The Mucopolysaccharidoses in the Dog.

M Haskins. R. Shull*,U Giger. J Fyfe. G Aguirre**. JH Wolfe. P Henthorn. A. Bouvet. D Patterson.

Schools of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA., *University of Tennessee, Knoxville, TN, **Cornell University.

Three of the mucopolysaccharidoses (MPS), a subclass of lysosomal storage diseases, have been discovered in dogs: MPS I (Hurler syndrome, c~-iduronidase deficiency, plott hound), MPS VI (Maroteaux-Lamy syndrome, arylsulfatase B deficiency, miniature pinscher and Welsh corgi), and MPS VII (Sly syndrome, B-glucuronidase deficiency, mixed breed).

All three syndromes have clinical features in common including a shortened broad face, low set ears, a laterally broad chest, diffuse corneal clouding, and growth retardation. Leukocytes in peripheral blood smears contain coarse cytoplasmic granules that stain metachromatically with toluidine blue. Affected animals also have large amounts of glycosaminoglycans in urine.

Toluidine blue positive granules in leukocytes and a positive urine MPS spot test are simple and reliable screening tests for MPS disorders.

Cardiac abnormalities are variable from having no clinical signs of heart disease, to murmurs consistent with mitral insufficiency, to signs of congestive heart failure before weaning. Prior to six months of age, affected animals have marked gait abnormalities. Synovial joint capsules are often swollen, with many joints extremely lax, easily subluxated, and crepitant. Radiographic features of the bones include severe, progressive epiphyseal dysplasia of long bones and vertebrae, and coxofemoral subluxation to luxation.

Major pathologic changes are found in many organ systems and include hepatomegaly, tracheal narrowing, and thickening of the atrioventricular heart valve leaflets and cordae tendinae. Histologically, cytoplasmic vacuoles are present in hepatocytes, Kupffer cells, keratocytes, retinal pigment epithelium, heart valves fibroblasts, aortic smooth muscle cells, leukocytes, and synovial cells in those animals studied. Central nervous system neurons contain cytoplasmic vacuoles in MPS I and VII. By electron microscopy, the cytoplasmic inclusions present in tissues are membrane-bound and are empty or contain granular and/or lamellar material. All three disorders are inherited as autosomal recessive traits, which is the same mode of inheritance as in humans. Enzyme activity of the respective lysosomal hydrolase in peripheral blood leukocytes and other tissues is less than 2% of normal canine values, whereas other Iysosomal enzyme activities are typically increased. Obligate heterozygotes for the diseases have respective enzyme activities approximately 50% of normal.

The cDNA coding for normal and mutant canine alpha-iduronidase has been cloned. 90% of the sequence of the cDNA for canine B-glucuronidase is known.

Dogs with MPS I and VII have been experimentally treated by bone marrow transplantation resulting in improvement in the pathology in both diseases. These results have provided the rationale for exploring gene therapy in these canine diseases.

These studies were supported by NIH grants DK25759, NS33526, RR02512, DK42707, EY07705.

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