Krabbe Disease (Globoid Cell Leukodystrophy)

Krabbe disease (globoid cell leukodystrophy, GLD) can be caused by genetic defects either in a lysosomal enzyme, galactosylceramidase (galc), or in its natural activator/ protective protein, saposin A. The latter was first established in a mouse model, but the first human GLD patient due to saposin A deficiency has very recently been discovered. The primary natural substrate of the enzyme, galactosylceramide, is nearly exclusively localized in the myelin sheath. Consequently, the disease is one of the two classical genetic leukodystrophies, the other being metachromatic leukodystrophy due to arylsulfatase A (sulfatide sulfatase) deficiency. Mode of inheritance is autosomal recessive. Typically, the disease occurs among infants and takes a rapidly fatal course, but rarer late-onset forms also exist. Clinical manifestations are exclusively neurological with prominent and progressive white matter signs. A normally insignificant but highly cytotoxic metabolite, galactosylsphingosine (psychosine), is also a substrate of galactosylceramidase. It appears to play a critical role in the pathogenesis of GLD. A set of neuropathology is unique and pathognomonic; a rapid and nearly complete disappearance of myelin and myelin-forming cells, the oligodendrocytes in the CNS and the Schwann cells in the PNS, reactive astrocytic gliosis, and infiltration of often multinucleated macrophages (“globoid cells”) that contain strongly PAS-positive materials. A large number of disease-causing mutations have been identified. The only human patient known so far with saposin A deficiency had an in-frame threebase deletion in the saposin A domain of the prosaposin gene. Either assays for galactosylceramidase activity or nucleic acid-based methodologies can be used for definitive clinical and prenatal diagnosis when the genetic defect is in the galc gene. The standard galactosylceramidase assay in the presence of detergents cannot diagnose the saposin A deficiency state.