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 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.

Enlargement of peripheral nerves in Krabbe disease: The diagnostic value of nerve ultrasound

“…Histological studies in Krabbe disease have demonstrated enlarged peripheral nerves with signs of de‐ and dysmyelination and fibrotic changes . Perineural edema has been demonstrated in a mouse model and infiltration of multinucleated macrophages (“globoid cells”) is a known characteristic of Krabbe disease …”

Canine Models of Inherited Musculoskeletal and Neurodegenerative Diseases

“…Histopathology of the brain shows diffuse, massive accumulations of previously described globoid cells, as well as extensive gliosis and perivascular lymphocytic cuffing confined to the white matter with sparing of gray matter (153). Demyelination of all areas of the brain, auditory system, and peripheral nerves is present in canine patients (149). Psychosine is elevated in tissues and CSF of GLD dogs (154) increasing significantly over time and may be a potential biomarker of disease (149).…”

“…In addition to humans, globoid cell leukodystrophy (GLD) has been documented in several other species, including dogs, mice, monkeys, and sheep. In dogs, GLD has been reported in Cairn terriers, West Highland Terriers, Australian Kelpies, Beagles, Poodles, and mixed breeds (144)(145)(146)(147)(148)(149)(150). As with NCL, GLD is thought to be the same disease occurring in different species, maximizing the usefulness of canine models in developing therapies for humans with GLD.…”

“…Spinal reflexes may be normal early in disease and affected as the disease progresses. Onset of clinical signs occur by 4-6 weeks of age with a survival time of 15.7 ± 4.8 weeks (149). Analysis of leukocyte β-galactocerebrosidase levels leads to a definitive diagnosis (147,152).…”

“…Demyelination of all areas of the brain, auditory system, and peripheral nerves is present in canine patients (149). Psychosine is elevated in tissues and CSF of GLD dogs (154) increasing significantly over time and may be a potential biomarker of disease (149). Although MRI and electrodiagnostics cannot accurately achieve a definitive diagnosis, they aid to increase the index of suspicion of GLD in canine patients and warrant blood sample testing for the defective gene.…”