Clinical, electrophysiological, and biochemical markers of peripheral and central nervous system disease in canine globoid cell leukodystrophy (Krabbe disease)

Abstract

Globoid cell leukodystrophy (GLD), or Krabbe 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 two years of age. To date 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 need for validated markers of disease in order to evaluate therapeutic efficacy. Herein we demonstrate clinically relevant and quantifiable measures of central and peripheral nervous system (CNS, PNS) disease progression in the naturally-occurring canine model of GLD. As measured by brainstem auditory evoked response (BAER) testing, GLD dogs demonstrated a significant increase in I–V interpeak latency and hearing threshold at all time points. Motor nerve conduction velocities (NCV) were significantly lower than normal by 12–16 weeks of age and sensory NCV 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 PNS. Additionally, cerebrospinal fluid (CSF) 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 using identical tools as used to assess human patients.

Graphical Abstract

Post mortem histological evaluations confirmed neuroimaging and electrodiagnostic assessments and detailed loss of myelin and accumulation of storage product in the CNS and PNS.