Krabbe disease and therapeutic approaches

Krabbe disease is a rare inherited neurodegenerative disease which affects both the central and peripheral nervous system. The disease is caused by a deficiency of the lysosomal enzyme galactocerebrosidase which leads to the inability to degrade galactosylceramidase and galactosylsphingosine. The incidence of the disease in the United States is reportedly 1/100,000 with 90% of affected patients having the early infantile phenotype. (These figures, however, have been brought into question with the advent of population based newborn screening.) In addition to the invariably fatal early infantile phenotype, there are the late infantile, later onset, adolescent and adult phenotypes, which have different clinical manifestations and disease courses. Moreover, there is wide phenotypic variability within families, especially in the later onset, adolescent and adult phenotypes. The sole available treatment for the disease is hematopoietic stem cell transplantation which has both significant morbidity and 10% mortality and is only effective if performed prior to the onset of symptoms. Transplanted presymptomatic children with the early infantile phenotype have significantly longer survivals than untreated children but the majority develops motor and language abnormalities. Newborn screening for the disease began in New York State in August 2006 in part to identify those presymptomatic infants who might benefit from transplant. The major issue with the screening process has been that since neither the level of GALC activity nor the genotype (with limited exceptions) reliably predict phenotype, it has been difficult to identify with certainty which children will develop the early infantile phenotype and should be considered for emergent transplantation as opposed to those with later onset, adolescent and adult variants who may not become symptomatic for many years.