Canine Fucosidosis: A Neuroprogressive Disorder

Abstract

The lysosomal storage disease, canine fucosidosis, is caused by the absence of the lysosomal enzyme canine α-L-fucosidase with storage of undegraded fucose-rich material in different organs. Canine fucosidosis is a severe, progressive, fatal neurological disease which results in death or euthanasia and is the only available animal model for this human disease. We analysed the progressive neuropathology from birth to severe clinical disease and related this to the clinical signs. At birth no vacuolation was observed in fucosidosis brain; however, a complex storage presence with vacuolation was well established by 4 months of age, before the clinical signs of motor dysfunction which occurred at 10–12 months of age. Purkinje cell loss, neuronal loss, gliosis, perivascular storage and demyelination accompanied disease progression. Increased vacuolation (15.3-fold increase compared to controls) coincided with advanced motor and mental deterioration in late-stage disease. Significant loss of myelin commenced early, with greatest impact in the cerebellum, and was severe in late disease (1.6- to 1.9-fold decrease) compared to controls (p < 0.05) contributing to clinical signs of motor and mental dysfunction. This detailed description and quantification of the CNS pathology in canine fucosidosis will inform monitoring of the onset, progression and response of this disease to therapy.

Oligodendrocyte Loss During the Disease Course in a Canine Model of the Lysosomal Storage Disease Fucosidosis

“…Central nervous system (CNS) myelin loss is an early pathological feature of infantile onset cases (1-4) and myelin abnormalities were identified by magnetic resonance imaging in the cerebellum and cerebrum of an 8-month-old child with fucosidosis (4). In canine fucosidosis, CNS myelin loss in the cerebellum and cerebrum is detectable from 8 weeks of age, many months prior to the first neurologic signs (5, 6). By 16 weeks, myelin deficits are more severe in the earlier myelinating tracts of the cerebellum compared to the later maturing corpus callosum of the cerebrum (5); however, clinical signs of anxiety and learning delay are inconsistent.…”

“…In canine fucosidosis, CNS myelin loss in the cerebellum and cerebrum is detectable from 8 weeks of age, many months prior to the first neurologic signs (5, 6). By 16 weeks, myelin deficits are more severe in the earlier myelinating tracts of the cerebellum compared to the later maturing corpus callosum of the cerebrum (5); however, clinical signs of anxiety and learning delay are inconsistent. Fine proprioceptive deficits and poorly modulated postural adjustments possibly caused by neuron loss and conduction deficits from hypomyelination in large, fast conducting sensory and motor tracts do not manifest in fucosidosis-affected dogs until considerably later, at 8 to 12 months of age (5, 6).…”

“…By 16 weeks, myelin deficits are more severe in the earlier myelinating tracts of the cerebellum compared to the later maturing corpus callosum of the cerebrum (5); however, clinical signs of anxiety and learning delay are inconsistent. Fine proprioceptive deficits and poorly modulated postural adjustments possibly caused by neuron loss and conduction deficits from hypomyelination in large, fast conducting sensory and motor tracts do not manifest in fucosidosis-affected dogs until considerably later, at 8 to 12 months of age (5, 6). At this time, white matter tracts show dispersion of myelinated axons and infiltration of vacuolated macrophages in addition to 21% loss of myelin relative to age-matched controls (5).…”

“…Fine proprioceptive deficits and poorly modulated postural adjustments possibly caused by neuron loss and conduction deficits from hypomyelination in large, fast conducting sensory and motor tracts do not manifest in fucosidosis-affected dogs until considerably later, at 8 to 12 months of age (5, 6). At this time, white matter tracts show dispersion of myelinated axons and infiltration of vacuolated macrophages in addition to 21% loss of myelin relative to age-matched controls (5). Myelin deficits in canine fucosidosis progress in advanced disease (≥24 months of age), as widespread vacuolation displaces myelinated tracts and infiltration of macrophages and glial reactivity increase (5).…”

“…At this time, white matter tracts show dispersion of myelinated axons and infiltration of vacuolated macrophages in addition to 21% loss of myelin relative to age-matched controls (5). Myelin deficits in canine fucosidosis progress in advanced disease (≥24 months of age), as widespread vacuolation displaces myelinated tracts and infiltration of macrophages and glial reactivity increase (5). …”