title: Clinical, electrophysiological, and biochemical markers of peripheral and central nervous system disease in canine globoid cell leukodystrophy (Krabbe's disease).
abstract: Globoid cell leukodystrophy (GLD), or Krabbe's disease, is a debilitating and always fatal pediatric neurodegenerative disease caused by a mutation in the gene encoding the hydrolytic enzyme galactosylceramidase (GALC). In the absence of GALC, progressive loss of myelin and accumulation of a neurotoxic substrate lead to incapacitating loss of motor and cognitive function and death, typically by 2 years of age. Currently, there is no cure. Recent convincing evidence of the therapeutic potential of combining gene and cell therapies in the murine model of GLD has accelerated the requirement for validated markers of disease to evaluate therapeutic efficacy. Here we demonstrate clinically relevant and quantifiable measures of central (CNS) and peripheral (PNS) nervous system disease progression in the naturally occurring canine model of GLD. As measured by brainstem auditory-evoked response testing, GLD dogs demonstrated a significant increase in I-V interpeak latency and hearing threshold at all time points. Motor nerve conduction velocities (NCVs) in GLD dogs were significantly lower than normal by 12-16 weeks of age, and sensory NCV was significantly lower than normal by 8-12 weeks of age, serving as a sensitive indicator of peripheral nerve dysfunction. Post-mortem histological evaluations confirmed neuroimaging and electrodiagnostic assessments and detailed loss of myelin and accumulation of storage product in the CNS and the PNS. Additionally, cerebrospinal fluid psychosine concentrations were significantly elevated in GLD dogs, demonstrating potential as a biochemical marker of disease. These data demonstrate that CNS and PNS disease progression can be quantified over time in the canine model of GLD with tools identical to those used to assess human patients. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. brada@vet.upenn.edu.
authors.forename: Allison M
authors.initials: AM
authors.lastname: Bradbury
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Bagel
authors.affiliation: Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Xuntian
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Swain
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Prociuk
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Caitlin A
authors.initials: CA
authors.lastname: Fitzgerald
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: O'Donnell
authors.affiliation: Veterinary Neurological Consulting Services, Dadeville, Alabama.
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Braund
authors.affiliation: Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Vite
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004558:Electric Stimulation; D016057:Evoked Potentials, Auditory, Brain Stem / Q000235:genetics*; D005260:Female; D005698:Galactosylceramidase / Q000235:genetics; D006801:Humans; D007965:Leukodystrophy, Globoid Cell / Q000150:complications* / Q000000981:diagnostic imaging / Q000235:genetics* / Q000662:veterinary; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D009420:Nervous System / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D009422:Nervous System Diseases / Q000000981:diagnostic imaging / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D009431:Neural Conduction / Q000235:genetics; D011609:Psychosine / Q000134:cerebrospinal fluid
chemical_list: D011609:Psychosine; D005698:Galactosylceramidase
keywords: CSF psychosine; Krabbe's disease; biomarker; electrophysiological testing; large animal model; neuroimaging