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Neuropathology of ovine ceroid lipofuscinosis : a thesis presented in partial fulfilment (30%) of the requirements for the degree of Master of Philosophy in Veterinary Pathology at Massey University

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(1)Copyright is owned by the Author of the thesis. Permission is given for a copy to be downloaded by an individual for the purpose of research and private study only. The thesis may not be reproduced elsewhere without the permission of the Author..

(2) NEUROPATHOLOGY OF OVINE CERO I D - L I POFUSCI NOS I S. A t h esis presented i n part ial fu lfi lment the requi remen t s for. (30%) of. the degree of. Mas t e r of P h i l osophy in Ve t e r i nary Pathology at Massey Un iversity. Ak i n o r i Sh imada 1987.

(3) ii ABSTRACT. The purposes of t h i s study we re to describe the neuropathol ogy of ovine ceroi d - l i pofuscinosi s ,. to c ompare. find ings with those of the related ent i t ies in humans and other domest i c animals , and t o pr ovi d e morphological informat i on that might h e l p eluci date the pathogenesis of these d iseases .. An. establ ished flock of South Hamps h i r e sheep carrying the ceroid­ l i pofuscinosis gene have made it possible to perform a l ongitu d i nal study on the central ne rvous system of affected sheep of vari ous ages incl uding foetuses .. The most s t r i k i ng gross pat hological change of affected sheep was brain atropy .. At t e rm i nal d isease,. the brain we ights of. affected sheep were 55% of those of normal sheep .. Atrophy. affected mainly the ce rebrum .. Sudan black and luxol fast blue posi t i ve autof luorescent neuronal pigment granu l e s were d e t e cted by l i ghtmic roscopy as early as the m i d stage of foetal devel opment , examined .. the ear l i est stage. Postnatal l y t h e re we r e t opograph i cal differences in the. quantity of accumulated l i popigments in neurones of var i ous areas .. S i mi lar l y ,. there we re age r e lated topograph i cal. d ifferences in secondary d egene rative changes .. Neuronal. l oss was. most seve r e in the par i e ta l l obe cortex showing an ini t ial l aminar d i st r i but i on .. Th is pat t e rn was we l l demonstrated by a. concomi tant astrocytosis .. In add i t i on to the compl e x e l e c t ron dense cytosomes simi l a r t o those reported in t h e h uman syndromes ,. there w e r e l ess compl e x. cytosomes o f sma l l e r s i z e i n affe cted foetal brains . T h e lat t e r we r e c l early bounded by a t r i l am i nar membrane and contained who rls o r l oose stacks of t r i l aminar membranes resembl ing those of the l im i t ing membranes .. I n some e l e ctronmi c rographs t h e re was. a sugges t i on of con t i nu i t y between the surrounding membrane and.

(4) iii the internal membrane s ,. but th i s wa s not d e f i n i t e l y demon s tra t e d .. Th i s i s prov i s i ona l ly interpreted a s being due interna l i z a t ion of. to an. surrounding l imi t ing membrane rather than a. re c y c l ing of membrane .. S ome of the s e sma l l cyt o s omes a l s o showe d. comp l e x mul t i l a me l l a r pro f i l e s s imi l ar to those of large compl e x cyto some s .. The s e l atter a ppeared to be formed b y c oa l e s cence o f. sma l ler comp l e x one s .. There thus appeared to be a sequence o f. change s i n t h e d ev e l opment o f storage cytosome s .. Th i s s tudy reve a l e d that the ovine d i s e a s e h a s not only many neuropa thologi c a l findings in c ommon with ana l ogous human d i s e a s e s , but a l s o s ome pa tho l o g i c a l fea ture s wh ich have not b e e n reported i n af f e c t e d humans o r anima l s . l i pofu s c i no s i s. Ovine cero id­. is thus a useful an imal mod e l for the s tudy of t h e. human cero i d - l i pofus c i n o s e s ..

(5) iv. ACKNOWLEDGEMENTS. Th is study was pe rformed using the faci l i t i es of t h e Department of Vete r i nary Pat h o l ogy and P u b l i c Health at Massey Unive rsi ty.. I wou l d l ik e to t hank P r ofessor B. W . Mank t e l ow ,. Head of the D e pa r tment ,. for mak ing these ava i l able. I am. parti c ularly grateful t o Professor R . D . Jo l ly , my supe rviso r , for providing me w i t h t h e oppo rtun i ty to unde rtake t h i s pro je c t and h i s continuous h e l p and encouragement throughout t h e stud y .. Advice on t h e inte rpretat i on of l i ght and e l ect ron m i c r oscopy was also pr ovided by Dr. W . J. at Taronga Z o o , Mart inus ,. Hartley ,. patho l ogist. Austral ia. D r. D.N. Palme r and Mr. R . D.. who are membe rs of the team work ing on ov ine c e r o i d ­. l i pofuscinosis in t h i s l aboratory ,. have a l so provided h e l p in. my unde rstand ing of b i o chemi cal aspects of the d isease.. The i r. encou rageme nt was great ly appr e c i ated.. I also wish to acknowl edge the h e l p of Mr. M.J. B i rt l e s of the Department of Physi o l ogy and Anatomy in the preparat i on of t issues for the immuno cytochemi cal study ,. Dr. A.S. Dav i e s of. the Department of Physi o l ogy and Anatomy in the study of ovine neu roanatomy , and Mrs .. L.R.. D i ckson of t h e Department of. Veterinary C l i n i ca l S c i ence and fifth year B . V. S c . students i n t h e caesarean sect i ons wh i ch provided foetuses for t h e study .. Special thanks a r e also due to Mr . R .J.. D . H. Hopcroft and M r .. Bennett of t h e D e partment of S c ientific and Industrial. Research wh o gave advi c e on t h e preparat i on of t issues for e l ect ron m i c r oscopy and printed t h e e l e c t r onmi c r ograph s , and Mr. T . G .. Law and t h e staff at t h e Central Photographi c Uni t who. printed the l i g h tm i c r o g raphs .. I would l i k e t o t hank Mrs .. P.M.. S lack and Mrs .. P.M.. Davey. for t h e i r g r eat h e l p in the preparat i on of tissues for l i ght and f l uorescent m i c r os c opy , Mr .. F.K.. Sharpe for his assistance.

(6) i n po s t -mortem room ,. a nd Mrs .. A.A.. Scott f or her a s s i s ta n c e i n. the u s e o f word pro ce s s i n g program and i n printing the f in a l copy .. F i na l ly I would a l s o l i k e to e x pre s s thank f u l n e s s to my f ami ly i n Japan f o r t h e ir con t i nuous encouragement , wi f e ,. Naok o ,. a nd my s on ,. Kentaro ,. a nd my. f or their patience and h e l p .. .V.

(7) TABLE OF CONTENTS. page. ABSTRACT. ii. ACKNOWLEDGEMENTS. iv. V. TABLES OF CONTENTS. L IST OF F I G URES. vii. L IST OF TABLES. xiv. 1. INTRODUCTI ON. CHAPTER. I:. Review - the n e u r o n a l ceroidl i pofusci noses .. 2. Gross pathol ogy .. 23. CHAPTER I I I :. Light rn i c roscopy .. 26. CHAPTER. IV :. E l e ctron rni c roscopy.. 41. C HAPTER. V:. Gen e r a l d iscussi o n .. 49. CHAPTER. II :. B I B L I OGRAPHY. 53.

(8) vii. LIST OF FIGURE S. F o l l owing page. Figure 2. 1. Brain weig h t s of. sheep with c e roid­. lipo f u scinos i s and age matched norma l 24. cont r o l s r e l ative to e a ch o t h e r and age . 2.2. Late r a l view of b rains f rom a 2 5 months o l d a f f e c t e d s h e ep and f rom a 27 months o l d norm a l s h e ep .. T h e greate st d e gr e e o f at rophy invol ve s. t h e c e rebrum .. Note marked thinning o f t h e gyri 24. o f t h e c e r e b r um o f the a f f e cted anima l . 2.3. Transv e r s e s e c t i ons of the ce rebrum f rom a 2 5 months o l d a f f e cted sheep and f rom a month s o l d normal o f t h e c e rebrum , c o rtex,. sheep.. 27. Note reduced si z e. marked thinni ng o f the. seve r e l y at tenua ted corpu s cal l o s um. and s l ight enla rgement of the lateral vent ric l e in the a f f e cted s h e ep. M i l d a t r ophy o f t h e d i encepha l on and moderate r e d u c t i on in si z e o f t h e subcortic a l wh i t e matte r a re a l s o noted in the a f fe cted 24. sheep . 2. 4. Transve r s e s e c t i on of t h e ce rebrum of a 2 5 month s o l d a f fe cted s h e ep. d e s c r i bed in F i g. demon s t ra t e d.. Change s. 2 . 3 a r e we l l. Note mye l in l o s s in the. s ub c o rt i ca l white m a t te r . 3.1. 28. Vent r a l h o rn ce l l s of t h e ce rvica l spina l c ord of a 23 month s o l d a f f e cted sheep . Note c l u s t e r s o f a u t o f luore s cent g ranu l e s in t h e neurona l pe rika rya .. 3. 2 a. 28. Vent r a l h o rn c e l l o f a 23 months old a f f e cted sheep .. Lipopigment granu l e s. a c c umul ating i n t h e cytop l a sm stain b l a ck with Sudan b l a ck B . 3 . 2b. 28. Ven t r a l h o rn c e l l o f a 2 3 months o l d a f f e cted sheep .. Lipopigment granu l e s. f i l ling t h e cytopl a sm s tain b l ue with l uxol 28. f a s t b l ue . 3 . 2c. Ven t r a l h o rn c e l l o f a 23 months o l d a f f ected s h eep .. Lipopigment g ranu l e s. f i l l ing t h e cytopl a sm stain r e d with PAS .. 28.

(9) viii Figur e. Following page. 3 . 3a. Ventral h o rn cells o f a f ull t e rm foetus a f f e c ted with ovine c e r oid-li po f u scinosis . Nume r o u s fine lipopigment g r anule s d i f f usely located in the c y topla sm.. 3 . 3b. 29. Ventral horn cell o f a 5 mont h s old a f f e cted lamb .. Note clu s t e r s o f lipopigment. g r anule s of rela tively la r g e r s i z e in the neu r onal pe rik a rya w i th i n c r e a s e d intensity of. the s taining with luxol f a s t blue .. They. h ave a pe rinucl e a r location . 3. 3c. 29. Vent ral h orn c ell of a 18 mont h s old a f f e cted lamb .. The l i popi gment granule s a r e. l a r g e r a n d st ain m o r e intensely than those i n F i g s . 3. 3a & 3. 3b and h ave a pe ri nuclear 29. loc a t i on. 3. 4. Ce rebellar cortex f rom an o bligate h omozygous a f f e cted mid t e rm f oetus. Dis crete S udan black s t a i ning inclu s i ons a r e already pre sent in P u r k inje cells.. 3.5. 29. C e rebral cortic e s of a f ull te rm a f fected f oe t u s ( b) ,. ( a) ,. a 5 months old a f f e cted lamb. a 18 month s old a f f e c ted lamb. a 23 months old a f f e cted s h eep. ( d).. ( c) and The. amount of Suda nophilic d e po s i t s in ne urone s a s well a s in t h e c e rebral cortex incre a s e s w i t h advancing age .. Large clu sters o f. Sudanoph i lic d e posit s w i t h va riation in t h e s taining a n d a neuronal lo s s a r e noted by te rminal d i s e a se. 3.6. 29. Ventral horn c ells o f a 18 months old a f f e c t e d lamb .. L i po p i gment g r anule s. a c c umulat e in the neu ronal pe rikarya , extending into axon hillock and even into t h e proximal part of t h e axon . 3.7. 29. Cerebral cortex of a 23 mont h s old a f fected sheep ,. s howing neu ronal los s and pronounced. gliosis .. Depo sit m a t e r i a l i s mainly in. macrophage s .. 29.

(10) ix. Following. Figure. page. 3. 8. A t ransve r s e s e c t i ons of t h e ce rebral cortex of a normal 5 mont h s old lamb. ( a) i s. compa r e d with t h o s e o f a 5 month s old and a 18 month s old. ( b). ( c) a f f e c t e d lambs.. At. 5 month s t h e r e i s a lready a evi dence o f a t rophy w i t h pa r t i c ular lo s s o f neurone s in t h e m i ddle area o f t h e i s o cortex . Th i s i s exa cerbated i n t h e 18 mont h s old animal with a gene r a l lo s s of ne u rone s in other areas a s well.. Note t h e f o cal a rrangements. of rema ining neurone s in t h e s upe r f i c i a l a re a o f t h e i s o cortex o f t h e 1 8 months old animal. 3.9. 30. Cerebral cortex of a 23 mont h s old a f fected s h eep ,. showing ma rked neu r onal lo ss and. promi nent gli o s i s. a r rangement of. Note t h e f ocal. rema ining neu rone s in the. s u pe r f i cial area o f t h e i s ocortex and a clu s t e r of l i p i d laden cells interpreted a s mac rophages.. 3.10. 31. A small glial nodule a s soci ated with a small f ocal a r r angement o f remaining neurones in the supe r f i c i al area of the c erebral c o r t e x f rom a 23 months old. ·31. a f fected sheep.. 3.11. A coronal s e c t i on of t h e pa ri etal lobe o f t h e c e rebrum i n a 5 month s old normal lamb ( a) i s compa r e d w i t h s im i la r secti ons of a 5 month s. ( b) and a 18 mont h s old ( c). a f f e cted lamb s .. The immunocytochemi cal. s ta i n for glial f i b r i lla ry a c i dic protein d emon s t rat e s a s trocyto s i s in the mi ddle a rea of band .. the i socortex wi th a clear - c ut d a rk. T h i s o c c u r s f i r s t in the dor s a l gyri. ( b) extending into t h e lateral gyr i with inc r e a s ed a g e. ( c) .. Concom i t ant with t hi s i s. a t r ophy o f t h e s ame a r ea s .. As trocyto s i s o f. t h e wh i te m a t ter i s a l s o prominent. 3 . 12. 31. M e d i um powe r magni f i ca t i on of the c e rebral cor tex f rom t h e s ame s e c t i on of 5 mont h s old a f f ec t e d lamb a s s hown in Fig. 3 . 11 .. It. conf i rms t h a t t h e d a r k band interpreted a s a n a st r ocyt o s i s d o e s c o ns i s t of cellular and f i brous component s . 3 . 13. 31. High power magni f i ca t i on o f the dark band as s hown in F i g s . 3 . 11 & 3 . 1 2 . Note hyperpla s t i c and hype r troph i c a s trocyt e s wi t h prominent f i br i llary proce s s e s .. 31.

(11) X. Fol l owing. Figur e. page 3 . 14. C e r e b r a l c o r t e x o f a 23 month s old a f f e c t e d s heep .. Hyper t rophic a s t r o c y t e s with bi z a r r e. n u c l ei contain lipopigment granu l e s i n t h e cytop l a sm . 3 . 15. 31. Higher power magnification o f a pe riva s c u l a r c u f f o f lipid l a den m a c rophage s in the c e r e b r a l c ortex o f a 23 month s old a f f e c t e d s h e e p .. Note. considerable h e t e r ogeneity in the staining of the g r unu l a r d e po sit s in t h e cytop l a sm . 3 . 16. I nterna l c a p s u l e o f a. 31. 23 mont h s old. a f fected s h e e p . Many va c u o l a r space s are dif f u s e l y seen in t h e white matter . 3. 1 7. Higher power magni fication of one part o f Fig . 3. 16.. A phagocyte w i t h c e l l debris in. its cytopl a sm is p r e s ent in a vacuo l a r space . 3 . 18. 32. 32. Note many mye l in ovoid s .. S ubcortic a l white mat te r s o f a 5 month s o l d a f f e c t e d l amb a n d o f an a ge -matched normal l amb .. Note the inc re a sed fibri l lary. a st r ocytic proce s s e s in t h e a f f ected. 32. anima l . 3. 19. S ubcortic a l white matte r s o f a 23 months. o l d a f f e c t e d sheep and of an age matched norm a l sheep .. Note a marked l o s s of myelin. in the a f f e c t ed anima l . 4.1. 32. Cereb r a l cortic a l neu rone f rom a mid t e rm ovine f oetus a f f e cted with c e roid­ l ipo f u s cino s i s .. Note pre sence of e l e ct r on. dense r e sidu a l bodie s up t o 0 . 7 pm in diamet e r in the cytop l a sm . 4.2. P a r t o f a c e rebr a l c o rt ic a l neu rone o f a 7 month s o l d a f f e c t e d l amb .. This cytosome. a ppe a r s to b e f o rmed by c o a l e s cence o f the sma l l e r den s e bodie s . 4 .3. 42. Mye l inated a xon in t h e c e re b r a l cortex of a 2 2 month s o l d a f f ec t e d s h e e p contains a storage cyto s ome and a mitochondria .. 4.4. 42. 42. Astro cyte in the c e r e b r a l c or t ex o f a 7 month s o l d a f f e c t ed l amb contains s torage cyt o s om e s and thick bund l e s o f fibril s in a hypertrophic proce s s .. I t i s adjacent to t h e. neurone t h a t is int e r p r e t e d a s showing signs of d egene r ation .. 42.

(12) xi Following. Figur e. page. 4.5. Dis c rete r e sidual bodie s within a membrane bounded c y t o s ome in a m a c r ophage in the cerebral c ortex of a 7 month s o l d affected lamb .. 4.6. Blood ve s sel in t h e c e r ebral cortex of a 2 2 month s old affe c ted s he ep .. Note e l e c tron. 42. dense bodie s in t h e endothelia l cells . 4.7. 42. Ele ctron dense body within a cerebr a l cortical neurone from a full t e rm ovine foetu s with cer oid-lipofus cinosis .. Note a. 43. s u r r o unding trilamina r membrane. 4. 8. Part of a storage cyto s ome within a ce rebral cortic a l neu r one from an affected full t e rm ovine foetu s ,. showing fingerprint. and c urvilinear profi l e s . 4. 9. S torage cyto some within a ce rebral cortic a l neurone from a sheep ,. 2 2 months o l d affected. sh owing a "tubular". st ructur e s and. 43. an ele c t r on- l u c ent va c u o l e . 4 . 10. 43. Part of a s torage c yt o s ome within an a s t rocyte in t h e c e r e b r a l cortex of a 2 2. mont h s old affected s h eep, c r y sta lloid pat tern .. showing a. Note g l i a l fibri l s on. t h e l eft . 4. 11. 43. Part of a cerebral c o r tical neurone from a full t e rm ovine foetus with c eroid­ lipofuscinosis .. Note e l ect r on dense body ,. s howing t h r e e -layered lame llae with approxima tely 6 . 5 nm in thickne ss and s ta c k s of multilamel l a r a r rays.. On the. 43. bottom i s a mit o c hondria . 4 . 12. P a r t of a multilam e l l a r cytosome within a cerebral cortical neu r one from a full t e rm ovine foet u s with c e r o id -lipofuscinosis .. It. s how s five -laye r e d lamellar structures with a periodicity of a pproximately 12 nm and s ta c k s of multilamellar a r ray s . 4 . 13. 43. P a r t of a cerebral c o r tical neurone from a full t e rm ovine foetu s with ce roid­ lipofus cinosi s ,. s howing a variety of. abnormal pigment c yto s ome s le ss than 1 . 2 � in diame t e r in t h e cytopla sm .. The s e. c ont r a s t with a n d a re generally smaller than mit o c h ondria .. 43.

(13) xii. Figu r e. Fol l owing page. 4 . 14. Pigment cytosom e s up t o 0 . 8 pm in diameter within a cereb r a l c ortica l neurone f rom a f u l l t e rm ovine f oe t u s with ce roid­ lipo f u s cinosis ,. showing a di s c rete. s u rrounding membrane .. Note a granu l a r. matrix and mul ti l ame l l a r c omponents within t h e s e cytosome s . 4 . 15. 43. P a r t of a neurite in t h e c e r e b r a l cortex o f a f u l l t e rm ovine f o e t u s with ceroid­ lipo f u s cinosis ,. showing a m u l ti lame l l a r. cytosome . i n a neurite o n the cent e r . 4 . 16. 43. P a r t of a c e r e b r a l cortic a l neurone f rom a f u l l t e rm ovine f o e t u s with ce roid­ lipo f u s cinosis ,. showing l ame l l a r cyto s ome s. l e s s than 0. 8 pm in diame t e r .. Note whor l s. and l o o s e s t a c k s o f t r i l aminar membranes . 4 . 17. 44. High er power magnification of one part of the l ame l l a r c y t o s ome with who r l s in Fig. 4. 16 .. Arrow poin t s to t h e. site at which. continuity between the s u r rounding membrane and the interna l membrane is s uggested . 4. 18. 44. P a r t of a c e r e b r a l c o r tica l neurone f rom a f u l l t e rm ovine f o e t u s with ce roid­ lipo f u s cinosis ,. showing a variety of. inc l u sion bodie s .. Mu l t i-l ayered and five ­. l ayered l amel l a e a re s een in the cytosome s . The long a r row indica t e s the site at which a f ive - l ayered l ame l l a e appe a r s to be f o rmed by the f u s ion of two three-l ayered l ame l la e . 4 . 19. 44. P a r t o f a cerebr a l c o r tica l neurone f rom a f u l l t e rm ovine f oe t u s with ceroid­ lipo f u s cinosi s ,. showing a cytosome on the. l owe r right , in which lame l l a r a r rays a ppear t o change t o a fine granu l a r profile .. Note m u l tive sic u l a r body ,. swo l len. r ough endopla smic r e t i c ul um and part o f a mitochondria . 4 . 20. 44. M a c r ophage in the c e r e b r a l cortex f rom a 9 months o l d a f f e cted l amb ,. containing. s torage cytosome s o f simil a r s t ru cture to t h o s e in neurone s , amorphous e l e c tron dense materia l , membranous bodie s and degene rated mye lin in the cytopl a sm .. 44.

(14) xiii. Figur e. Fol lowing page. 4 . 21. A st rocyte in t h e c e r e b r a l cortex f rom a 2 2 months o l d a f f e c te d sheep ,. showing nu c l e u s. o f bi z a r r e s h a p e a n d a hype rtrophic proce s s w i t h i n c r e a s e d numb e r o f f i br i l s and storage cyto s ome s .. Note dense network o f. a st r ocytic f i b r o u s proce s s e s in the a djacent neuropi le. 4. 22. 44. P a r t o f a c e r e br a l c o rt i c a l neurone f rom a norm a l f u l l t e rm ovine f o e t u s ,. showing. r e sidual bodi e s c omposed o f a f i ne granu l a r mat r i x and an e l e c t r on-l u cent vacuole.. 44.

(15) xiv. L I S T OF TABLES. Fo l l owing Tab l e l.I. page C l in i c a l c l a s s i f i ca t i on of t h e neuronal cero i d - l i po f u s c i n os e s .. l.II. T i s su e s valuab l e. 5. in morph o l og i c a l d i a gno s i s. in t h e neurona l c e ro i d - l i po f u s cinose s .. 14. 2 . II I. L i s t o f a f f e c ted s h e e p u s e d in t h i s s tudy .. 23. 2. IV. L i s t o f norma l c ontrol sheep u s e d in t h i s study .. 3.I. Evolut i on of h i s t olog i cal changes accord ing to age in bra ins. of. s heep a f f e c ted wi t h. ceroid-l i po f u s c i n o s i s . 3. I I. 23. 29. Rela t i ve d i s t ri b u t i on and s eve r i ty o f l e s i ons in t h e s elected a r e a s of the cent ral nervous s y s tem o f 1 2 to 25 mont h s old s h eep a f f e c t e d wi t h c e r o i d­. 30. lipo f u s c i nos i s . 3.I I I. D i s t r ibut i on and evolut i on of Walle r i an type degene r a t i on in brains of. sheep. a f f e c ted with c e r oi d-l i po f u s cino s i s . 3 . IV. 30. Aut o f l uore s cence and h i s t o chemi cal rea c t i ons o f ne u r ona l pigment granu l e s i n sheep a f f e cted w i th c e r o i d - l i po f u s c i no s i s .. 3.V. 32. Autofluore s cence and h i s to c h emi cal r e a c t i ons of neu rona l p i gment granu l e s ( li po f u s c in) i n norma l. sheep .. 33.

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Here we describe production of ESCs from blastocysts obtained from a standard mouse strain in the absence of feeder cells or sera, with an emphasis on a laser-based ICM

A larger panel of allogeneic HLA-matched and - unmatched melanoma, glioma, breast and colorectal car- cinoma cells were used as targets in cytotoxicity assays. Four of the

The study compares the number of sickness absence days during the last 12 months and the impact of employment status, psychosocial work stress, self-rated health and demographics

Background: CEA, CYFRA21-1 and NSE are tumor markers used for monitoring the response to chemotherapy in advanced adenocarcinoma, squamous cell carcinoma and small-cell lung