talasemia de hb s y talasemia de hb c

7/27/2019 Talasemia de Hb S y Talasemia de Hb C

1/10

S tud ies on A bn orm a l H em og lob in sX III . H em og lob in S -T h a la ssem ia D isea se an d H em og lob in C -

T ha la ssem ia D ise a se in Sib l ingsBy I 1 tL S ixu i t,t A A uox \I . ,JosEPm Isd)x , L iix S IN nER , PAUL Hm LLEIm ANI )

Hy x J. Zm uuEut nNS L ilIC IEN T FAM ILY STUD IES h av e bee ti reported dem om istra t.ing tha tmicrodrepanocy t ic d isease represet it s the doub le he terozygous s ta te for the

ab iio rm iia l s ick le ce ll h em og lob in and the th ala ssem ia g en es.4 Th e in he ritancepattert i is th a t o f tra tism ission o f th e n on -a .lle lic g en es for th a la ssen iia am id sick lecell h en iog lo b in to the sa tne itid liv idu al, m nos t frequen tly w ith in teractio n o f the segenes . Th e pa ttern seem s to b e th e samne in C -tha lassem nia am id E -tha lassem iad iseases . R ecen tly , case reports h ave app ea red dem o tis t ra ting the inh eritance o fth es .e genes w ith n o dem otistrab le in te raction .4 T hese la tte r d iscove ries pose ap rob lem o f gene tics and of d iagno sis o f the hem og lob in opa th ie s w h ich th is pape rw ill try to presen t a .n (l d iscu ss .

H em oglob in ana lys is in the usua l case o f sick le ce ll-th ala ssen sia d isease bymean s of the standard e lec tro phoretic techm ncs revea ls a pa tte rn w h ich is oftenind ist ingu ishab le from th at see ti in pa tie tits w ith (hom nozygous) sick le cellanem ia . T he e lect rophoretic p atte rm i is tha t o f a m ajor com nponen t fu rm iished byH b S , and a m inor com ponen t o f lib A + F , F ib A , or F ib F a lone .3 lib F ma ybe dem otistra ted by m eans of th e a lka li d etia tu ra tion tech n ic . (om nb in itig t.h etech n ics of e lec t ropho resis (p referab ly m oving bo im ndary) a tid a lka li dena tu ra tio nis n ec es sa ry fo r d em ouistra .tin g these variou s pa tterns. C la ssica lly , the p atte rnseem i in m icrodrep anocy tic d isease is tha t of the S + A + F group ing .3 O cca -sional ly , how ever, the H I) A frac tio n is la ck ing an d th e d iffe ren tiatio n o f micro-drepano cy tic d isease from iu re s ick le ce ll an em ia4 9 1 m m a be qu ite d ifficu lt,requ ir ing genet ic s tud ies and pe rh ap s eva lua t ion of cer t a i a o t her h em at o log icfea tu res .

A m o st in trigu in g aspec t o f F ib S -tha lassem n ia d isea se is th e freq u en t. find ing o fh ig h p e rcen tages o f H b S in the hem olysate o f th e affec ted ind iv idu a l.3 This phenomnenot i has beeu i in terp re ted to rep re sen t e ithe r su ppre ssion 3 o f H b A fo runa tion by th e tha la ssem ia ge tie, o r enhancem etit3 of produ ction o r ofexpressiv ity o f the gem ie fo r th e abnorm al h em og lob in b y th e th a la ssem ia gene .

In a p reced ing pap er o f th is series ,15 tw o N eg ro p atie tits w ith F ib C -tha la s-sem ia d isea se were de sc ribe d. ile ma to log ic ally , th ey show ed a m icro cy tic hyp o-

F rom the 1 )ep artm ent of Hema to lo g i c Research , M ed ica l R esearch In stittm te , M ich ae lReese Ho sp ita l an d the .1 )epan t m e rit o f M ed ic in e, W est S ide \.A . hospita l, Ch icago,Illinois.T he 1)epart m ciii o f H em sia to lo g ic Resea rch is su ppo rted in par t. by t lie M ichae l R eeseR esearch Founda tion . This wo rk wa s carr ied o tm t w ith th e aid of a grant from th e U nitedS ta tes Pub lic H ea lth Serv ice , an d also sup porte d in pa rt. by the ilu lda I I. :113(1 Mau r i c eL . R ot.h sch i 1 (1 Founda t ion for S c ien t i h e R ese arch .

Subm u itted O ct. 24 , 1956 ; accep ted Feb . 17 , 1957 .59 3


2/10

59 4 STUL )IES O X .o msxom tM. L 1 1E%IO (Ld ) I I IXS

ch rom ic ery th ro cy tos is . H etn og lob in an a lys is revea led th e jrc scn ce o f ab out 73p e r cen t o f H b C in assoc ia tion w ith H b A , o r a m ix tu re o f lib A + F , re spec -tive ly . Th us, a p a tte r ti fo r H h C -th a lassem ia d isea se s im n ila r to tha t see ti itt H bS -th ala sse tu ia d isea se was uncov ered .Th is paper rep or ts th e h em ato lo g ic and genetic fea tu res o f tw o s ib ling s, on ew ith H b 5-tha lassem ia an d the o ther w ith H b C -tha las sem nia d is ea se . T he ab-norm al he inog lo b ins w ere supp lied by the fa ther w ho w as afflic ted w ith H b C + Sdisea se , and th e tha lassem ia gene b y the m o the r w ho h ad a e ry m ild alth oug hde fin ite tha lass em ia.

\ I ET1 IODS

H em og lob in a ila lV ses w ere l)erform i3 e(I wi t Ii I he technies of a lka li (le na ttm ration ,6 elec-t rophores is in th e T ise liu s apl)ara tus at pH 6.5 , a nd p ape r electrophoresis at pH 8 .6 .18T he techn ic o f sta rch e lec tropho res is was tha t o f K im nkel and W a llen iru s as part ia l ly modi -fled in th is la bo ra to ry .9 20 Herna t ohog i c data were obta in ed w ith the con ven tio na l st.a n (1-a rdized p ro cedure s.2 Se rum iron w as (lete rm ined 1w th e nw thod of H am ilton et a l.,2 2 :u idiron b ind ing g lo bu lin as d esc rib ed by Ca rt w right and W int robe.23

CASE REPOR TS AN I) H EMO GLOB IN A NA LY sE S1 .-R etm ben \V ., a 34 yr . o ld c olo re d male , 1 1:1 (1 b ee n d iagnosed as hav in g sick le ce ll-H b

C d isease a t ano ther hosp ita l. T he na tu re of the h en log lob inop a th v w as estab lish ed by e lec-trophore tic h em og lob in analys is (figs. 1 :011 (1 2 ).* H e h ad b een adm itted to the ho sp ita l for aleg u lcer in 19 48 , an d for a un ila tera l op hth a lm ic (v itreo tm s) hem o rrh age in 1951 . P.E . re -vea led h ear t and lu n gs n orm a l; liver , sp leen i, a nd kid neys no t p alpable . R ad iog raphic bonesurvey wa s nega tive . H ena to log ica lly , the pa t ien t ha d a com pensa ted h em oly tic pro c e s s( tab le 1) a s ev idenced by a ret ictmlocv t e coun t o f 3 .6 to 7 .4 p er cen t w ills a red ce ll leve l o f4 .6 m ill. T h ere wa s no ev idence of b leed ing . N um erorm s ta rg et ce lls w ere seen in th e film .Inve stig at ion o f th e pa tien ts fam ily w as prom p ted by th e statem en t. th at h is w ife w asnorm al, how ev er on e of hi s ch ild ren 11 :0 (1 d ied o f sick le ce ll an em ia .

2 .-B ern ice W ., 27 yr . o ld N egress , w ife of H euiw n W ., w as an ap paren tly hea lth y m di-v idua l, excep t fo r a mark ed (h egr ee of deafn ess wh ich d ev e lo ped after an ep isode of m easlesdur in g h er ch ildh ood . H er fam ily h is to ry is non-con tr il)u to ry . N o m em bers of her imm e-d ia te fam ily w ere ava ilab le fo r stim dy . P .E . w as essen tia lly n orm al excep t fo r tile d eafness .A s m ay be seen from table 1 , th e re ticu lo cyte le ve l is w ith in n orn la l lim its. T he s ick lin gtest w a s negat ive . T he perip hera l b lood fi ln l revea led sonw ova locyto sis an d the pre sen ce ofnumerou s ta rge t. ce lls (26 pe r cen t). T he osm o tic fra g ili ty w as m a rk ed ly d ecreased . N ofeta l h em oglo bin wa s d em on stra b le by th e m eth od of a lk a li d en atim ra tio n . E lec troph ore sisin the T iseliu s a ppara tu s (fig . 1 ) dem on strated the Jr esen ie o f a m ino r com pon en t w h ichm igra ted s lig h tly fa ste r th an the m a in com pon ent , R b A . Th is m in or com pom ien t., d es ig -na ted her e a s A 2,j am oun ted to 10 .2 pe r c en t . o f th e tota l h em oly sate . Th e T iseliu s e lec tro-p ho res is w as p erform ed at a pH of 6 .5 , A 7 wa s ther efo re fas ter w ith th is typ e o f elect roph ore -sis, as com pared w ith the m a in com ponen t A , than in th e starch elec t roph iore sis w h ich w ascar ried ou t a t pH 8 .6 . Such a faster com pon ent h ad Prev io us ly b een observ ed in pat ientsw ith tha las sem ic syn drom es. It w as referr ed to as the u n iden tif ied com ponen t ( tiC .)in comm un ica tio n 1 1 of th is se rie s.3 R ec en t ly , K unke l :111 (1 \Vallen ius dem on strated th ish em og lob in com ponent, in sm all am ounts, in n orm al hem olvsa tes by m ean s o f s tarch elec-

* W e ar e indeb ted to M r. C . Sch lu tz at th e M ich ael R ee se R esear ch Foumid a t ion for th ed ete rm ina tion of th e 1)10(3(1 groimps .

f T he c lass ifica tion of the sub types of norm al a (I tilt R h w as giv en at t l ie P an ic ! on G enet-ics o f H e m og lo b in o pa th ie s at th e V Ith In tern at ion a l (on igre ss o f H em ato log y , B oston1956 , as fo llow s: sym bol A, fo r main coml)onent , A 2 fo r s low com pon ent , :u id A 3 fo r fastcomponent.


3/10

I

C 63 .7% ,.5:36 .3% (U .C .): 1 0 .2%

I ________ I1

5: L43, Q/ , 5 :38 .0%- ;w- 1 N 9 .0% NI0.9A: 7.S%

R e ub en ( .(? o tb .r

Eee l c4 Lu . (11 oth.r)

P c1 tr ki 5 # {231}s .

r4 .eve, S4Ps.

I

six i; i i t F ;T AL . 39 3

Fm( ; . 2 .--R esi ,lis o f h)al)en e lec t ro ph io re s is s tud ie s on \V . fam ily

i .f l , A 5WIIS to tntk% udib l i st C O mp O n( n t U.C. ( Un f as ts t% ( In ip on en t)vousk j tncoun te rtd in som e tbca lasce .m Ic . sndrom e (see ta t )

F IG . 1 .- S t au u lam (l e lec t ro l)hores is a It em s on V s. fam i lv

P lerns Pcit (snts


4/10

59 6 ST II)IES OX ABNORM AL HEM OGLOB IX STABLE 1 .-H en ia lo lo q ir D a ta o n H . Fa?ni! ! ,

: H H . . , .ii 1 10 , - I - = E 80Pat ien t D iagnosis 1 : - . ., ..s . _ ,IJ . -. = H #{ 176} .-. .. a . a. : E ,

. . n R_ p . o 80 80 . V , ._____ ) E C n

Reuben (father 34 ni HbC+Sdiseas m 4.4 4 .6 44 95 :3m.332.7 3 5 _ 7 4 1 O.44-O.224.5 m.3 3 -B ern ie e (m ottie r 27 T ha la ssem ia t itin ini , m2 .3 4 .2 37 5 5 292 31 .0 0 .4 -m .2 O .32 -O .m 6 26 .O 0 .9 18 0 42 0Patrice 5 ,f , Sickleceiltrait m3.0 4.2 17 55 30.935.m 0.4 0.4S.32 Ci 0.6 73 420Sena 4 f Sicklecelitrait u2.9 4.5 to Sm 20033.0 1.0 0.40-0.32 m. 4 0.8 118 4 68S t eve 3 ni Fib 5-t1ia1asseriii 7 .9 1 .5 2 5 71 27 .33m .2 4 .2 0 .4 0 -0 .2 231 .4 6 118 3 83

d isea se G regory 1 1m lib C- tu iah tssemia ,m O .4 4 .0 29 7 2 .5 26 .0 35 .5 , 1 . m 0 .2 2-0 . m 2 53 .0 0 .8 1 20 42 0

i 8 F i . . 8 e _____ _____0 Al l l)a tiefl ts w ere b lood typ e 0 eD e M N .

trophoresis arid found it to h)e increase (l in Ih ia lassen lim o nun or. In our ow n lab ora tory have con sisten tly fo und an in cr ease iii A 7 in a ll l )a ti en ts i tis tha lassem lia n i iilo r 50 fa r s tud -ied . T he am oun t o f A 2 as (le term n ine (l in sta rch elec tro pho res is in th is patien t w as 9. 2p er (cu t.. Th is correla tes very w ell w ith the an io un t o f the fa st nov ing con lj)o nen it no te( lin the T iselius e lectro phores is. B ecause of these hem atohog ic and ehec trophore tie find in gsit seem ed w arran ted to assu lne t ha t . Mrs . \V . had a m ild forns of thah assen sim i (I h a la ssem iamin ima ) .

3 .-P atr ice \V ., 5 y rs., w as c l imsica l ly an d hem ato log ica lly norm al excep t fo r ha vin g as ick le c ell tr a it ( tab le 1; fig s. I a nd 2).

4 .-S ena W ., aged 4 , wa s also a hea lth y ch ild ex cep t fo r th e dem ons trah )le s ick le cell tra itp at.term i (ta b le 1; f igs. 1 m in d! 2).

5 .-S tev en W ., ag ed 3 , sh ow ed a h yp och rom ic m icro cy tic an em ia . H b 7.8 Gm . per cen t.Th e hemm ito log ic ind ices an d o the r pa rticu lars m ir e r eco rded ins tah)le 1 . P .R . revea led iigrade I I systo lic m urm u r ove r th e b ase of th e hea rt; x -ra y of the ch est sh ow ed thse hea rt am idlung s to b e no rm al. L iver w as no t p alp ab le , bu t. th e tip o f the sp le em i cou ld lie fe lt b elow theleft c os ta l m argin . A rad iog raph ic bone surv ey wa s no rm a l. S erum iron s and iron b in (h ingcap ac ity w ere w ith in th e rang e o f normal. A few sick led ce lls were se ers on i the Per iphera lb lood fi lm (f ig . 3 ). H em a to log ica l ly , the p ic tur e th at o f H b S -thm ilm issem im i (h is ease .H ow ev er, hem og lob in i an alysis in the T iseh ius ap pa ratus m is w e ll m is by p aper e lectrop ho res isu ncove red a pa ttern in d is tingu ishab le from tha t fou nd ins class ic sick le cel l an sem ia (f igs .1 an d 2). T he m ov ing b ound ary e lec tropho re sis revea led th at th e m ajor com pon en t (9 1per cen t) w as p rov id ed by Hb S and the rem ainder by a slow er m ov insg nons-S frac tion . F eta lhem og lob in , as de term in ed by alka li denaturatio n , am oun ted to 10 .0 pe r c en t . Th ere is,ther efo re, ex ce llen t ag reem ent b etw een t.h e n on -S H i) fra ction f ound in th e T iseh ius app ara -tu s an d th e am ount of a lka li res istan t h em og lob in . T he s low er m oviu sg fra ction r soted in th eTisel ius wa s thus com posed of H i) F on ly .

6 .-G regory W ., a ge 18 m on ths , w as sl igh tly anem ic (H b 10 .4 Cm . p er cen t). Th e MCVand M CH are d ecr eased a lth ou gh the M CHC is norm a l. H is per iph era l b lood film revea lsthe gr ea test n um ber of ta rg et cel ls s een in t .h is fam ily , 53 .0 pe r cen t. (fig . 4 ). T he sick le ce lltest w as neg ative . I)e sp ite th e h ypo ch rom ia m ind m ic rocyto sis the se rum iron and ironb ind in g g lo bu lin w ere no rm a l. P .R . w as es sen tia lly no rm al. H em og lob in ele ctroph oresisb y m eans o f the m ovin g bound ary techn ic irs con ijim nct io t i w it Is the a lk a li d enm itu ra tion p ro-ced tm re un cov er ed a C + F + A pa ttern . W h eth er th e large amoun t o f H b F found is pm or tlyd ue to th e a ge o f the pat ien t. ca nn ot, as ye t l ie sta t,e (l.* Th is p attern is read ily d iflere rs-t ia ted from th e H b A -1 - C trm u t ins wh ich 1 )0th com pon ents m ir e usua l ly pre sen t in abouteq ua l am orm r its , a nd from pu re H b C disemise w ise re ord in ari ly on ly Rb C is found .4 11 -1 4. 24

* A t the tim e o f w ritin sg th is pm tp er , th is p atien t w as 24 m on ths old am s(l the am oum n st. o fH b F had rem a ined im rsch ang ed


5/10

tI

4,

SINGEII ET AL. 59 7

.4 $p#{182}

, 4

-... 1 1

3 .- P en ip lsera l 1 )1 (10 (1 s rsse an ii i Rh S-I ha lasseis iia d ise ase ( po t ie n i I St eve \V .)

99

.

I

IIG . 4 -Per iph era l 1 )100(1 sm ea r iii Rh (-I h ia lasscm nia d ise ase (pat i emi t ( negorv V s .

M icro sph ero cvt o sis w as mio t ed om i the pen Ph iem al 1 ) 1 0 0 (1 s m i s e a r. 8 The riiim sil er o f t h iese cellsw as appa u emi t l v i ns uf fi ci en t to ailed the sali use fuagil i tv st r md y . A 24 hou r i n erd )ate (1 sal iusef rag i l i tv di (I nso t revea l I l ie I m esen ice of t h iese sphelocvt ( 5

l ) i s cuss ioxThe d iagnosis oh tha lassemnia m inor is occasion ally ra t he r d if ficu lt. to estab lish .

It is o ften confu sed w ith tlsat of iron defic ien cy anemm a, and d ifferen t its1 d iagnosisfrequen tly depends on serum inns stu d ies , m easurem ent. o f erv th rocv t.e p ro to -porphyr in ,1 21. 26 an (l gem ie tic eva lu a tio ti. M ost o ften th e d iffe ren tia l d iagn osisis based on th e response to iron therapy . T he tech tiic o f s tarch e lec t ro phores isas descr ib ed by Kunke l and \V allen iusu Isas p rov ided the Isem ato lo g ist w ith a


6/10

59 8 5Tti)1E5 (I N .iNo1tM.tL I1EIoGLOIitN5

1 . ibC .S d t a s e lha lassuu io m nm o

(T h (Th _d ied rrom sckk c .tIl s c .k k cdl Sihaiossemnks C lhoIassda a

sk%th , c tU c ie mc s trcs tra

U , eQk T ha tcs ;siic 9 (1St

fd. : i-lb C Q cnC

d .Qd , FIG. ). ( en iei ic (1:11 a (0 1 \ \ . an si lv

re la t i ve lv in lp l( n se t h od t( r s le t e rm snr sa t i( us of t l ie acccssom y hcm uogl( )I ) i m i s . r f } 5 ( ( , workers fo und th at henso lvsat es d) f iio rm isa l b loo d sp lit. iiito th ree f ract iomss,a u sa irs con sp ou se nt , A1; a s low com ponen t , A2; ari(l a fast com ponen t , A. \Vc haveconf irm ed th is wo rk in ou r labora to ry2 aiid ou r resu lts a rc essen tia lly the s ameas tho se of Kurik el am id \V allem sius . The slow corsip om ieri t , A7, am ounts to les s tha is3 P e r (em it ito iiorrnal Isem uo ly sa tes . It is les s tliam i I .. P(r cen t in most case s of irondcl ic ie rscv anem sira, an d it is b e tw een 3 arid 10 per ( (m it in a ll cases of tha lasscm uiamit ior so fa r s t tid ied . In the few cases of tlsa lassens iia m ajo r sttm dicd in our lab ora -tory a tid a lso by I )r. K unike l, no c leva t ions of A2 was found. These f imsd ings irs ou rpatient, _\ irs. Bern ice \V ., w ere of grea t a id iii est I 1 i sh i rig t Ise p re sence o f t halas-senn ia m inor.

In th is fam ily s tu (.ly ive mog ain have ar t in s ta n ce o f an t + F p attern w lsich isn o t d ue to ho rsiozygous sick le ce ll disease. It ru tty lie sa fe ly s ta ted tha t thepheno type S + I is r io t d iagn ostic li)r sickle c ell ariens ia, and fam ily stud ies tsiaybe m secessarv to ru le ou t lIb 5-tlsa lassem ia d isease as t lie cm iu sc of th is hemsiog lob inan aly sis p atte rns. Smuith am id (o n ley ,9 I t an iii ct til ., am s(l Zue lze r hav ( Pm \ D ) t t5 lYrepo rted th is type of pattern in Fib S-thalassenuia disease.

lhe do ttb le h ctc rozygous s tate fo r t.lsc ab miorm ua l lscr isog lo l iii) arid t he tha lassem iais m arrifes t in th is fam ily as o ne pa t ierst with lib S tha lassem ia d isease am id onew ith lib (-tha lasscm ia d isease (fig . 5 ). Irs th is fam ily there is ev idence o f m a;kedin tera c tio n o f the m obr iorn sa l hem og lob in gene w ith the gcrsc (s ) fo r tha lassensia in seach ir istam icc . T h e ch ild w ith F ib S -tha la sscnu ia d isease h as 91 per cent. of th eabnormal hemog lob in in h is h cm o ly sa tc (fig . 1 ). T he ch ild w ith F ib ( - thalasscmia


7/10

5 .n .W .

tC og ; l, s uen c o f ik#{248}Io e ,snsa1h s eP c . of thcns lassem(cs

S IN GE II E T AL . 59 9

T he a b ov e te rm n o logs T ha t wb c . I ) iuos csccep t td b T he Pons i on G ene t(c s o f 14emoa t Th e 6T h In tQ rna ton (ln2rtis. o I -kmoto lo j , B oston 9 S6 .

Fio . 6 .-G em io tvp e s o f \V . fan isi!y

. hoIo 9!! . .

2SOanc4 lnsn t of c .b no rm ol h c. no gl ob fn. i ! ! Io$s#Mc. 9t

fL ,_ I f f P ! 9!! !

Tb

AA

fbotau.fa 9.

5. Th alo ss t. si a an d/ or * .k I. dsscast of m u( t. pk 5. ktd QM S

T h a t e m c a S ), qo.oF m o . 7. - Poss i h ie gene t ic I iieo ri e s fo r i n ih eri I m in ce o f :11 )!i( nmssa I henssog ! o l .d us in t h e I )nes -

enice o f I h ia la ss ei si a.

disease has 81 .3 per (emit lib C (fig . I ). T hese p at iem it s rece ived om ily om ic g en ie fo rthe abno rm al hem oglob in (f ig . (i). Iheoret-ica lly , the m uarufcs tat ion s of this gen iein the ind iv id ua ls rece iv in g just on e g e tic sho u ld be e ithe r equa l am ounts of theabm io rm al hem isog lob in an d H I) A , o r les s than 50 per (em it o f the abno rm a l hcm sio -g lob in i, a s iw ay I)e seem s iti a ll cases o f the s ick le ce ll tra it . ii. 2-i (.)I.)v iou sly so n ic-th in g has af fected the expressiv ity of the gene for the a bn orm al h em og lob in in th e


8/10

60 0 STUD IES O N ABNORM AL HEM OGLOBINS

cases und er con sidera tion . P rev ious wo rkers have pos tu lated tha t the gene fort.ha lasse rn ia in h ib its o r su ppresses the pro duc tio n of H b A .3 . . C onsid er ing tha tthe tha las sem ia g en e is a sing le gene , one m ust. a ttem pt to exp lain the ph enom e-no n of no sup pre ss ion in the m o the r o f th is fam ily , w ith alm ost. com ple te su pp te s-sion of the p ro duc tion of H b A in th e ch ild ren m an ife sting the doub le he te ro zy -gou s state . A n exp lan atio n fo r th is ph en om enon m ay be th e e ffec t o f m od ify in ggenes. A no the r w ay of sta ting the p ro b lem is tha t w e m ay be d ealin g w ith d is ea se sw hich have m ultip le gene tic causa tio ns (fig . 7 ). A num ber of repor ts hav eappea red w h ich have d em ons tra ted th e in he ritance o f an al)no rm a l hem og lob inand tha las sem ia in th e sam e in d iv id ua l w ith no ev idence o f in te rac tion o f th egenes. N eel e t a l.4 repo rt the o ccu rren ce o f H b S tra it accom pan ied b y a tha las -sem ia m inor . T he am oun ts o f H h S in 3 such pa tien ts w ere 36 .2 , 27 .7 , and 2 2 .3pe r cen t, re spec tive ly . H um ble e t al.6 from Eng land h av e a lso rep orted a fam ilyin w h ich th ree ch ild ren had inherited a F ib S gene an d a t.ha las sem ia m in or , ye ton ly o ne of the th ree had any ev idence o f in te rac tion o f t.he genes. R oche e t a l.7repo rt a fam ily o f T un isian m u se lm an in w hich o ne ch ild show ed in te rac tion o fthe H b S w ith th e tha lassem ia gen e and ano ther h ad a sim p le sick le ce ll trait w iththa la ssem ia m inor . Z ue lze r8 reports a ease o f H b C -tha la ssem ia d isea se in w h ichthe p atien t h ad on ly 2 9 .0 p e r cen t H b C . O ne of tw o prim e inh eritance pa tte rn sw ou ld seem to be m an ife st in th e inhe ritan ce o f the do ub le he te ro zy gous sta tes .T h e tha la ssem ia gene m ay b e p re sen t in tw o d iffe ren t fo rm s, i.e ., a gene w hichhas th e in trin sic ab ility to in te rac t w ith th e g en e fo r the abno rm al hem og lob ino r o ne w hich do es no t have th is ab ility . T h e o the r pos sib ilit.y is the p re sence o fm ultip le o r m od ify ing g e ties . N o de fin ite an sw er to the se p rob lem s is p resen tlyava ilab le. T he au th o rs p refe r the la tte r theo ry as th is w ou ld h elp ex p la in th em arked clin ica l v ar ia tions seen in the he terozyg ous fo rm of t.ha las sem ia .

In sick le cell anem ia the re is a lso som e ev iden ce tha t th e re m ay be m ore th ano ne gene in vo lv ed . Z a ra fone tis e t al? have recen tly show n tha t the hy posth enuriafou nd in pa tien ts w ith hom ozygous sick le ce ll d isea se is p resen t, to a la rg erd eg ree , th an in pa tien ts w ith th e s ick le ce ll tra it. T he re seem s to be no re latio n o fth e h ypo sthenu ria to the am oun t o f H b S p re sen t. It is also q u ite p ossib le th at asin g le g en e w ith p le io trop ic e ffect m igh t produ ce the ren al concen tra tion de fec t.A m ultip le g en e t.h eo ry w ou ld po ssib ly a lso ex p la in the fac t th at pa tien ts w iths ick le ce ll anem ia have a m arrow regu la tio n d iffe ren t from tha t o f norm al in -d iv idua ls .24 28 W hereas th e norm al m arrow can com pensa te or in crease itse ry th ropo ies is som e six to e igh t tim es its no rm a l leve l,29 th e m arrow of a pa tien tw ith sick le cell anem ia h as o n ly a fo u rfo ld inc rea se o f red ce ll p rodu ctio n .3#{176 } Apa tien t w ith sick le ce ll anem ia w ho receives transfusion s to a norm al red ce lland hem og lo b in leve l w ill have a m arrow show ing v ery little o r no red cell popu la -tion , and the d isappearance o f rad ioac tiv e iron from the p lasm a w ill show acurve s im ila r to tha t seen in ap la stic an em ias. The cau sa tion o f the se va rio usde fec ts cann o t be log ically ex p la ined on the p re sence o f H b S a lone . If th en w ea re d ea ling w ith d isea se s w h ich are co n tro lled by m ore than o ne gen e it becom espo ssib le to exp lain the va rious inhe ritan ce p atte rns o f th e d oub le he te ro zy gou ssta te s o n th e b asis o f transm issio n o f genes w hich are spec ific fo r in te rac tion w iththe abnorm al h en io g loh ins , o r on t.he absence o f tran sm iss ion of such genes .


9/10

SIXGE1I ET AL. 60 1

Th e m a jo rity o f ca se s o f F ib S - on H b C -tha la ssem ia d is ea se so far s t.tn d ied havebeen n ian ifes t. by an soum its o f the ab tso rm al hem og lo b in grea te r th an 60 percen t . .4 I n -n4 24 A h igh ind ex of su sp ic ion fo r the do ub le h e t.e ro zygous state s m ayl)e n iecessa ry to de te rm ine those cases hav ing sm all am ounts of the ab norm alhem og lo b in . T he u se o f sta rch e lec trophores is sho u ld prove ex trem ely he lp -fu l in u ncovering those cases of very m ild tha lassem ia , o r pa tien ts hav ing tha las -sens ia toge ther w ith ab norm al hem nog lo b ins .

SUMMARYA fam ily stud y is rep o rted in which th e sim u ltaneou s p re sence o f C -tha la ssem ia

an d 5-tha lassem ia d isease is no ted . M arked in terac tion of the genes fo r th eab norm a l hem og lob in s and fo r t.h a la ssem ia is ev iden t.

T h e va lue o f th e accesso ry hem og lob in is fo r the d iagn osis o f t.ha las sensia m inoris d is cu ss ed .

T he Hb S + F pa tte rn can no long er be assum ed t.o be d iagnos tic o f sick le ce llanem ia. E va lua tio ts o f a ll hem ato log ic da ta and the fam ily background o f th epa tien t m ay b e necessa ry to ru le ou t. the presence of the tha lassem ia gene .A discuss io n of the gene tics o f the d oub le he te rozygou s sta tes fo r th alassem iaan d an abnorm al hem og lo b in is p resen ted .

SUMMARIO ix I NTERL I NGUAEs rep orta t.e un stu d io fansilia l in s q ue le p resen tia sim u lta tie e de m o rbo de

hen iog lob in a C p lu s tha lassem ia e d e m orbo de h en sog lo b ina S p lus t.ha lassem iaes notate. M arca te g rad os de in te rac tion s d e l gen ies pro le h em noglob insas an orm alco n le g en ies pro tha lassem ia es ev idenst.e .

E s d iseu tite le va lo r d e hem oglob inas accessori p ro le d iag nose d e th alassem iamimsor .

Il ha d even ite im possib ile com isidera r le con fig ura tio ns de hem oglob im sa S e Fcom iso d iag tsostic de anem ia a ce llu las fa lc ifo rm e. Ii p o t.e esse r necessar i eva lu t.a rom ne le da tos hem at.o log ic e he h is to ria fam ilia l an te c iue le presen t.ia de l gem s proth alassem ia po te esse r tsega te .

E s p resen ta te uns d iscuss ions dc l gense tica de dup le st.a to s he terozygo tic p roth alassem ia e u n he inog lo b im ia ansorm al.

REFERENCES1 POWELL , W . N ., RODARTE, J. G. AN !) NEEL , J . V .: T he occur ren sce in a fam ily o f S ic ilia n

ancestry o f th e tr a it s for sick l in sg arid tha lassem ia . B lo od 5: 887 , 1950 .2 S ILVESTRONI , E . AND BIANcO, I. : G er se tic a sp ec ts o f s ick le cel l ansem ia m in d m icrodrepano-

cytic d isea se. B lood 7 : 429 , 1 952 .S I NGER , K ., S I NGER , L. ANI ) GoLDBERG , S . R .: S tud ies on s abn orm al heu sio g lo b in ss . X I.

Sick le ce ll-tha lassen sia d ise ase in s tis e N egro . The sign ificance of the S + A + F ar idthe S + A p atter ns ohtmiinsed b y h em oglob in ana lys is. B lood 10 : 40 5 , 1955 .

ZUELZER , \V . W ., NEEL , J. V . A N!) R OB IN SO N, A . R .: A bno rm al hsem oglob inss . In s To can tin s,L .: P rog re ss in H em a to log y , N ew Y ork , G rune & Stra tton , In c. vo l. 1, 1956.

NEEL , J. V .: Th e inher i tance of the sick lin g phenom enon w ith pa rticu lm ir reference tos ick le ce ll d isease. B lood l 6: 38 9 , 1 95 1 .

6 HUMBLE, J . G ., ANDERSON, I ., W nm tv J . C . AND FREEMAN, T .: A fam ily i llu s tra tin g th ed oub le in he rita nc e o f th e s ick le cell tra it an d M ed ite rra rsem ins an em ia . J . C lin . P ath .7: 201 , 1954 .


10/10

60 2 STU I)IE S ON ABNORM AL HEM OGLOB INS7 R oCHE , J. , I )ER R IEN , 5 ., l)IA coN o , I)., I ) IRIEux , J. , LAURENT , G ., REY NAUD , R oux ,

M . AN D BR AN GIER , C. : Co existen ce de s tare s sickl#{233}m iques et th ala ss# {233}m iqines dansonne fam ille t.tm nisienne . R ev . d H em . 2 : 26 , 1956.

8 ZUELZER , \V . W . A ND K An LA N, E. : T halm issem ia -hem oglobin C disea se. A new syndrom ep re slnm a i)1y (l ine to the con sh insa tio n of th e g enses for tha lassem ia an d h em og lob in C .Blood 5: 1047, 1954.

9 SMiTH , E. \V . A ND C ON LEY , C . L . : C lin ica l featirre s o f the g erse tie v arim in its of sickle ce lld isease. Bull . Joh rs s H opk in s H o sp . 9 4: 2 89 , 1954 .

10 S TURGEON , P. , IT .&No , H . A . AN D BERGREN , W . It. : C lins ica l m an sife stm itionss o f abnorm alh ensog loh in is . I I. In term oc tio ns of h enn og lob in E ar id tha lm issem ia trm iit, . B lood JO : 396 ,1955.

WAT SON , J . It .: H ern og loh ins s an d l d ise ase . A d vance s lis t. M ed ., vo l. V III, 1 )o ek m ind Sn ap-pe r .

2 WH I TE , J. C. AND BEAVEN , G . H .: A review of th e va rie tie s of hum ans h aenso g lo h in in sh ea lth arid d isea se . J. Chin . Pm ith . 7 : 175 , 1 954 .

#{ 176} I T ANO , H . A ., BERGREN, \V . R . AN D STURGEON , P .: T he abr sorm ssm ol h um min i hensog lob inss .Med i c ine 35 : 121 , 1956 .

#{ 176} CHERNOF F , A . I .: T he h unnm in hem og lob ins s in s h ea lth m in d d isease . N ew E nsg l. J . M ed . 253:322 , 1955 .

SINGER, K ., KRAU5, A . P. , SINGER, L. , RUBINSTEIN, H . M . AND GOLDBERG, S . H .: S tud ieson a bno rma l hemoglobin s. X . A n sew syndrom e: hem oglobin C -tha lassem ia disease.Blood 9: 1 032, 1 954.

16 CH ERNO FF , A . I. AND SINGER, L .: S tu d ie s on abm sorm al hem og loh in s. I. T heir dem on s-s tra tio n in sick le cel l anem ia and o the r hem ato log ic disord ers by m eans o f a lk a li d ie-n atu rat ion . B lo od 6 : 413 , 195 1 .

17 AND F IsH ER , B .: S tn nd ies on ab norm al hem nog lo b inss . V II. T he com position s of then on -S hem oglob in fract ion in s ick le cel l anem ia b loods. A com parative stu dy by th em e thods of e lec t-r oph oresis and alk a li den atu ra tion . J . L ab . & C lin . M ed . 42 : 19 3 , 19 53 .

18 SM ITH , E . \V . AN D CO NLEY , C . L .: F ilter pap er ele ctr op horesis o f h um an h em og lob in w ithsp ec ia l refe ren ce to th e inc idenc e and c lin ica l s ign ific an ce o f hem og lob in C . Bull . J ohnsH opk in s H osp . 93 : 94 , 1953.

9 KUNKEL , H . G . A ND W A LL EN IU S, (4.: New hem oglob in in s n so rm al adu lt b lo od . Sc ien ce 122:288 , 1955.

20 MASR I , M . S., J o sEnHsoN , A . M . AN D S INGER , K .: I np on bli sh ed observat ions.21 WINTROBE , M . M .: C lin ica l H em ato log y . Ph ila delph ia , L ea m in d F eh ige r, 1 9 5 6 .22 HAMILTON , L . 1.)., GUBLER , C . J., CARTWR IGHT , G . K . A ND % Vn NT RO BE , M . M .: l)iu rm sal

v ar ia tion ins th e P la sm a iron s lev el o f m an . Proc. So c. Expe r . B io l. & M ed. 75 : 65 , 1950.23 CARTWRIGHT , G . E . AN D WINTROBE , M . M .: Chemica l , c lin icm sl, a nd im munso log icm sl stu d lies

o n the p rod sn cts of h tm nsan s p lasm a frac tio nat ion . 3 9 . Th e anem ia o f in fect ion . S tu d ie s onthe iron -b ind ing cm tpa city of serum . J. Clin . Insvest . 28 : 86 , 1949 .

24 S I NGER , K .: H ered itary henn oly tic d isorder s a sso cim ited w ith ab norm a l hem oglob inss .Am . J. Med . /8 : 6 33 , 1 955 .

25 ERLAND5ON, M ., SM ITH , C . H . ANI ) S CHULMAN , I.: T hm ila ssem im i-hem og lob in C disease in sw hite sib lings . P ed . 17 : 740 , 1956 .

26 S TURGEON , P. , IrA NO , H . A . AND BERGREN, W . H .: G ene tic a rid b iochem icm il stud h ie .s o f in term ed ia te typ es of C ooleys anem im o . B rit . J. Ha em 3: 264, 1955 .

27 ZARAFONET I S , C . J. 1 )., MCMASTER , J. 1)., M0LTHAN, L. AN!) STEIGER, % V. A .: Appa r en trensa l de fec t in s sick lem ic ind iv idu als . Am . J. Med . Sc . 2 3 2 : 76 , 1956.

28 C r-lA n L IN , H ., KE ITEL , H . G . A ND P ET ER SO N, It. E .: H emm ito lo g ic observ atio is s o n pa tien itsw ith sick le cel l m inem ia sin sta in sed on normm ol h em oglob in le vels by mult ip le t rmtmss f rn -s ionis . B lo od 11 : 834, 1 956 .

29 CROSBY , W . H .: T he n sse tab olisn ss of h em oglob in ans (I ho le p ignssen st in s h em oly tic d is ease .Am . J. Med . 18 : 1 12 , 19 55 .

30 Unpublished oi)se rva tion ss.

talasemia de hb s y talasemia de hb c

Documents