxia, vision loss, weakness, and psychomotor regression typically presenting from age 6 months to the seventh decade of life.

Newborn screening for Krabbe disease recently has been implemented in some states. The early (presymptomatic) identification and subsequent testing of infants at risk for Krabbe disease may be helpful in reducing the morbidity and mortality associated with this disease. While treatment is mostly supportive, hematopoietic stem cell transplantation has shown some success if performed prior to onset of neurologic damage.

Newborn screening can typically identify patients with Krabbe disease, even before onset of symptoms, as well as unaffected patients with GALC pseudodeficiency alleles. For these reasons, second-tier testing that includes both psychosine and 30-kilobase (kb) deletion analyses has been developed. Second-tier testing reduces the number of false-positive results and limits the identification of affected individuals to patients needing immediate follow-up.

Psychosine (PSY), a neurotoxin at elevated concentrations, is 1 of 4 substrates degraded by galactocerebrosidase. It has been shown to be elevated in patients with active disease and, therefore, may be a useful biomarker for the presence of disease or disease progression.

The common 30-kb deletion spanning intron 10 through the end of the gene accounts for a significant proportion of disease alleles that contribute to infantile Krabbe disease. While enzyme activity alone is not predictive of age of onset, there are known genotype-phenotype correlations. Individuals who are homozygous for the deletion or compound heterozygous for the deletion and a second GALC genetic variant (with the exception of late-onset genetic variants) are predicted to have infantile Krabbe disease.

Although rare, a few infants with an early onset Krabbe disease phenotype due to deficiency of saposin A (SAP-A) have been identified. SAP-A is a sphingolipid activator protein that assists galactocerebrosidase in its action on galactosylceramide.