DTI as a Tool to Identify Infants with Krabbe Disease in Need of Urgent Treatment

Maria L. Escolar, M.D., M.S.

University of North Carolina School of Medicine

Funded in December, 2007: $200000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Imaging May Identify a Marker to Diagnose Rapidly Progressive Deadly Krabbe Disease in Newborns

This study will assess the feasibility of using conventional diffusion tensor imaging (DTI) of the brain’s white matter in newborns to make treatment decisions concerning those who are at risk for developing the severe and rapidly progressive form of potentially deadly Krabbe disease. 

Krabbe disease is rare, genetically determined, and produced by a deficiency in an enzyme that is essential for development of myelin, the fatty sheath that surrounds nerve cell axons and facilitates neuronal communication. In its most severe form,  Krabbe disease begins to produce cognitive and motor symptoms at three to six months of age, including dementia, blindness, deafness, seizures, and spasticity. Infants usually die by age two. Some infants who carry the gene develop a much less severe form that does not develop until adolescence or adulthood. While some benefit has been derived from treating infants with adult bone marrow transplants, recent studies in a small number of infants indicate greater benefit from treatment that uses umbilical cord blood from unrelated adults, which is rich in stem cells.  To be effective, however, this treatment must be provided before symptoms emerge.

The effort to make decisions on whether to provide umbilical cord treatment to at-risk newborns depends on the ability to determine if they have the severe rapidly progressive form of Krabbe disease. A potential approach to accurately making this diagnosis may rest with DTI.  The investigators hypothesize that DTI of at-risk newborns’ white matter may be able to differentiate newborns with the severe form from those with the milder form, enabling clinicians to decide whether umbilical cord treatment should be provided.  The investigators’ preliminary data using DTI in newborns suggests this may be feasible, and this larger study should determine whether this is indeed the case.

Significance:  If DTI is found to be a feasible way to identify newborns with the genetically determined deadly form of Krabbe disease, the study would lead to further studies to demonstrate its utility in making critical treatment decisions that would significantly benefit affected infants.

ABSTRACT

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DTI as a Tool to Identify Infants with Krabbe Disease in Need of Urgent Treatment

We propose to examine the potential for Diffusion Tensor Imaging (DTI) to be used prognostically to identify at-risk asymptomatic newborns with infantile Krabbe Disease, an inherited neurodegenerative disease due to galactocerebrosidase enzyme deficiency that is fatal if untreated within 2 years.  We will also evaluate if this tool can be used as a marker of disease progression associated with motor disability after treatment with Unrelated Umbilical Cord Blood transplantation. If successful, this approach will be a key component of the New York State population screening program.

Specific Aims:
1. To determine if DTI can identify which newborns with low enzyme will develop infantile Krabbe disease;
2. To compare the longitudinal progression of corticospinal white matter tract myelination in babies treated for infantile-Krabbe disease, infants with low enzyme who do not develop disease, and healthy controls; and
3. To determine, among transplanted children, whether long-term motor function can be predicted by baseline FA measurements.  The measure has the potential to be validated as a surrogate marker of diseases progression when evaluating the efficacy of new treatments.

INVESTIGATOR BIOGRAPHIES

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Maria L. Escolar, M.D., M.S.

Dr. Escolar is an Associate Professor of Pediatrics at the Center for Development and Learning at the University of North Carolina at Chapel Hill, where she established the Program for Neurodevelopmental Function in Rare Disorders in the year 2000. Dr. Escolar graduated from the Escuela Colombiana de Medicina in Bogota, Colombia. She has a Master of Science from Columbia University and completed her internship and residency in Pediatrics, and a fellowship in Child Development and Behavioral Pediatrics at The New York Hospital-Cornell University Medical Center. Dr. Escolar’s research focuses on characterizing neurobehavioral phenotypes in children with genetic disorders that affect the brain and finding treatment strategies to improve outcomes.