Associations between neurologic dysfunction and lesions in canine fucosidosis

Abstract

Canine fucosidosis in English Springer spaniels is the only animal model of the neurovisceral lysosomal storage disease fucosidosis available for preclinical therapeutic trials. For this reason, it is crucial to identify critical time points in disease progression, and if there are particular lesions associated with specific aspects of neurologic dysfunction. Historical records of 53 canine fucosidosis cases from 1979 to 2009 containing a neurologic dysfunction score assessing motor, behavioral and sensory dysfunction were interrogated by statistical analysis. Motor and behavioral dysfunction scores assessing gait deficits and apprehensive behavior first significantly increased at 12-17 months, and increased at each 6-month interval thereafter. Sensory dysfunction scores, assessing hearing loss, balance and vision deterioration, did not significantly increase until 18-23 months, and coincided with a rapid decline in neurologic function. Regression analysis incorporating published neuropathology data, measured by image analysis, identified neuroinflammation and apoptotic cell death as significant informative predictors of increasing neurologic dysfunction. These findings indicate that the level of neuropathology required to induce consistent and conspicuous clinical signs in canine fucosidosis is reached by approximately 12 months of age in the absence of other disease processes. Significant association between neuroinflammation and apoptotic cell death also suggests that specifically targeting these lesions combined with enzyme replacement in future studies may reduce disease burden in fucosidosis. Overall, examining this historical clinical data to identify associations between the extent of neuropathology and degree of clinical dysfunction provides a useful reference tool for monitoring disease and evaluating therapeutic trials conducted in canine fucosidosis.

Sensorimotor and Neurocognitive Dysfunctions Parallel Early Telencephalic Neuropathology in Fucosidosis Mice

“…Progressive neurological dysfunction in Fuca1-deficient mice parallels disease progression in the dog model. Recently, Fletcher and Taylor ( 2016 ) performed a meta-analysis on historical canine fucosidosis records (Kondagari et al, 2011b , c ). First signs of motor and behavioral dysfunction are reported after 6 months, with subtle gait and proprioceptive deficits as well as apprehensive behaviors becoming consistently increased after 12 months.…”

“…Affected dogs suffer from progressive neurovisceral defects, mimicking human pathology and symptomatology. The dog model has been valuable in several preclinical studies, gaining new insights on pathological processes (e.g., Fletcher et al, 2011 , 2014 ; Kondagari et al, 2011b , c ; Fletcher and Taylor, 2016 ) and potential treatment (e.g., Taylor et al, 1986 , 1992 ; Ferrara et al, 1992 , 1997 ; Kondagari et al, 2011a , 2015 ). However, there is currently no effective treatment available for the human disease.…”

A mouse model for fucosidosis recapitulates storage pathology and neurological features of the milder form of the human disease

“…Because only very few data are available from human fucosidosis individuals, the dog model has already been very valuable. Analysis of the dog model has furthered understanding of the biochemistry, pathology and neurological alterations underlying fucosidosis ( Abraham et al, 1984 ; Fletcher et al, 2014 ; Fletcher and Taylor, 2016 ; Kondagari et al, 2011b ), as well as the development of therapeutic approaches such as bone marrow transplantation and intracisternal ERT, overcoming the blood-brain barrier ( Kondagari et al, 2011a ; Taylor et al, 1992 ). Nevertheless, our mouse model, which also reflects many aspects of human fucosidosis, has several advantages over the dog model, such as easier breeding, a defined genetic background, a shorter life span and much lower body weight, which in total are cost-reducing factors, in particular for the establishment of ERT.…”

“…Very few individuals have been successfully treated with bone marrow transplantation (BMT) but there has been at least some neurological improvement in some cases ( Krivit et al, 1999 ); however, graft-versus-host complications also occurred ( Miano et al, 2001 ). A dog model in English Springer spaniels was characterized a long time ago, which closely resembles the human disease ( Abraham et al, 1984 ; Fletcher et al, 2014 ; Fletcher and Taylor, 2016 ; Hartley et al, 1982 ; Kondagari et al, 2011b ), and thus was used to establish BMT ( Taylor et al, 1992 , 1986 ) as well as enzyme replacement therapy (ERT) ( Kondagari et al, 2015 , 2011a ). Moreover, a domestic shorthair cat model lacking fucosidase activity has been reported, and shows cerebellar dysfunction and storage pathology ( Arrol et al, 2011 ).…”