Maria Escolar

Krabbe disease, also known as globoid-cell leukodystrophy, is a rare autosomal recessive disorder caused by deficiency of the lysosomal enzyme galactocerebrosidase (GALC), which is essential for normal catabolism of the principal lipid component of myelin. This is a very rare disorder, with an incidence of 1 in 100,000 live births. Most patients with Krabbe disease suffer from rapidly progressive demyelination before six months of age (infantile form). Death usually occurs before the age of 2 years. The phenotypic expressions of the mutations vary, and rare cases of the disease present as late-infantile, juvenile, and adult form.  A test for GALC enzyme activity has been developed to screen newborns for Krabbe; the screening involves a serologic test for the missing GALC enzyme followed by mutational analysis to confirm diagnosis. However, neither genotype nor GALC activity can reliably distinguish the infantile form from the juvenile and adult forms, which do not need immediate treatment. Furthermore, some individuals

who show low levels of GALC activity never develop clinical symptoms. Umbilical cord blood stem cell transplantation is the only available treatment for Krabbe disease and is only effective before symptoms develop. The transplantation treatment is most effective in the presymptomatic stages of the disease.  Therefore, it is extremely crucial to have a predictive measure that can identify changes in the brain before symptoms develop, to determine the optimal time of treatment.  DTI can be a potential imaging biomarker to detect early changes in the white matter of the brains of patients with Krabbe disease before clinical symptoms develop, and to predict outcomes after treatment. In our paper in AJNR, we show that DTI with quantitative tractography has been shown to detect early neurologic changes in the corticospinal fiber tracts of presymptomatic newborns with Krabbe disease. This technique may therefore be useful in determining which patients have the early infantile form of the disease and need immediate treatment. In addition, we show that pretreatment FA values may predict gross motor function after transplantation in these patients.

Our laboratory has a multidisciplinary approach in which we correlate advanced neuroimaging findings with longitudinal neurodevelopmental outcomes  (cognitive, receptive and expressive language, fine motor, gross motor, and adaptive behavior) and other types of serum genetic and molecular markers in rare developmental disorders. We are currently expanding the findings in our AJNR paper to include a larger population of patients with Krabbe disease. We are correlating neonatal DTI metrics with long-term neurodevelopmental outcomes and serial imaging in 2 groups of patients: those untreated and enrolled in a natural history of disease progression and those who receive umbilical cord blood transplantation. We are also moving toward multimodal imaging by including functional connectivity studies in our research imaging protocols and expanding this approach to other newborns at risk for neuromotor abnormalities. This work is being done in collaboration with Dr. Weili Lin and Martin Styner at the University of North Carolina at Chapel Hill, and with Dr. Panigrahy’s group and the Neuro-NICU team at Childrens Hospital of Pittsburgh of UPMC.

Read this article at AJNR.org . . .