Krabbe Disease via the GALC Exons 11-17 (502T/Del)

Krabbe disease or globoid cell leukodystrophy (OMIM 245200) results from deficiency of galactocerebrosidase, a lysosomal enzyme involved in the metabolism of galactosylceramide. Galactosylceramide is a component of the myelin sheath, and with deficient galactocerebrosidase activity, this complex lipid is known to accumulate in globoid cells. Accompanying the appearance of globoid cells is loss of myelin and associated progressive neurological deterioration leading to death (Wenger et al. in Scriver et al. Metabolic and molecular bases of inherited disease, 3669-3694, 2001). Most cases present in early infancy with nonspecific signs such as irritability and delays in reaching developmental milestones. The clinical course is rapid, spanning 1 to 3 years and includes hypersensitivity to external stimuli, hypertonicity, motor and mental deterioration, blindness, and deafness. Less commonly the disease presents later in life with neurological signs including weakness, vision loss, and mental changes (Satoh et al. Neurol 49:1392-1399, 1997; Kolodny et al. Dev Neurosci 13:232-239, 1991). Disease progression in later-onset cases is typically protracted although an initial rapid deterioration is common (Loonen et al. Neuropediatrics 16:137-142, 1985).

Krabbe disease is inherited in an autosomal recessive manner. Intrafamilial variability of the clinical symptoms occurs. Over 50 GALC variants, mostly missense, have been reported. The most common variant in patients of European descent, however, is a large deletion encompassing exons 11 through 17 of GALC (Luzi et al. Hum Mol Genet 4:2335-2338, 1995; Rafi et al. Hum Mol Genet 4:1285-1289, 1995). This deletion (referred to as 502T/del) accounts for approximately 50% of all disease alleles in northern European patients (Kleijer et al. J Inherit Metab Dis 20:587-594, 1997), and is similarly common in patients from the USA, including those with Mexican ancestry (Wenger, Krabbe Disease, GeneReviews, 2007). Late-onset cases frequently have at least one copy of the c.809G>A (p.Gly270Asp) variant (Kolodny et al. Am J Hum Genet 57:A217, 1995).Galactocerebrosidase is coded by exons 1-17 of the GALC gene on chromosome 14q31.

Diminished galactocerebrosidase activity due to GALC variants is the only cause of Krabbe disease and late-onset globoid cell leukodystrophy. Analytical sensitivity for deletion testing and sequence analysis should be high in cases with demonstrated enzyme deficiency. The exon 11-17 deletion accounts for approximately half of all disease alleles.

Testing involves determination of the 502T/del status as described by Luzi et al. (Hum Mol Genet 4:2335-2338, 1995). A separate test is available to evaluate the entire GALC coding region by direct sequence analysis (see Test #7883 NGS GALC).