FELINE MUCOPOLYSACCHARIDOSIS

1. FELINE MUCOPOLYSACCHARIDOSIS Christina Copple, DVM Radiology Resident NCSU CVM-VTH April 13, 2009 Accession #57629

2. Feline Mucopolysaccharidosis (MPS) • Uncommon, autosomal recessive inherited disorder = reduction or absence of glycosaminoglycan (GAG) dermatan sulfate catabolism • > 10 forms are recognized in humans due to various enzyme defects • Many of the same forms have been recognized in both canines and felines

3. Feline Mucopolysaccharidosis (MPS) • Lysosomal degradation of mucopolysaccharides is necessary for normal growth • Undegraded product is stored in tissues and excreted in the urine • Abnormal catabolism → chronic, progressive, and multisystemic disease • Stimulation of inflammation and apoptosis in cartilage and synovial cells • Two subclasses have been identified in cats (esp. those of Siamese ancestry) • MPS I • MPS VI

4. MPS I Deficiency of alpha1-iduronidase DSH cat Similar clinical features as MPS VI Lacks bony proliferative changes, spinal cord compression and neurologic deficits MPS VI Deficiency of lysosomal enzyme: arylsulfatase B Siamese cats Feline Mucopolysaccharidosis (MPS) http://www.dkimages.com/discover/previews/928/60025166.JPG

5. Physical deformities noticeable by 8 weeks of age (facial dysmorphia & disproportionate dwarfism): Small head Flat and broad face Wide spaced eyes Depressed bridge of nose Small ears Large forepaws Pectus excavatum Generally smaller than littermates Corneal opacification Cardiac valvular thickening Skeletal changes: Fusion of cervical vertebrae Variable fusion of thoracic and lumbar vertebrae Hyperextension of distal extremity joints due to laxity Bony proliferation: In the intervertebral foramina causes nerve root compression Into the vertebral canal causes compression of the spinal cord Clinical Features of MPS VI

6. MPS VI • Bony proliferative changes and associated spinal cord compression occur prior to or at the time of epiphyseal closure (~ 9 mths). These changes are probably nonprogressive after this point. • Neurologic deficits (indicative of a transverse T3-L3 myelopathy) are seen between 4 -7 mths of age with progression over the next 2 -4 weeks. • Loss of conscious proprioception in the pelvic limbs • Normal to increased pelvic limb reflexes • Decreased pain perception in the pelvic limbs

7. Accession #57629 • Radiographic changes of both the axial and appendicular skeleton: • generalized epiphyseal dysplasia of long bones and vertebral endplates • delayed and incomplete mineralization of the epiphyseal cartilage model • ossified regions of the epiphyses are smaller than normal & have a nonuniform opacity with a granular appearance • vertebral bodies are shorter than normal and cuboid in shape • maxilla is short and flat • frontal sinuses are small or absent • hip subluxation or luxation may result from femoral head epiphysis remodeling

8. Diagnosis and Treatment of MPS VI • Signalment, clinical signs and radiographic abnormalities of the spine • Measure arylsulfatase B activity in leukocytes • Potential for decompressive surgery of the spine after 9 mths of age since disease is nonprogressive • Possible to have multiple sites of compression • No treatment for the lysosomal enzyme deficit • Bone marrow transplantation?? • Enzyme replacement therapy??

9. Radiographically Visualized Skeletal Changes Associated With Mucopolysaccharidosis VI In CatsKonde, Thrall, Gasper, Dial, McBiles, Colgan, and HaskinsVetRad, 28:6, 1987. pp223-228 • Characterized radiographic abnormalities of 11 cats of Siamese ancestry with MPS VI • Definitive diagnosis via: • Measurement of increased urinary GAG excretion • Presence of typical Alder-Reilly bodies in neutrophils • Absence of measurable leukocyte arylsulfatase-B activity • Most severe changes centered in areas of enchondral ossification: accumulation of GAG inhibits normal transition from cartilage to bone in the physis and on bone formation in epiphyseal ossification centers • Diseases with similar radiographic appearance: congenital hypothyroidism, epiphyseal dysplasia, hypervitaminosis A, and hyperparathyroidism

10. Radiographically Visualized Skeletal Changes Associated With Mucopolysaccharidosis VI In CatsKonde, Thrall, Gasper, Dial, McBiles, Colgan, and HaskinsVetRad, 28:6, 1987. pp223-228 • All affected cats had severe decreased bone opacity with thin cortices and a coarse trabecular pattern • Epiphyseal dysplasia • Abnormal nasal turbinate development • Coxofemoral subluxation • Impaired development of skeletal growth • Pectus excavatum • Hyoid hypoplasia • Aplasia, hypoplasia, and fragmentation or abnormal ossification of the dens • Aplasia or hypoplasia of frontal and sphenoid sinuses

11. VetRadUS, 28:6, 1987. pp223-228

12. Normal MPS VI VetRadUS, 28:6, 1987. pp223-228

13. References • Ettinger, Stephen J., DVM and Edward C. Feldman, DVM. Textbook of Veterinary Internal Medicine Diseases of the Dog and Cat. 6th ed. Volume I. Elsevier, St. Louis, MO. 2005. 872-873. • Thrall, Donald E., DVM, PhD. Textbook of Veterinary Diagnostic Radiology. 5th ed. Saunders, St. Louis, MO. 2007. 276-277. • Konde, Linda J., DVM, Mary Anna Thrall, DVM, MS, Peter Gasper, DVM, PhD, Sharon M. Dial, DVM, Kit McBiles, Sean Colgan, Mark Haskins, VMD, PhD. Radiographically Visualized Skeletal Changes Associated With Mucopolysaccharidosis VI In Cats. Veterinary Radiology, 28:6, 1987. 223-228. • Yogalingam, Gouri, Tom Litjens, Julie Bielicki, Allison C. Crawley, Vivienne Muller, Donald S. Anson, and John J. Hopwood. Feline Mucuopolysaccharidosis Type VI: Characterization of Recombinant N-Acetylgalactosamine 4-Sulfatase and Identification of a Mutation Causing The Disease. The Journal Of Biological Chemistry. 271:44, November 1996. 27259-27265. • Simonaro, Calogera M., Marina D’Angelo, Xingxuan He, Efrat Eliyahu, Nataly Shtraizent, Mark E. Haskins, and Edward H. Schuchman. Mechanism of Glycosaminoglycan-Mediated Bone and Joint Disease: Implications for the Mucopolysaccharidoses and Other Connective Tissue Diseases. The American Journal of Pathology. 172:1, January 2008. 112-122.