A family of familial hypercholesterolemia with cerebral infarction and without coronary heart disease

1( )

Oou,n,d of the ,Veuroh~gt~'al ,Scwn~'e~. I0~ ( I t~91) 111 18 c" ITS91[-Iscvicr Scicncc I"ublishcrs B.V. All rights reserved 0022-510X/91/$1)3.51)

,INS {1~t3,.',3

A family of familial hypercholesterolemia with cerebral infarction and without coronary heart disease An unusual case with corneal opacity, polyneuropathy and carpal tunnel syndrome in the family: therapy with probucol and tocopherol nicotinate Yuctsu Ihara ~, Kcigo Nobukuni ~, Rciko Namba ~, Ken Kamisaka ~, Masayoshi Kibata : Kouji Kajinami ~ Hajime Fujita 3 Hiroshi Mabuchi ~, Teruo Shirabc 4. Koh-Ichi Ohshima 5, Akitane Mori ~' and Hajimc Kodama 7 ' IhTmlttm'nt ~)I ,'Veurologv and -' l)~Tmrtment ~f Internal ,'~h'dicme, Natumal ,'~linamtokayama Ito,vntal, 40hh ltava~htma-cho, li~ukuho-gun. ol~awtma 7#l-IO.¢ ¢JapatH, ¢ Sc~ oml Delmrtment of hm'rm*l :lh'dicme, Kana:_awa Uniter~it.v 3fi'dwal School. 13-1, "l'akara-mmht, Kanazawa O20 I.lapun~, 4 IhT~artmcnt
(Rccci,,cd 31 ,lanuat3. 19c~1) (Revised. received 2(),lun¢. I~)t)l ) (Accepted 3 Jtdy. 1~91) Key w o r d w Familial hypcrcholcstcrolemi,'~; Cerebral infarction" Polynet.ropath~: ('orncal opacity: l,ipid peroxide" Free radical;

Monocytc: Ptobucol Summan'

A study is presented of a 48-year-old female patient and her three siblings w,ilh familial hypercholcstemlcmia. The family members had cpisodcs of cerebral infarction and vpparcntly had alherosclerosis of the intcrnal carotid artery, but no coronary heart disease dllc 1o their almost normal level of cholcsterol. "]'hc laboratory studies of the family members revealed the elevations ~1 sernnl lipid peroxides, serum lipoprotein(a), Icukotriene (",~ in blood, the thromboxane B,/b-kcto-prostaglandin FI, ' ratio in plasma and serum hydroxyl radical. Thcrcfore, it is suspected that these factors acccler:,ting athemsclerotic process Catlsed the cercbral infarction. The patient demonstrated corneal opacities, palpebral xanthomas, thickened Achillcs tendons, polyncuropathy and the carpal tunnel syndromc, l,aboratory studies revealed an elevation in the O K T 4 / 8 ratio, monocytc dysfunction with respect to phagocytosis and chemotaxis, and thc prcscncc of the 4 6 X X / 4 5 X O mosaic chromosome, l,ipid deposits wcrc obscn, ed in the Achilles tendon, the transverse carpal ligamcnt, the Schwann's cells and axons of the sural nerve. and in the kcratocytes and stroma of the cornea. Following the administration of tocopherol nicotinatc and probucol, the patient's serum lipid pcroxidc normalizcd and there was improvement in her palpebral xanthomas, thickcning of the Achilles tendons and polyncuropathy. We conclude thal the lipid deposits in this patient wcre due to the abnormal oxidative metabolism of hr,v-dcnsity lipoprotein and a disturbance of the scavenger pathway due tO the monocyte dysft, nction.

Introduction f o a m cells loaded with cholesterol-esters are a recognized [cature of thc atherosclerotic placque. The major precursor of foam cells which is present in fatty streak lesions is the macrophage which originates in

U , , r e v u m d r m r to: l)r. Y. Ihara, M.D.. Department of Neurology, Nalicmal Minami~kayama t]ospilal. 4()6~. Hayashima-cho. Isukubt~-gtHL (.)kayama 701-(13, ,Japan. Tel.: (0864) 82-1121; Fax: (0N64) b;2-3SN.'~.

the monoeytc (Tsukada ct al. 1086). It is therefore important to determine how cholesterol-esters are stored in the macrophages. Although patients with familial hypercholesterolemia (FFI)show a decrease in low-density lipoprotein ( I D L ) receptor activity, they display severe atherosclerosis with foam cells in fatty streak lesions. Because the macrophage has only a small number of LDI, receptors, native LDL does not transform the macrophages into foam cells. I! is thus concluded that macrophages take in cholesterol-ester not by the LDL receptor for native LDL but rather by

II rABLI.: I BL.()(.)D LIPII)S OF 4 FAMILY MEMBERS Patient l.ipid peroxides (2-4 mmol/ml) Leukotriene C4( < 0.90 ng/ml) TXB2/6-keto-PGF~,, ratio ( 1.06 .+_0.44) Cholestcrol (130-220 mg/dl) IIDL-cholcsterol (35-75 mg/dl) Triglyceride (34-150 mg/dl) Lil~)protein(a) ( < 25 mg/dl)

f)lder sister

Older brothe~

9.66 4.75 4.71

'r t~ulv,el ,,iMcl

t).9() tL71)

4 (12 ,,,~4 ,, ":,6

3.21

174

222

35 II11 36.5

~

I~,'1

__4

53

5t

<~)

109

128

~{'

29.5

TABLE 2

t h e s c a v c n g e r r e c e p t o r for m o d i f i e d L D L . In 1983, Brown and Goldstein reported that macrophages c h a n g e i n t o f o a m cells by acetyl L D L ( B r o w n a n d G o l d s t e i n 1983). In 1990, t h e c o n s t r u c t i o n o f t h e acetyl L D L r e c e p t o r was d e f i n e d ( K o d a m a et al. 1990). C u r rently, o x i d a t i v e L D L is v i e w e d as m o d i f i e d L D L ( S t e i n b r e c h e r et al. 1984; Y o k o d e et al. 1988). Recently, we consulted on a female with FH who displayed corneal opacities, palpebral xanthomas, thickened Achilles tendons, polyneuropathy and the carpal tunnel syndrome. Lipid deposits were recogn i z e d in t h e c o r n e a , p e r i p h e r a l n e r v e , t r a n s v e r s e c a r p a l l i g a m e n t as well as t h e A c h i l l e s t e n d o n s . T h e lipid d e p o s i t s w e r e b e l i e v e d to b e d u e to a d i s t u r b a n c e in t h e m e t a b o l i s m o f o x i d i z e d L D L d u e to a d y s f u n c t i o n of t h e s c a v e n g e r p a t h w a y in m o n o c y t e derived macrophages. On the other hand, the patient's family m e m b e r s s h o w e d f i n d i n g s o f F H . H o w e v e r , t h e s e indiv i d u a l s s h o w e d n o e v i d e n c e for c o r o n a r y h e a r t d i s e a s e d u e to an a l m o s t n o r m a l s e r u m c h o l e s t e r o l level. T h e y cxperienced frequent episodes of cerebral infarctions p r e s u m a b l y d u e to f a c t o r s a c c e l e r a t i n g t h e a t h e r o s c l e rotic p r o c e s s o t h e r t h a n e l e v a t e d c h o l e s t e r o l . T h e results o f o u r s t u d y o f this p a t i e n t a n d h e r 3 siblings a r e

I D L RECEPTOR Af'TIVITY OF PAq'IIi.N1 (FIBROBLAST) . . . . . . . . . . . . . . . . . . . . . . .

Binding

Internalization

1)egradation

Patient Cbntrol Patient Contr~)l Patient Control Total Non-specific Specific Activity (%)

58 13 45 43

130 25 105

835 '91 744 711

I. I {)4 1115 I,II5q

3,972 277 ~i,6t)5 50

• Bmdmg: receptor-bound 12':' I-I.DL (ng/mg ot cell protein1. Intermdization: internalized I:SI-LDL (ng/mg of cell protein). Ikegradati()n: degraded t2Sl-LDL (ng/6 h/rag of cell protein1.

reported here.

Case report The history of this 48-year-old female revealed that she had experienced visual disturbances, and demonstrated corneal opacities at the age of 8 years. Although corneal transplantation was performed, her cornea again became opaque. At age 39 she demonstrated palpebral xanthomas, and at age 43 mu~ular weakness and

atrophy. At age 45 she showed sensory disturbance and was admitted at that time to our hospital. Physical examination revealed a short woman (151 cm) who weighed 52 kg. She evidenced muscular weakness and atrophy in all four limbs and a sensory disturbance of the extremities and thc face. The Achilles tendons were thickened. Other findings included palpebral xanthomas, visual disturbance and corneal opacities. A gait disturbance (steppage gait) was observed. Serum cholesterol was normal (174 mg/dl) on admi~ion. Her laboratory studies revealed an elevation in serum lipid peroxides (9.66 mmol/ml; normal, 2-4 mmol/ml), leukotriene C 4 in blood (4.75 ng/ml; normal, < (}.9(I ng/ml), the thromboxane B 2 to 6-keto-pr(rstaglandin Fi,, rati~ (TXB 2/6-keto-PGF I,, ratio, 4.71; normal, 1.06 4.: 0.44), serum lipoprotein(a) (36.5 mg/dl; normal, < 25 mg/dl) (Table I). The isoform of apolipoprotein E was 3/2. LDL receptor activity was reduced in the patient as compared to controls (binding 43%, intcrnalization 70%, degradation 50%) (Table 2). Southern blot analysis of the LDL receptor gene revealed no abnormality. The free radical and superoxide dismutase (SOD) were measured by electron spin resonance (Janzen et al. 1985). The hydroxyl radical (2.75 spins: normal, 2.06 + 0.52 spins) and SOD (8.27 unit/ml; normal, 4.70 ± 3.53 unit/ml) were increased (Table 3). Protein C, protein S and lupus

TABLE 3 FREE RADICALS AND SOD IN SERA OF 4 FAMILY MEMBERS " Peroxyl radical ltydroxyl radical SOD

7.;gHI 461 7,34 tl

Patient

Older sister

Older brother

2.86 2.75 8.27

1.76 2.86 1.44

2.20 1.98 1.68

Younger sister 2.20 3.95 3.55

Control (mean ± 2 SD) 2.01 +_ 1.34 spins 2.1)6 +_0.52 spins 4.70 .~ 3.53 unit/ml

12 ;It+tict~;i~ttl~Itlt \+.ctu llt+ri'llltl C)KI4 (('~().3",:: IIOl'rll~l]. 25 ~'('/,') '.~,il', u+n.'lu:t',ud. ( ) K I , " ; (12 n ' , : n~+rn~:d. 17.44~.; ) ,.',u,, dL.cru:~sud. :rod the.. ( ) l ~ l 4 <~ ILlli() (4.7~): nt~rnlal+ I).(~ 2.9} w~ts incr,..,:i~.¢,.i. "rhu mt,,~t,q~t~. chcln(+t+lctiu I'Cn[)(Hl~,l. ' \~.,ln m~_'itsuru'd ill ~itn+ by l]o~,d~_'n's n+illipor~_' tl.'chnlqt]~-" tl~,Jlll~ /~,llltllHII-ilCli\~llUd htlnl~lll ~,,.-'I+U111 il'~ 111~.' ch(?llltl(ittr:i,.htnl (l'h+~,,+Ici+ It~(+)Z) h ',+.:i~. t c d u u c d in t h e F)~diu'nl (2tJ.3)cou+r0 • l+:it~..~.l It+ ,+.~+++t0t)ls (~5.1) • ~.:~). lh,.: a b i l i t y (+I' th,,.' rr0('mt~,,,,..' ut)r++l'~l~_'u++cnt-l'ixit+~ l~lllttS~lll ~.~.ils al',t', r~.'dt£¢.'u'd in t h e l+,uti~.+nt (.~4) c(+Unl'~+r,._'d It+ ,.'tmtrtdx (.+3.7 J 7.4). .%cuurn cl+H+l,+.',,tuI~(d (I. ~) i.+.,_,, r+tl), lh,.+' ,.crunl uh~d¢:-,tant+l ,.'lltd,..',.tcrol ralio ( [ ) . I ' ; : nt+inl~d. U.~,', ) ~tlld /~-slh+,,tur~+r ( I ( ) ,u~ 1111: nt)rrnul. • 17.() ,ug rnl) v+,,.'ru nt~rr~M .\n:tl~,,q-, t+t" l+ilu +Lcid': in h],.t(+d rc'..culcd n,.t al',nt)rm~dh).. %+...itli11 Ic,,ul,, t+l ,.,,._'IcniUln. l'~[i~.t~llli[." acid. sphirlg(mlyu.lirl l~lll3 :it.+i,.l. luuitii~ ,uht4,.',,tcrol uuyltr~tnqu'im, c +rod Ivt, ot.,on]al un2').rn,,. +,, ,,,.u.ru :ill III)IIII~IL J]1~.' p~llJ,+.'llt", l~,nl]+>h~t+c+vlc ,._'hronlost+nlu. ,,[1~Y,~.~_'d il ~.I+X\ • 4:~X() tltt~'.,uic. %'hilt :lll tdI~oclonal I~(i I+i~t+++.] ,,+,a:< l,,_',+.'t+L,~niz,.',,I in h,.:I '.'L'IUI'ut)',I"iI+~II fluid ( ( ' F d L bur l'trolcin, l+..t(i :~i~,.I o...'II counts '++.~_'Ik' llt+l'/11JI+ I'h,._uu' %~,~1'~ il tJu'liI~, ill 111()tor 11',-+1%,..' Ct111dllCliOn ",,..'h)cit~, ( ~ | ( ' \ . ' ) (riphl i+nu,.]ian ncF,.c'..".~,.I) nl/n¢c" lu'tt i.iln~H ruu+~.u. IJ.() 111 ~u.c) +ind ~,,+_+n,,t+r~ i+,.:r',,,." c(+tl,.ItnctiOll v¢l(+cil+', (.%('%") (l,+_qt 111c~.Jiiln n,+++r',u I(++5 n+ ~,,+..c:lu.lt ulnar nu+i~,u", 17.+~ tll/:-,cc), l:lihtt,._+rul lllickunii1~ ol th,.' ..\L'hiil,...'s lcl1+.h'tl1~ ".~,.~l~, ~d',,,cl~'ud on x-ray ,..'X~llllill~lli+.+ll (t'i+~ht 11) Inrn. lull I I urn+hi. St,..'n,~+si:.+ t+1" the irutcrnal cart)lid ;~rt~.'t> dtnu h+ :utl'~,..u~t'.,,.'lclt+,,it, v+a,. ,.lulllt+llstF~ilct.I on ccrcl'~l'al itllgio~+-trill)h~,. T]1¢ I ( "( i. t.il{Ci hl:un ("1 :tr+,.I I',rain ,MR] ,,vcru. all n(+rrnal+ I$iop',,.', ,;l~¢cim,.:ns ~ht:0incd lrt~u'n Ihu' ,\chillu's tcl+d~n disclosud lipid dcposils (()il rud ()

,,t~till) t)ll light nlicrt+,,C~)l+~ic CXililli11111lOll ;tllLI th,,." I')rL",,._'II~.+L' t'~J chol,.-',,t,..'ut)l cry,,hd,, (Fi~. I...\) ~II+~.<.Ixunthort~t o._']I', (l'i~. II'~) ,.m ,.'l,.',.'Iz(+n llliCl.t)~.++..,tlr~iL, ,._,X~llllill~l|iOl1+ |Ii,..,~..._ • l+u(+l+~,.}. ~.11+..'.,.'i111',.'n'~ t.]u'llll~llnll';llu'i.I HI+ iTlcr,..'a",c in chc, l~.",tL'r',+] C~ICl ( I I~34._+ /.z .,.:' I()() rn~ ~.'I li,.,,,uu') m1,.l Ir~.',.' ,.:hol,+..,,lt.'r~)l (]()~').I /.£.~.' II~(! m.u w,..t lin,,uu): uhtd<.',,hlnt+l ,..ouk.l nt+t hu d,...l,.:,.'tud+ .%ur~d rv,.'u",u' l',iop,,y ,,l',.'cin1,..r+,, ,.li',c],.~:,.,.-',.l ~i ,.l,..'c'r,.:a:,,.: in th,..' nllnll'~u'l o l nl~,u'litliitu'd l'ihcl,, (3(~()2 m m ' l . F+ru,.h)min;mtl), ' m th,.' lur~u' rtlt, u'lii~:~lu'd lihu.r,,. [.ipid ,.~tcuol,..',, ,.',ur,.. rco.+~nb.'u,,l 01] lhu" :~xt)n,, :rod S,,;h'.,,,ui~n's uull>, t)l 111+.."nLtz;il I1uU~.U (l'i.~. 2). Mu~,l t)l I11~.' lipid ".:l++.'Ht)I'.. TM had ;I 111c111III(I11+,. '+ ]]I(+11~, ~' Xllt-'Cill1¢llh ln+nl the." 11~llJL'lll'n Cl11"lIt':l ",ho~.+,l-'~.1 JJllld X,ilCll(lJL "~, JLIgkilli~ ~l 111~.'lllbr~lllt' I11 lhc :ixi,)llS oI ri~ydirmlcd lil',cn,, II:i~. J,L ( ~+inc:d ku.l:~locylc', h~v.l ]il'~k.l ~di~.'u,.~l++:~. ',,.0lh :i rn,..'i+~d'~rui~u ~ti~.l highlt, t.l,+..n,,,., ho,.lict, (Fi..~. 4k Th,+:,+u hi.~hlt, d,+_u~-.,: l',odics ,,ho'.,.u'd ~ dark,+_'u ,.'unl0ul ,iic:l ,ti~ioundu+.l I',). :i li~hlcl :II'~-NI+ ;\n t+~111~.)pJlilic ~.IL'Ft<~)NJ| %~+~IS IL'CI+L'IlJ/~.'LI ill lhL + 'slrt)llILi (~I lJIc C~+IIII.'LI (J-'i~2. 5). ']hc hOllC 111;IrIo~. +, [lioJl',\ ~.~.il:., 11<.+iiiIi11. .\t thu ut2u o l .|~+. lhL' l'~atiClll ',',4". ru~idlllill,..'t.l li+r t,)lT11+~lt)lll '+, t)l hiliutuu'id carpal Iti1111,..'I ~11dI1.)111,,_'. Lllld dcutm~l)ru's~,i',',.' ~,urgu'rt, ~it', p,.uh)rrn,,+,,l ,.;n lhu. h..ll l+~nd, l h u I~..II mu,.li~u+ n~.'rv,... ',+,:i~. ctm11"~ru',SL",l h', :i t h i c k e n e d tr:ti],.',.crs,,: L'ilrl'~;II li,~m~unl, l]iol'~,t, :-,l'~ccir~cn,. t+l thi~, li~uri~cnt disl',la.,,u.d lipid ,.]cl~tr-,il,, (()il lud () ',hun)t~n li,~ht rnicr,ascopic cx:~rnin;~ti,.',i~, m;~cr,,)ph;~gc>, v, ith ]iF, id ~-':lCtlt.~JL'>, illld highl~, ~.Juul,,,..' ['+Odl¢,~ t)ll u'h.:t.'Iru~ll rnicro:..,Ct+l+~i,. • ~_'~.Lllllir1Ltlit~ll (Fig. ~,). Nt~ ~I111~l,.',i,.l dL'l~'.+:'.il:, WL'rc ,.d','<¢rv,..',.l ,~I1C ~,%iI~ gi'+L'll [+tilt) 111g "dH~+' ~.+l t'.+,.:t)l'~h'+.'ltd I11C,alil1:du ~llt.l II)IH) n ~ d~t~ ol i~u'ot~uct)l h+r ?,2 i~]()uth~, l.t+lh)~ in~ tlli~, m c d i c u t i o n , ncrum

FiL~. I. (,A) ,'\¢hilI¢~, l,..'zl,.Jon ol l~Jti,..'ni. ('h,,~1¢stcrol

cL3.r,,lab, ar,..' :Jppar,,.ult.

× .~[)I)().

!3 lipid pcroxidc (3.113 mmol/ml) and the plasma TXB, ./t~-keto-P(ifh. ~ati~ (I.51 normalized, and the level tff lipoprotein(a) (27.3 nlg/dl) v,as decreased. However, the serum cholesterol level remained at 2111 mg/dl. Other signs and symptoms were improved including the palpcbral xanthoma" the thickening of the Achilles tendons (right. 7.5 ram: left, 9.1) ram): muscular weakness: gait disturbance: M('V (right median nerve. 37.8 m/see: left ulnar nerve. 16.5 m/see).

Patient's family history An investigation of this patient's family history revealed that her g r a n d m o t h e r s were sisters, and that 10 of her 12 blood relatives had died of ccrebral infarction. T h e age of onset of the infarct was in the range of 42-61 years. T h e y frequently showed m o t o r a n d / o r sensory aphasia. T h e r e was no known history of coronary heart disease, diabetes mellitus or hypertension. Corneal opacity, polyneuropathy, x a n t h o m a and carpal tunnel syndrome were not recognized except for the patient.

Wc wcrc able to examine three ol the patient's siblings: an older sister (age 591, older brother (age 53). and y o u n g e r sister (age 40) (Tables 1 and 3). Scrum lipid peroxides were increased in ~hc brother (6.t.1() m m o l / m l ) and y o u n g e r sister (4.02 m m o l / m l ) . I.'1"('~ in blood was also increased in thc brother (().70 n g / m l ) and the younger sister (6.94 n g / m l ) . Also the T X B : / 6 - k e t o - P G I ' I , ' ratio in plasma was increased in both the b r o t h c r (3.21) and the y o u n g e r sister (6.56). The serum cholesterol was slightb, increased in the oldcr sistcr (222 m g / d l ) and the brother (224 m g / d l ) , but was normal in the y o u n g e r sister (169 m g / d l ) . I.ipoprotein(a) (29.5 m g / d l ) increased slightly and the isoform of apolipoprotein E was 3/'2 in the brother. The scrum hydroxyl radical was increased in the older sistcr (2.86 spins) and the y o u n g e r sister (3.t,~5 spins). Serum peroxyl radical, serum S O D , lymphocyte chromosome, MCV, SCV, results of immunological and x-ray examination of the Achilles tendons wcrc normal in thc 3 siblings.

Fig. 1. (B) Achilles tendon. Lipid vacuoles without membrane in the macrophages The surrounding area of the hpid vacuole h~, p ~tmlb osmophilic. × 3(XX).

14 Discussion

L,! ~ Patient's ./Wnih' l?,ccausc of the lrcqucnt episodes of aphasia, we infer that ccrcbral ischcmia in the family members affected rm, inly thc cerebral cortical artery. Cerebral angiography revealed athcrosclcrosis of ttlc inlcrnal carotid artery. Several infarctions in the family werc likely caused by athcrosclerosis of the inturnal carotid arlcry. I.ct us consider thc risk factors for alhcrosclcrosis in the family. (;cnurally. in Ftt the serum cholcstcrol is incrcascd I(5 ;.lbotlI 3(1() nlg/dl in the hcterozygous and t(5 about 70(I m g / d l in thu homozygous individuals. Ncarl.v all those with FII develop coronary heart disease (Mabt, chi c t a l . 1986). Rcccntly. a milder type of FH has been reported ill which there was a milder clcvalion of serum cholesterol a n d ~1 slow progression of coronary athcrosclcrosis as compared to typical FH (Kajinami ct a[. Iq,'.;9). II is thus suspccted that the family in our stud\ has Ftt. although none of the members showed

corona~' hear! disease, attributud to thuir virtually normal cholesterol level. Thu four mcmhers of the family uvaluatcd in our study showed an inurcasu in ',crunl lipid peroxides. Lipkt puroxidcs injure the ~asuular upithuliunl and acucluratc the athurosclurotic proucss (Yagi u! al. 1081 ). ()n thu other hand, lipid puroxidus exist mainly in L[)I, in blood (Hagihara c t a l . 1084). It is thus suspected that oxidativu LDI, inuruascd in the family, ltowuvcr. oxidativu I.I)L buhm, thu epithelial culls of the blood vussuls would bc more important for foam cull formation than oxidative I,D[, in bl(~od, since thu latter is cleared by lhc liver (Sluinhrcchur cl al. 19~7). On lhc other hand. the macrophagcs that pllagocytosc oxidative I D L secrctu lJl'(" 4, whurcas those that phagocytizu lhc modified LDI, other than oxidative LDi, do not secrete I/1"('~ (Yokodc ct al. 108~,). Therefore. the finding of an inurcascd 1,1('+ supports the view. that the macrophagcs phagocytosc oxidative LI)I_ helot' the epithelial cull in the family. The scrt,m hydroxyl radicul was increased in the

Fig. 2. Sural ilcr'..¢. M a l l } IJpJd vacuoles arc shown in the Sch'~ann's cells and a'.,ons. Most ol them have a mumhran¢. × 7(H)IL

15 family mcmbers, Free radicals injure the vascular epithelium, produce lipid peroxides (oxidative LDL) and accelerate the atherosclerotic process. In general, the tormation of oxidative LDL is mainly caused by superoxide because the oxidation of LDL is disturbed by SOD (Heinecke ct al. 1986). However, the hydroxyl radical can produce oxidative LDL because the reaction of the hydroxyl radical is high (Samuni et al. 1981). We believe that free radicals are involved in atherosclcrosis and the increase in the lipid peroxides (oxidative LDL) in the family. An increase in the level of LTCa and the T X B , / 6 keto-PGFL, ratio accelerates the penetration and contraction of blood vessels, the coagulation of thrombocytes, and thus the development of atherosclerosis (Mclntyre et al. 1986; Cryglewski et al. 1986). Lipoprotein(a), which is a risk factor for atherosclerosis (Berg 1963), is increased more remarkably in patients with a cerebral cortical infarction than in patients with a cerebral perforativc infarction. Therefore, lipoprotein(a) is a more important risk factor for cerebral cortical infarction (Murai et al. 1986). (.'ere-

bral infarcts in the family mainly involved the cerebral cortical artery. Therefore, lipoprotein(a) is involved in cerebral infarction in the family. Consequently, free radicals, lipid peroxides (oxidative LDL), LTC~, TXB2/6-keto-PGI'~, ratio and lipoprotein(a) are all involved in cerebral infarction in the family. It should be noted, however, that we need to determine why these risk factors caused cerebral infarction but not coronary heart disease.

(B) The patient While the patient's palpebral xanthomas and thickened Achilles tendons were clearly due to FH, the carpal tunnel syndrome, polyneuropathy and corneal opacities exhibited in this case were not previously recognized in FH. We do not think that the factors which accelerate the atherosclerotic process caused these symptoms, because they were absent in her brother and sister with the same risk factors. On the other hand. the patient showed monocytc dysfunction, an increase in the O K T 4 / 8 ratio and in serum SOD. and the presence of the 4 6 X X / 4 5 X O mosaic chromo-

Fig. 3. Corneal myelinated fiber. Lipid vacuoles without a membrane are shown in the axons,. × 50(I(X).

some. It has bccn reported that patients with "lurncr's syndrome present immunologic abnormalities (Williams ct al. 19(~4: Gcrmain and Plotnick 1986). "lhcrcli~rc, the disttirbancc of the scavenger pathway for oxidized l.l)l, in this palicnl may havc bccn caused by a dysfunction of the monocytes duc to the 4 6 X X / 4 5 X ( ) |llOSiliC ch rotllosolllc.

The patient's left median nerve was compressed by a thickened Iransvcrsc carpal ligament. Since thc biopsy. spccilllCllS dclllOllstralcd lipid deposits alld xanthoma cells in the ligament, it is thought that the carpal tunnel syndromc in this case was caused by lipid deposits atlrJbulcd to the nlacrophagc dysfunction. ('ornual biopsy specimens showed lipid vacuoles and highly dense bodies in the kcralocytcs and osmophilic deposits in the slroma. ( o r n c a l kcratocytcs cal3 phagt)cytosc and lrcaL a foreign body in the lyst)som¢ as a macrophagc (Mishima ¢1 al. 1987 and 1c)88). Kcratocytcs ma.~ phagocytosc and treat the oxidative [ D I .

accordingly. Since the lipid \acuolcs in the kcratocylcs have a membrane, fl~cy may be cholesterol ester treated by [ysosomes. Because polycthcnoid fatty acid is oxidized easily and is osmophilic, the highly dense bodies sccn in the kcratocytcs and osmophilic deposits in the stroma of the cornea may bc polycthcnoid fatty acids. Biopsy spccimcns of lhc sural nerve showed lipid vacuoles with a membrane and lipid \acuolcs without a mcmbranc in Schwann's cells and the axons. Lipid vact, olcs without a membrane arc recognized in the axon ol thc cornca. This patient's palpchral xanthonms. thickened Achilles tcndons and pol~.ncuropathy wcrc improved by the administration of toct+phcrol nicotinatc and probucol. These drugs prevent the illacrophages from phagocylosing oxidative 1.I)1~ by disrupting I.DL oxidation (Parthasaralhy cl al. 1987). l'hcrc was also a decrease in lipid peroxides following therapy. It is therefore thought that the free radical and lipid peroxides (oxidative kl)l.) may be inw~lvcd in the

fig. 4. ('orncal keratocyte. [.ipid ~acuoh:swith a membrane and highlydense bodice,arc ap[~aren|, l'hc highlydv'nsL-bodies ,,h~ a darker central area and a lighter ~urrounding area. ~:25 (}l)(I.

Fig. 5. Corneal stroma. Osmophilic deposits are shown in the collagen fibers, x 5(1(IOII.

ctioiogy of the polyneuropathy. However, we cannot cxplain the process of lipid deposition in Schwann's cells and axons which requires further investigation.

Acknowledgments For their help in examining the patient and her family, we thank the following: Dr. Koji lnui of the Department of Pediatrics, Osaka University Medical School Dr. Yoichiro Kondo of the Department of Orthopedic Surgery, National Minamiokayama Hospital: Dr. Hiroyuki Hashizume of the Department of Orthopedic Surgery, Okayama Saiseikai General Hospital, and Dr. Shigetoshi Kuroda of the Department of Neuropsychiatry, Okayama Universit,~ Medical School.

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