1. Case # AP07-02381 Midori Asakawa and John Cullen NC State University, College of Veterinary Medicine Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

2. History 11 month old, male neutered Dachshund 11 month old, male neutered Dachshund Derived from consanguineous mating (mother and son) Derived from consanguineous mating (mother and son) 3 month history of stumbling and falling which had progressed to severe vestibular ataxia, nystagmus, and possible seizure activity 3 month history of stumbling and falling which had progressed to severe vestibular ataxia, nystagmus, and possible seizure activity No response to antibiotics No response to antibiotics Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

3. Dura intact Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

5. HE Low HE Low Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

7. PASSudan Black LF B Fluorescence Microscopy Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

8. TEM Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

9. DNA Analysis A frame shift mutation in canine TPP1 * (the ortholog of human CLN 2) - - Encodes a lysosomal enzyme, tripeptidyl 1 peptidase - - Causative gene of human infantile neuronal ceroid lipofuscinosis - - Accumulating curvilinear cytosome * Performed at University of Missouri Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

10. Morphological Diagnosis Diffuse, moderate, neuronal degeneration and necrosis with cerebral atrophy and abundant neuronal intracytoplasmic granular pigment Disease Diagnosis Ceroid lipofuscinosis Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

11. Other Histologic Lesions Cerebellum Retina Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

12. Neuronal Ceroid Lipofuscinosis Inherited lysosomal storage disease Inherited lysosomal storage disease Progressive neuropathy and accumulation of autofluorescent lipopigment in neurons and other cells. Progressive neuropathy and accumulation of autofluorescent lipopigment in neurons and other cells. PAS, LFB and Sudan black positive, autofluorescent granules PAS, LFB and Sudan black positive, autofluorescent granules Human NCLs are classified into several forms based on age of clinical onset and causative gene Human NCLs are classified into several forms based on age of clinical onset and causative gene Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

13. EM Findings and Stored Proteins Ultrustructure Ultrustructure Stored proteins Stored proteins Subunit C of mitochondrial ATP Subunit C of mitochondrial ATP Sphingolipid activator proteins A and D Sphingolipid activator proteins A and D Unknown Unknown Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

14. NCLs in Veterinary Medicine NCLs have been described in cattle, sheep, goats, cats and more than 18 breeds of dogs NCLs have been described in cattle, sheep, goats, cats and more than 18 breeds of dogs English Setter, Border Collie, Bulldogs, Golden Retriever, Australian Cattle Dog, Dalmatian, Saluki, Chihuahua, Tibetan terrier, Dachshund, Cocker Spaniel, Miniature Schnauzer and Corgi English Setter, Border Collie, Bulldogs, Golden Retriever, Australian Cattle Dog, Dalmatian, Saluki, Chihuahua, Tibetan terrier, Dachshund, Cocker Spaniel, Miniature Schnauzer and Corgi The causative mutation in dogs The causative mutation in dogs English Setters - a missense mutation in CLN 8 English Setters - a missense mutation in CLN 8 Border Collies - a nonsense mutation in CLN 5 Border Collies - a nonsense mutation in CLN 5 Bulldogs - a missense mutation in CTSD Bulldogs - a missense mutation in CTSD Juvenile Dachshund - a frame shift mutation in canine TPP1: the ortholog of human CLN 2 Juvenile Dachshund - a frame shift mutation in canine TPP1: the ortholog of human CLN 2 Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

15. Acknowledgement Dr. John Cullen Dr. John Cullen Dr. Keith Linder Dr. Keith Linder Dr. Edward MacKillop Dr. Edward MacKillop NCSU Histology Lab NCSU Histology Lab All my resident mates and senior pathologists All my resident mates and senior pathologists Presented at SEVPAC 2008 – Permission granted for use on SEVPAC website only

16. Questions?