Ovine ceroid lipofuscinosis : a thesis presented in partial fulfilment (70%) of the requirements for the degree of Master of Veterinary Science at Massey University

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(2) OVINE CEROID-LIPOFUSCINOSIS. A thesis presented in partial fulfilment of the requirements for the degree of Master of Veterinary Science at Massey University. Antonie Janrnaat. 1979. (70%).

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(4) ABSTRACT. Ov ine ceroid-l ipofu scino s i s i s a rare inh e ri ted neu rological di se a s e which ha s only been di agnosed in one fami l y of the South Hampsh i re breed o f sheep .. Th i s breed i s o f re la tive recent origin a nd was e s tab l i shed. from a n initia l cro s s between Sou thdcwn and Hampsh ire Down sheep .. Af fected. sheep show loss of vi s ion and behav iou ra l abnorma l i t i e s starting at 1 1 - 1 2 month s o f age , wi th motor dysfunc tion commenc ing soon a fterwa rds.. The. c l i n i c a l s i gns inc r e a s e in sever ity a s the d i s e a s e progre s s e s and unde r field con d i t ions a f fected anima l s are not expected to l ive b eyond 2 years .. Ovine ceroid-l ipo fu scino s i s i s cha racte ri zed h i s tologica l ly by the i ntracytopl a smic accumu la tion of PAS and Sudan b l ack po si tive autof luorescent l ipop igment ma te r i a l in neuron s and a wide variety of other c e l l type s .. The proce s s l eading to the accumu l a t ion o f l ipopigme n t. seems o n l y t o dama g e n eurons a nd there i s degenera tion a n d l o s s o f neurons , e specia l ly in the cerebra l cortex a nd the v i sua l neuroepi the l i um o f the re t ina i . e . retina l a trophy . reduc t i o n in s i z e a nd we i gh. Gro s s l y , a f fected bra ins show. on average 66% of those of norma l sheep .. U l t ra s tructura l l y , the typ ica l l ipop i gment inc l u s ion i s a round or ova l body 0 . 2 - 5 . 0 �m in s i ze , o f va rying e l ectron density, a wide �ariety of memb ranous profi l e s may b e seen .. in which. Some o f the. (. memb ranous patterns have rece ived spec i a l names such as curvi l i n e a r , finge rpr int a n d crysta l l o i d ..

(5) Pathological examinat ion of l i ver , skin and recta l biopsy mate r i a l o f l ambs a t 4. -. 5. mon ths o f age shows the pre sence o f ac cumul ated. l ipopigment , and i s a means of early d i agno s i s be fore the onse t o f c l i n i cal s i gn s .. Thi s obs e r va t i on and the fa c t that l ipopigment h a s be e n. demon s t ra ted in a f fe c t ed lambs a t bi rth , show ovine cero i d - l ipofu s c i no s i s to be a s soc iated w i th a true inborn e rror o f me taboli sm .. The fami ly tree o f a l l a f fe c ted sheep and the resul t s o f s i re­ daughte r mat ings of a hete rozygou s ram show the d i se a se to be inh e r i t e d a s a s impl e au to soma l rece s s ive tra i t .. The d e l e t e rious gene for ovi ne. c e roid-l ipofusc ino s i s i s u n l ike ly to b e of economic importance to the sheep industry a s the Sou t h Hampsh i re breed was developed to suppl y s i r e s for termina l cros se. s a s soc iated with table l amb produc t ion .. Th e obj e c t s of this study were to d e f i n e ov ine ceroid-l ipofu s c i no s i s i n c l inic a l , patholog i c a l a n d genetic te rms , and to compa re i t w i th s im i l a r d i se a s e s in man and dome s t i c a n ima l s .. I t is conc l uded that the. ov ine di sease doe s indeed be l ong to the hete rogeneou s g roup o f d i s e a s e s o f ma n and dome s t i c anima l s known a s Batten ' s d i s ease o r the neuron a l o r genera l i sed c ero i d - l ipo fu s c i no se s .. Of th e s e the ovine e n t i ty mo s t. c l o s e l y resembl e s the l a t e i n fant i l e and the j uvenile forms of the human synd rome , and the can ine disea se .. I t i s proposed that ovine c e ro i d -. l i po fu sc ino s i s woul d make a u s e fu l e xperimenta l mode l for Batten ' s d i s e a se ..

(6) ACKNOWL E DGEMENTS. This the s i s re f l ec t s a substantial part o f the rese arch I d id wh i l e employed as a Re sea rch O f f ic e r in the Depa rtment o f Ve te rina ry Patho logy and P ub l i c Hea l th a t rla s s ey Un iver s i ty ove r a per iod of 3 yea rs . I am g ra te fu l to Prof . B . W . Manktelow , as Head o f Depa r tmen t , and to Dr R . D . Jo l l y ,. as leader o f th e r e s earch team , f i r s t l y for a l lowing me. to u s e the r e s e arch find i n g s i n th i s the s i s and second l y for the pert i nent advi c e , pa r t i cu l a r l y Dr Jo l l y ' s , pro ffered in the i r r ol e s a s supervi sor in i t s prepa ra t ion .. A number o f peop l e gave pro f e s s ional. advic e an d technical a s s i s t a nce du ring th e course o f my s tudy i nto ovine c e r o i d - l ipofusc inos i s .. Mr. D.M . We s t gave generou s l y o f h i s time w i th the c l i n i c a l. exam i na t i on o f the anima l s a n d supervised the an a e s thet ic , surg ical and po s t-operat ive procedures i nvolved in the taking o f sk i n , l iver and r e c ta l biops i e s .. He a l so suppl i e d the norma l retinograph. fi gure 2 . 3 as a contro l . haemogram e st imation s .. u se d in. Dr R . H . Sutton and h i s s t a f f performed the Ms . K . C a to took the radiog raph s wh ich we re. inte rpreted b y Dr M. O ' Ca l l agha n .. Prepa r a t ion o f t i s su e s for l ight and f luore scent mic ro scopy was c a r r i ed out by Mr C. Fletche r , Mr R . P . Han sen , Ms . S . L . Ma l l och a nd Mr s P . M . S l a c k . coope rat ion .. I thank them for the i r cheerful and f r i endly. Mr A.S. C ra ig and Mr D . Hopcroft o f the Departmen t o f. S c i e n ti f i c a n d Indu s t r i a l Research gave very helpfu l a dvice on the preparation of t i s sues for e le c t ronmicro scopy and printed the e l ec t ronmic rograph s .. M r T. Law mos t obl igingly prin te d the o th e r.

(7) photographs used i n th i s the s i s .. I am i n debted to Mrs E . Br i s tol. and Al i s o n for typi n g the f i r s t draft of the manu script , and to Mr s F . S . Wicherts for typ i ng the f i na l copy .. Fina l l y ,. I wou ld l ike to thank the farm and hosp i t a l techn i c a l. s taff for the ir care o f and i n terest i n the anima l s , and espec i a l l y Mr. A . T . DeCl eene for hi s cheerful and knowl edgeable a s s i s tance w i th. the handl i n g o f the sheep i n the f i e l d , hosp ital and post-mortem room .. The research pro j ec t i n which I was i nvolved w a s supporte d by the U n i t e d S tates Na tion a l In s t i tutes o f Health Gra n t No . RO l NS 1 1 2 3 8 - 0 4 and 5 from the National I n s t i tute of Neuro logic a l Di sord ers and S troke ..

(8) TABLE OF C O NT E NTS. Page LIST OF TABLES. LIST OF FIGURES. INTRODUCTION. 1. CHAPTE R I :. Review - the neurona l ceroid - l ipofu s c i nose s .. CHAPTER I I :. C l inica l f indings .. 43. CHAPTE R I I I :. Pathology .. 63. CHAPTER IV :. Genetic s .. 104. Ge ne r a l d i sc u s s ion .. 109. C HAPTER. V:. REFERENCES. 2. 115.

(9) LIST. OF. TABL E S. Table. Page. l. I. Cl a s s i f icat ion o f the neuronal c e roid -l ipofu sc ino s e s .. 2.I. C a s e h i s tories of Sou th H ampshire sheep af fected with c ero i d - l ipofu sc i no s i s.. 3.I. 64. Di stribut ion o f l ipop i gment i n ceroid - l ipo fu s c i nos i s o f sheep over 1 2 mon ths o f age .. 4.I. 46. L i s t o f South Hamp s h i r e s heep wi th ceroid­ l ipofu s c i no s i s that we r e examined pathologic a l ly .. 3. II. 9. 71. Re su l t s o f s i re -daughter ma t ings of a South H ampshire ram hetero zygous for c eroid- l ipo fu sc i no s i s .. 107.

(10) LIST. OF. FIGURES. Figu re. 2.1. Page. South Hampshire ram , 2 4 months of age ,. 52. a f fected w i th c e roid-l ipo fu s c i nosi s .. 2.2. Graham-Knol l techn iqu e to d emon strate perox ida s e act ivity i n sheep neutroph i l s.. A part i a l ly reacted. a nd a comp l ete l y reacted c e l l a re shown .. 2.3. 55. Retinog raphs o f the ovi ne eye showing attenuat ion and stra ighten i ng o f retina l ve s s e l s in an a f fected 2 4 months old ram , when compa red to a control sheep .. 3.1. 57. Dor s a l v i ew o f bra ins f rom two 1 3 months old ewe hoggets .. The b ra in o f the a f fected sheep i s reduced. in s i ze and shows thinning o f the c e rebral gyri .. The. b ra i n we ight of the a f fe c ted animal is 5 7 . 2 g , compa red with 8 6 . 2 g for the norm a l control she ep .. 3.2. 67. Late ral v iew o f brains f rom two 1 3 months o l d ewe hoggets .. The ce rebrum o f the a f fe cted an ima l shows. reduct ion in s i ze , th i nn i ng of the ce rebra l gyr i and a s l i ght dor so-ventra l f lattening , when compared with the b ra i n o f the normal control sheep .. 68.

(11) Page. Figure. 3. 3. Transverse s e c t ion o f the cerebrum of an a f fected 1 3 month s old ewe hogget and of an age and sex­ matched control she ep .. No te r educ ed size o f c e rebrum ,. ma rked thi n n ing o f cortex, th i nning o f corpus callosum and sepb� pellucidum and e n l a rgement of late r a l vent r i c l e s i n the a f f e c t e d sheep .. 3.4. 69. Cerebral cortex of a 1 5 month s o l d South Hampshi re ewe hogget wi th ce ro i d - l ipofu scinosis showing neuron s l aden with l ipop i gme n t granul es .. 3.5. 73. Tha lamus o f a 2 5 mon ths o l d a f fected ram. Lipopigment granu l e s s ta i n bl ack and in some neurons appe a r to almo st compl e t e l y f i l l the cytopla sm .. 3.6. 73. Cerebra l co rtex of a 2 5 mon ths o l d a f fe cted ram . The whi te s t ruc ture s are a u tofluore scent l ipopigme n t granul e s , s i n g l e o r in cluste r s .. 3 .7. 75. Cerebel l a r cortex o f a 2 5 months old affected ram .. Inclu s ion s in a Purk i n j e ce l l are nume rous. and show va riation in s i ze .. 75.

(12) Page. F i gure. 3. 8. Cerebral cort e x o f a 2 5 month s old ram with c ero i d - l ipofusc inosi s , show ing a neuron surrounded by an increased number of gl i al c e l l s .. Astrocyte s. predominate and may show unusu a l l y shaped nuc l e i.. 3.9. Cerebra l cor t i c e s of two approx imat e l y old South Hampsh ire ewe hogge t s .. 15. 77. mon ths. The affected. an imal shows an incre ase in number and size of a s trocyte s , compare d to the control sheep .. 3 . 10. 77. The h i s tology of the re t i na o f a n 18 months old South Hampsh i re ewe w i th ceroi d -lipo fuscinos i s , compared w i th that o f a norma l sheep .. The a f fected. an ima l shows severe atrophy o f the l ayer o f rod s '. a nd cone s and the outer nuc l e a r l ayer .. The re t i n a l. p igment ep i the l ium , i nner nucl ear l ayer and gangl ion cel l l ayer appear normal .. 3 . 11. Lymphocyte s from a 25 months o l d a f fected ram . Note absence o f l ymphocytic vacuolat ion .. 3 . 12. 78. 84. Re sidual body i n cort i c a l n euron showing l obul ated shape .. 84.

(13) Page. Figur e. 3 . 13. Storage material appare ntly free in the cytoplasm o f a men inge al cap i l lary endothelial c ell .. Shor t. arrow po ints t o a five - l ayered membrane , wh ich a t long a rrow seems to b e formed b y the fu sion o f 85. two tr iparti te membrane s .. 3 . 14. Part o f l i popigment body i n ret in al neuron showing granu l a r matrix of vary ing e l ec t ron density , and five - l ayered membrane s .. The arrow ind i cate s a 85. mye l i n pattern .. 3 . 15. P a r t o f res i dual body i n a ventral horn neuron showing stacks of alte rna t ing dense and l ight l ine s , with a period i c i ty of approx ima te ly 5 . 2nm .. 3 . 16. Panc rea t i c acinar c e l l w i th curv i l i near inc lus ion bod i e s .. 3.17. The cellula r a rch i tecture appears no rma l .. 88. Storage body w i thin a c e reb r a l c o r t i c a l neuron showing membranous pro f i l e s and tubu l ar a rray s .. 3.19. 87. I nclu s i on i n c e rebral cor t i c a l n euron showing f i n gerprint and c rysta lloid pattern s .. 3.18. 87. 88. Part o f ventral horn neuron o f lumbar cord showing a l a rge numb e r o f inc l u s ion s .. The c ytop l a sm shows. spa r s ity of norma l organe l l e s .. 89.

(14) F i gure. 3 . 20. Page. Membranous inclus ion body in c e l l a t the cort ico­ medu l l ary j unction of the adrenal g l and .. 3 . 21. 89. Membranous inc l u s ion in a thick bun d l e of a s trocyte fibre s in the cerebra l cortex of a 25 months old ram with ceroi d-l ipo fuscino s i s .. 3 . 22. 91. Pancre a t i c ac inar c e l l showing two type s of residua l bodi e s .. A curv i l inear body typical for. ovine ceroid-l ipo fu s c ino s i s , and a granul ar , more e l ec tron den se , body wh i ch may a l so be seen in norma l sheep .. 3 . 23. 91. Lymphoid fo l l ic l e in rec ta l wa l l of a 5 months old ewe l amb .. Ma cropha g e s cont a i n nuc lear remnants. a nd l ipopigment inc l u s i on s. 3 . 24. 94. .. Ultra s truc tural deta i l o f part o f m a crophage showing typic a l curvi l i near bod ie s .. Thi n sec tion. obtained from s ame t i ssue a s shown in figure 3 . 2 3 .. 3 . 25. 94. Granular electron dense inclusion in a m acrophage in the rectal wall of a 5 months old normal lamb. These inclusions are encountered in both normal and affected sheep, and carry no significance in the diagnosis of ovine ceroid-lipofuscinosis.. 95.

(15) Page. Fi gure. 3 . 24. Autofluore scent ma t e r i a l ou t l i n e s the sweat g l a nds i n the sk i n of a 25 months o l d ram affected w i th ceroid-l i pofusc ino s i s .. Before the on set of c l i n i ca l. s i gn s , th i s autofl uore scence i s a l re a dy pre sent i n affected l amb s a t 4. 4.1.. -. 5 months o f a ge .. Fam i l y tree of affected i n d i vi dua l s .. 95. On ly ma t i n g s. o f heterozygot e s a n d othe r pertinent i ndividua l s a re shown .. 106.

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Figure 3. 3 Transverse section of the cerebrum of an affected

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Figure 3 . 13

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