Case # AP07-02381Case # AP07-02381

Midori Asakawa and John Midori Asakawa and John CullenCullen

NC State University, College of Veterinary NC State University, College of Veterinary MedicineMedicine

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HistoryHistory 11 month old, male neutered 11 month old, male neutered

DachshundDachshund

Derived from consanguineous mating Derived from consanguineous mating (mother and son)(mother and son)

3 month history of stumbling and 3 month history of stumbling and falling which had progressed to falling which had progressed to severe vestibular ataxia, nystagmus, severe vestibular ataxia, nystagmus, and possible seizure activityand possible seizure activity

No response to antibioticsNo response to antibioticsPresented at SEVPAC 2008 –

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Dura intactDura intactPresented at SEVPAC 2008 – Permission granted for use on SEVPAC

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HE LowHE Low

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PAS

Sudan Black

LFB

Fluorescence Microscopy

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TEM

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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

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Morphological DiagnosisMorphological Diagnosis

Diffuse, moderate, neuronal Diffuse, moderate, neuronal degeneration and necrosis with degeneration and necrosis with cerebral atrophy and abundant cerebral atrophy and abundant neuronal intracytoplasmic granular neuronal intracytoplasmic granular pigmentpigment

Disease DiagnosisDisease Diagnosis

Ceroid lipofuscinosisCeroid lipofuscinosisPresented at SEVPAC 2008 –

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Other Histologic LesionsOther Histologic Lesions

CerebellumCerebellum RetinaRetina

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Neuronal Ceroid Neuronal Ceroid LipofuscinosisLipofuscinosis

Inherited lysosomal storage disease Inherited lysosomal storage disease

Progressive neuropathy and Progressive neuropathy and accumulation of autofluorescent accumulation of autofluorescent lipopigment in neurons and other cells. lipopigment in neurons and other cells.

PAS, LFB and Sudan black positive, PAS, LFB and Sudan black positive, autofluorescent granulesautofluorescent granules

Human NCLs are classified into several Human NCLs are classified into several forms based on age of clinical onset and forms based on age of clinical onset and causative gene causative gene Presented at SEVPAC 2008 –

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EM Findings and Stored EM Findings and Stored ProteinsProteins

UltrustructureUltrustructure

Stored proteinsStored proteins Subunit C of mitochondrial ATP Subunit C of mitochondrial ATP Sphingolipid activator proteins A and DSphingolipid activator proteins A and D UnknownUnknown

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NCLs in Veterinary NCLs in Veterinary MedicineMedicine

NCLs have been described in cattle, sheep, goats, NCLs have been described in cattle, sheep, goats, cats and more than 18 breeds of dogscats and more than 18 breeds of dogs English Setter, Border Collie, Bulldogs, Golden Retriever, English Setter, Border Collie, Bulldogs, Golden Retriever,

Australian Cattle Dog, Dalmatian, Saluki, Chihuahua, Australian Cattle Dog, Dalmatian, Saluki, Chihuahua, Tibetan terrier, Dachshund, Cocker Spaniel, Miniature Tibetan terrier, Dachshund, Cocker Spaniel, Miniature Schnauzer and Corgi Schnauzer and Corgi

The causative mutation in dogsThe causative mutation in dogs English Setters - a missense mutation in English Setters - a missense mutation in CLN 8CLN 8 Border Collies - a nonsense mutation in Border Collies - a nonsense mutation in CLN 5CLN 5 Bulldogs - a missense mutation in Bulldogs - a missense mutation in CTSDCTSD Juvenile Dachshund - a frame shift mutation in canine Juvenile Dachshund - a frame shift mutation in canine

TPP1TPP1: the ortholog of human : the ortholog of human CLN 2CLN 2Presented at SEVPAC 2008 –

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AcknowledgementAcknowledgement

Dr. John Cullen Dr. John Cullen Dr. Keith LinderDr. Keith Linder Dr. Edward MacKillopDr. Edward MacKillop NCSU Histology LabNCSU Histology Lab All my resident mates and senior All my resident mates and senior

pathologistspathologists

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Questions?Questions?

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