Krabbe disease (
globoid cell leukodystrophy, GLD) is an inherited disease caused by a deficiency in the lysosomal
enzyme galactocerebrosidase (GALC). The major galactosylated
lipid degraded by GALC is
galactosylceramide. However, GALC is also responsible for the degradation of
galactosylsphingosine (
psychosine), a highly cytotoxic
glycolipid. It has been hypothesized that
GALC-deficiency leads to
psychosine accumulation that preferentially kills oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system.
Krabbe disease has traditionally been considered a
white matter disease characterized by the loss and disorganization of myelin, infiltration of multinucleated monocytes/macrophages (globoid cells) and lymphocytes, and dysregulation of pro-inflammatory
cytokines and
chemokines. However, new studies have revealed unexpected neuronal deficiencies. Infantile
Krabbe disease is believed to be the most common and aggressive form. However, juvenile and adult onset forms have been described. Children affected with infantile
Krabbe disease present with motor
dysfunction, cognitive decline, intractable
seizures, and premature death between two to five years of age. Murine, canine, and primate models of
GALC deficiency have been described and have played an important role in our understanding of this invariably fatal disease. Although there is no cure for
Krabbe disease,
hematopoietic stem cell transplantation can slow the progression of disease. Recent pre-clinical data indicate that simulataneously targeting multiple pathogenic mechanisms greatly increases efficacy in the murine model of
Krabbe disease. A better understanding of the underlying pathogenesis will identify new therapeutic targets that may further increase efficacy.