Magnetic resonance imaging (MRI), pathologic examinations, and biochemical analyses were performed on 2 different canine mutants with GM1 gangliosidosis (i.e., English Springer Spaniel and Portuguese Water Dog) and on age- and sex-matched controls. Serial MRI studies were also performed on a child with infantile-onset GM1 gangliosidosis. The affected dogs had abnormalities on MRI, including a relative increase in gray matter and an abnormal signal intensity of cerebral and cerebellar white matter observed on T2-weighted MRI. White matter changes on MRI were similar to white matter abnormalities observed in a 15-month-old boy with GM1 gangliosidosis. The weight ratio of white to gray matter from the frontal lobe was markedly reduced. Microscopic examination revealed characteristic ballooned neurons which stained lightly with Luxol-fast blue. The central cerebral and cerebellar folia white matter exhibited pallor and gliosis, while the corpus callosum and fornix stained normally with Luxol-fast blue. Axons appeared intact on Bodian staining. Ultrastructural studies revealed fewer myelinated axons in affected puppies. Total gangliosides in gray matter were elevated. Thin-layer chromatography demonstrated GM1 ganglioside as the predominant ganglioside. The amount of cerebrosides and sulfatides was reduced in the gray and white matter when compared to controls but the ratio in gray and white matter remained unchanged. Immunostaining of neutral glycolipids disclosed increased amounts of stage-specific embryonic antigen-1 glycolipid in gray matter. These findings suggest that canine models for GM1 gangliosidosis are associated with abnormal myelin development which may be similar to the human disease.
"There have been several reports concerning MR images of human GM1 gangliosidosis      , but only 2 reports examining MR findings in canine disease have been published  . The canine reports describe the discrete MR features in an ESS and a PWD at 9 months of age  and 3 SIDs at 3–8 months of age . However, serial MR changes from the preclinical to terminal periods should be determined in an animal model to establish MR biomarkers for both the reliable diagnosis and evaluation of the efficacy of newly developed therapeutic strategies. "
[Show abstract][Hide abstract] ABSTRACT: GM1 gangliosidosis is a fatal neurodegenerative lysosomal storage disease caused by an autosomal recessively inherited deficiency of β-galactosidase activity. Effective therapies need to be developed to treat the disease. In Shiba Inu dogs, one of the canine GM1 gangliosidosis models, neurological signs of the disease, including ataxia, start at approximately 5 months of age and progress until the terminal stage at 12 to 15 months of age. In the present study, serial MR images were taken of an affected dog from a model colony of GM1 gangliosidosis and 4 sporadic clinical cases demonstrating the same mutation in order to characterize the MRI features of this canine GM1 gangliosidosis. By 2 months of age at the latest and persisting until the terminal stage of the disease, the MR findings consistently displayed diffuse hyperintensity in the white matter of the entire cerebrum on T2-weighted images. In addition, brain atrophy manifested at 9 months of age and progressed thereafter. Although a definitive diagnosis depends on biochemical and genetic analyses, these MR characteristics could serve as a diagnostic marker in suspect animals with or without neurological signs. Furthermore, serial changes in MR images could be used as a biomarker to noninvasively monitor the efficacy of newly developed therapeutic strategies.
The Scientific World Journal 03/2012; 2012(3):250197. DOI:10.1100/2012/250197 · 1.73 Impact Factor
"We found a significant decrease in cerebrosides and sulfatides in the forebrains of the R6/1 transgenic mice (Table 4; HPTLC plates not shown). Interestingly, these are myelin-enriched lipids (Sandhoff et al., 1971,Seyfried and Yu, 1980,Kaye et al., 1992) and this decrease may be suggestive of abnormalities in myelin content in the R6/1 transgenic mouse model of HD. Our detection method did not show differences in cholesterol content between the R6/1 transgenic mice and wild type controls, as previously suggested in other models of HD (Sipione et al., 2002,Valenza et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: We have explored genome-wide expression of genes related to glycobiology in exon 1 transgenic Huntington's disease (HD) mice using a custom-designed GLYCOv2 chip and Affymetrix microarray analyses. We validated, using quantitative real-time PCR, abnormal expression levels of genes encoding glycosyltransferases in the striatum of R6/1 transgenic mice, as well as in postmortem caudate from human HD subjects. Many of these genes show differential regional expression within the CNS, as indicated by in situ hybridization analysis, suggesting region-specific regulation of this system in the brain. We further show disrupted patterns of glycolipids (acidic and neutral lipids) and/or ganglioside levels in both the forebrain of the R6/1 transgenic mice and caudate samples from human HD subjects. These findings reveal novel disruptions in glycolipid/ganglioside metabolic pathways in the pathology of HD and suggest that the development of new targets to restore glycosphingolipid balance may act to ameliorate some symptoms of HD.
Neurobiology of Disease 10/2007; 27(3):265-77. DOI:10.1016/j.nbd.2007.05.003 · 5.08 Impact Factor
"The primary changes are the consequence of the abnormal accumulation of substrates or catabolites that lead to severe impairment of cellular structure and function (Herschkowitz and Schulte, 1984). The secondary changes are likely due to disrupted recycling and are manifested in abnormal synthesis of cellular and extracellular elements (Nanto-Salonen, 1984, 1987 ; Lovell, 1990 ; Kaye et al., 1992 ; Holleran et al., 1994 ; Maatta et al., 1994 ; Pitto et al., 1996). "
[Show abstract][Hide abstract] ABSTRACT: The presence of cloudy corneas is a prominent feature of mucopolysaccharidosis (MPS) types I and VI, but not MPS IIIA or IIIB. The cause of corneal cloudiness in MPS I and VI is speculative. Transparency of the cornea is dependent on the uniform diameter and the regular spacing and arrangement of the collagen fibrils within the stroma. Alterations in the spacing of collagen fibrils in a variety of conditions including corneal edema, scars, and macular corneal dystrophy is clinically manifested as corneal opacity. The purpose of this study was to compare the structural organization of the stromal extracellular matrix of normal corneas with that of MPS corneas. The size and arrangement of collagen fibrils in cloudy corneas from patients with MPS I were examined. The alterations observed were an increased mean fibril diameter with a broader distribution in the MPS corneas. The MPS I corneas also had altered fibril spacing and more irregular packing compared with normal control corneas. The clear corneas of patients with MPS IIIA and IIIB also showed increases in mean fibril diameter and fibril spacing. However, there was less variation indicating more regularity than seen in MPS I. In addition, corneas from cat models of certain MPS were compared to the human corneas. Cats with MPS I and VI, as well as normal control cats, were examined. Structural alterations comparable to those seen in human MPS corneas were seen in MPS I and VI cats relative to normal clear corneas. The findings suggest that cloudy corneas in MPS I and VI are in part a consequence of structural alterations in the corneal stroma, including abnormal spacing, size, and arrangement of collagen fibrils.
Experimental Eye Research 06/1999; 68(5):523-30. DOI:10.1006/exer.1998.0622 · 2.71 Impact Factor
Martijn D Steenwijk, Hugo Vrenken, Laura E Jonkman, Marita Daams, Jeroen Jg Geurts, Frederik Barkhof, Petra Jw Pouwels,
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