Neuronal Ceroid- Lipofuscinosis in Two Cats
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Transcript of Neuronal Ceroid- Lipofuscinosis in Two Cats
Neuronal Ceroid- Lipofuscinosis in Two Cats
MARK CHALKLEY – 3rd YEAR ANATOMIC PATHOLOGY RESIDENT
History & Signalment• Similar history and signalment for both case #1 and
#2: - Both between 1 or 2-years old male DSH cats- Submitted to animal shelters as strays with no previous history- Prolonged, progressive history of visual
dysfunction (running into walls, difficulty tracking moving objects) and neurological deficits (falling, frantic running, behavior abnormalities)• Both euthanized and submitted for necropsy
Case #1 Control
Cerebral Cortex
Normal Case #2Normal
H & EH & E
H & ELFB/ H&E
PASAF
Immunofluorescence
• Normal and abnormal
H & E GFAP
Normal Case #2
Lesion DistributionAnatomic Location Lipopigment/Ceroid Neuronal/ Cell Loss Gliosis
1 2 1 2 1 2
Cerebral cortex +++ ++ +++ ++ +++ ++
Thalamus + ++ + + + +
Hypothalamus + + + + + +
Basal Nuclei + ++ + + + +
Hippocampus +++ +++ + + ++ +
Cerebellum ++ + ++ + ++ +
Spinal Cord + ++ + + + +
Retina + + +++ ++ - -
Extra-CNS tissues - - - - - -
* + = mild, ++ = moderate, +++ = severe; 1 = Case No. 1; 2 = Case No. 2
Disease Cause Organs affected Storage material
Special stains
Lectin histo-
chemistryEM
1. Ceroid-Lipofuscinoses
Unknown or lysosomal protein defects
Predominantly cerebrum, cerebellum & retina in cats but can be inmany tissues
Subunit c of mitochondrial ATPase, amyloid-β, precursor protein, SAPs
Magneta with PASLFB+Sudan black+Auto-fluorescent
Variable to nil reactivity
Curvilinear bodiesFingerprint profiles Granular osmophilic deposits
2. GangliosidosesLysosomal enzyme deficiency
CNS, PNS, liver, kidney, lymph n., cardiac Purkinje cells
Glyco-sphingolipids
PAS+LFB+Sudan black+
O-linked
Membranous cytoplasmic bodies and/or zebra bodies
3. Gluco-cerebrosidoses
Gluco-cerebrosidase deficiency
CNS, macrophages (esp liver, LNs)
Gluco-cerebrosides
PAS+ in macsPAS – in neuronsLFB+
O-linked
Twisted, branching tubules or zebra bodies in neurons
4. Mannosidosis(glycoproteinosis)
Lysosomal α or β mannosidase or α-L-fucosidase deficiency
Many cells (neurons, epithelium, endothelium, mesenchyme)
Carbohydrate (saccharides with mannose residues)
PAS+, diastase resistant, Variably alcian blue+
N-linked
Membrane bound vesicles, with floccular material & fine membrane stacks
5. Muco-polysaccharidoses(MPS VII in cats)
Various enzyme deficiencies
Predominantly bone and other connective tissues, neurons
Gluco-aminoglycan
Variable PAS+LFB+Sudan black+Auto-fluorescent
N-linked
Empty vesicles, or floccular material /zebra bodies
Gangliosidoses
Mannosidoses
Ceroid-lipofuscinosis
Sphingolipidoses & Mucopolysaccharidoses
Diagnosis
Brain, spinal cord, eyes: Degenerative lysosomal storage encephalo-
myelopathy and retinopathy, widespread, marked, chronic, with neuronal loss and astrogliosis
- Consistent with neuronal ceroid-lipofuscinosis (NCL)
Lysosomal Storage Diseases (LSD)
What is LSD anyway?• LySergic acid Diethylamide• Lumpy Skin Disease• Lichenoid-pSoriasiform
Dermatoses• Louisiana School for the
Deaf
NCL in Animals and Humans• Four main variants – infantile, late-infantile, juvenile, adult• 160 mutations in 10 human genes (CLN1-10)• Lead to defects in 8 known proteins• Gene defects also recognized in dogs, sheep and cattle• Similar distribution and character of lesions & material• Main storage material in animals and humans - subunit c
of mitochondrial ATP synthase (SCMAS) or sphingolipid activator proteins A and D (SAPs)
• A correlation between the age of clinical onset of disease, ultrastructure of the storage material and the variants of NCL has not been established in animals
Lipofuscin vs Ceroid Characteristic Lipofuscin Ceroid
Circumstance of deposition Aging Pathological
Location Lysosome Lysosome
Autofluorescence Positive Positive
Storage components
Protein Heterogenous mix, amyloid-β protein Subunit c of mitochondrial ATPase, amyloid-β, precursor protein, saposins
Lipids Triglycerides, FFA, dolichols Phosphorylated dolichols, phospholipids, neutral lipids
Carbohydrates Dolichol-linked oligosaccharides Dolichol-linked oligosaccharides
Metals Fe, Cu, Al, Zn, Ca, Mn Predominantly Fe
Histochemistry (including lectins)
Sudan Black Positive Positive
Luxol fast blue Positive Positive
PAS Positive Positive
Concanavalin A Positive Positive
Agglutinin Negative Positive
Ultrastructure
Granular osmophilic deposits Positive Positive
Fingerprint profiles Negative Positive
Curvilinear bodies Negative Positive
*Table adapted from SS Seehafer, DA Pearce, Neurology of Aging 27 (2006), p580.
Mechanisms of Ceroid Accumulation
Seehafer S & Pearce D (2007)
Autophagy
Oxidation
Lysosomal Function
Acknowledgements• ACVP/STP coalition fellowship• Pfizer & Dr Peter Schmidt• University of Minnesota – - Dr Anibal Armien & Dr Gerry O’Sullivan
- Electron microscopy laboratory
Questions?