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TANGIER DISEASE
Report of a Case and Studies of Lipid Metabolism
l’ ~:~.II;.I.~N-BI.IGII,
. M.R., M.R.A.C.P., B.Sc. (MEI>.), P. J. NESWL, M.D., F.R.A.C.P., ASD
H. M. WHYTE, D.PHIL. (OXON.), F.R.A.C.P., F.R.C.P.
Abstract ::J elucidaii: the deranged metabolism of density lipoprotein. In vivo turnover of plasma es-
Tangier dizase, the turnover of esterified choles- terified cholesterol, measured after injection of ra-
terol, and the activities of lipoprotein lipase and of diolabeled mevalonic acid, was 48 mg per hour,
lecithin-cholesterol acyltransferase (LCAT) were similar to values obtained in normal subjects. Post-
studied in a patient with typical findings. The plas- heparin plasma lipoprotein lipase activity was 0.071
ma concentration of high-density lipoproteins, as- pmoles of free fatty acids released per minute per
sessed by electrophorctic, immunologic and ultra- milliliter of plasma, compared to a normal value of
centrifugal means, was greatly reduced. Of a total 0.218. LCAT activity was 2.5 pg of cholesterol ester-
plasma cholesterol of 59 mg per 100 ml (70 per ified per milliliter per hour of incubation, about half
cent esterified), only 7 mg was present in high- the normal value.
T ANCIEH
children
disease \rras first described
by Fredrickson and his associates’ in
in two clotting times rvere normal;
A blood transfusion
were removed
rva\ given.
and unusual
an enlarged spleen \cac palpable.
Latet- in childhood.
hemorrhage again occurred.
2 teeth
.\t
1061. Ten other cases have since been descril>ed.2-x the age of 6Y2 !ears. persistent tleafncss. thought to be due
The features of the disease are a very low content to
‘ eustachian-tube bloc Lage. de\rllq)ed. and adenoidal [issue
of high-density lipoprotein (HDL) in the circulating and tonsillar remnants \\ere remo\cd. The escised rissue
plasma, the accumulation of a large quantity of had an unusual yellow appearance. microscopy of \\hich
revealed increased numbers of large. pale. foam! macro-
esterified cllolesterol in the macrophages of man) phages scatlerc(l dilTuwly thr-ou$~out the rissue.
tissues,‘ ,” enlarged tortsils having a yellow-orange .Aftcr the ‘ Ld operation the patient remained well. Ifer
color, reflecting their high content of esterified cho- schoIa\tic achievemenrs were above average. \lensrru;trion
lesterol, frequentl) elevated plasma triglyceride had been normal since the menal-the in 196X. Octa~mnal
concentrations and almormal quantities of circulat- spon’ aneous nosebleeds of small volume had occurred r-e-
centlv. There had hecn no symptoms of dial-r-hea or pares-
ing chylomicrolls in tile fasting state. 40th parents
thesia.
of affected persons ha\.e IO\V plasma concentrations
of HDL, indicating that the disorder is transmitted
as an autosomal recessilre trait. high-density lipoprotein
In the additional cast reported below, since disor- lecithin-cholesterol acyltransferase
+I
dered metal)olism of esterified cholesterol is a fea-
ture of the disease, the turnover of this class of lip- very-low-density lipoprotein
ids in the plasma was measured. Furthermore, HDL The pa’ ienl \+as I(i2.5 cm lall and \\eighed :ii..i kg; nutri-
may be criticall>, connected with the activity of two tion seemed normal. The blood pressure \vas IOiiO. Heart
enzymes, lecithin-cholesterol acyltransferase (LCAT) sounds Irere normal. There was no I~mphad~nol,ath\. and
and lipoproteirl lipase, which are in\.olved respec- -the Iiwr and spleen were not palpable. The lundi \\ere
normal. as \\ere the co,-neas on superficial examinnrion. The
tively in the metabolisln of esterified cholesterol hard palate was high arched and associated wirh displace-
and triglyceride in plasma, and these enzymes were ment of the secondar) teeth. Small. ol-angr->ellou. solid le-
therefore studied. sions. I cm in diamctel, ere presenr
\\‘ on the poswr-ior. a\-
lxct of. the phar) nx. Esamination of the nerwws S\\I~III
CASE REPORT revealed no almorm,tlit~ UI-inalysir was negza’ ive f.or- hlootl.
protein, sugar and hilt. ‘ hc Iiess ~$1 lbr- capill,rt \ I‘
I’ ra~:il~t\
\vas negalive. A radin~ral~h of rhc c-hr\t and a pInill r,ldi-
ograph 01. the abdomen beI-e nor-ma1. IIenio~Iol~in. \\ hicc-
wll count. sewm alkaline l)hosl)h;ctaw. SC, um glutamic- oxalo-
acetic tr;~1is;llllill;l~(‘. lxw’ hionil)in time. 1h1-omll1n clotting
time and lk~srna fil~rinogcn H’~I-e alw normal. I
‘ hr-onlbol~l.~\-
rin gcncr-afion xi,\ onI> .56 per ~cnl of’ normal. .I-he platelet
coltnt W;I\ X2.000. h
I‘ e Io\v piatelct count and I-cduc cc1
Ihi-oml~ol)l;lrtin gwwacion wcw no1 e\al~l;ktctl lur ther-.
Plasma Lipids and Lipoproteins
Blootl wits tdc~i1 in tlicb fxsliiig 5t;ltc \3,itll tliso-
dium EKW4 ;IS antico;ii:illn,lt, and tllcx plkisma lippro- The plasma trigi~u!ritie concentration for the p;l-
teins HUL, low-tleusit)~ iipoprotein (LIIL) and very- Cent was nt the extreme upper limit Of the norlij;tl
low-density iipoproteili LI>L)
(\‘ were sepurated I>> range expected for a person of her age mcl sex.1~
the preparative nletiuik: of Fredrkkson and his CO- \Vhen pinsnm from the patient was sul>jected II I
workers’ O; p-chi0ron~c:~~~ i~riphen)~is ~!fonnte \viis adci- eiectrophoresis on 1 per cent ngarose, no alpha I
ed to the piusmu in i; j+l concent: ,;.ion Of 2 In>1 to (high-dellsity) or prebeta (very-low-density) iipoprt,-
inhibit the activity of I CAT during handling of the tein was seen. No precipitin line was seen when
plasma.” The conte:it of ohoiesteroi’ ~ and of plasma from the patient was diffused against auti-
triglycerideI was measured in each lipoprotein frac- IIDL untiserlmi in agnrose. Precipitin lines \\rere
tion. Plasma was submitted to eiectrophoresis on 1 seen when the parents’ and a normal person’ play- s
per cent agarose after prestaining of the lipoproteins ma were used.
with Sudan Black B.14 Plasma from the patient and
both her parents was tested against antihuman HDL Esterified Cholesterol Turnover in Vivo
antiserum (Behringwc::-ke) in 1 per cent agarose iI>. Specific activity time curves for esterified and
the method of double diffusion. unesterified cholesterol in whole plasma are show11
in Figure 1. Similar kinds of curves were obtained
Esterified Cholesterol Turnover in Vitro
for LDL and VLDL. The curves for HDL obtained
Approximateiy 110 PC of 3H-DL-nlevaionic! acid* for each parent are shown in Figure 2. The HDL
(Radiochemical Centrr, Amersham) was injected in- curves for the patient could not be obtained be-
travenously illto the patient and into each of her cause of low levels of radioactivity in the HDL cho-
parents, and the specific activity of unesterified and lesterol.
esterified cholesterol in whole plasma and in HDL, The steepness of the rise of a given specific activ-
LDL and VLDL was measured at frequent intenais ity-time curve for esterified choiestcroi is an esti-
after injection for as long as 72 hours. Specific activ-
ity-time curves were constructed, and the turno\,er
of esterified choiesterc~i was then calculated with
FATHER
the method of Sestel aid Monger.15
0 UNESTERIFIED CHOLESTERO
Plasma LCAT Activity (Ro?a of Cholesterol Esterification . ESTERIFIED CHOLESTEROL
in Vitro)
The method of Glo;;:yet and \\‘right was ‘used.16
Plasma sim~ples of the patient with Tangier disease
s
and her parents and a riormal person’ plasma \vere
heated at 56°C for 4,s minutes to ai~oiisi~ enzyme
activity and used us Ihe sollrce of substrate iipo-
proteins.
Post-Heparin Lipoprotein Lipase Activity
Two methods were used: that of Fredrickson et
al.” and that of Bobei-g anti Carlson.’ Hepariu was
given intravenously to the patient, her father and a
normal person in R dose of 0.1 mg per kilogram of
body weight. Blood was tilken 10 and 20 minutes
after injectioll and imnlediateiy ciliiled, and the
plasma frozen at --10°C: until ready for use as the
source of enzyme.
Plasma Lipids and Lipoprsteins
The concentr;ltim)s of cholesterol anti triglyceride
in whole plasma ailtl iii indi\.idliiii lipoproteiils iire
shown in Tal~ic 1. The c~l~oiesterol content of the
whole piasnl;i of the p!ticllt was 59 mg per 100 ml
(70 per cent esterifieti), ;ciiti Of this oni}. 7 infi per
TIME-HOURS
100 1111 M ’ilS in tile 1 IDL fraction, ;Ibout l/8 the
normni value for ff3n:!les.19 The choi~sterol content
of the IllII, in Ijot paretlts WilS lower tha11 nOrm;il.2 Figure 1. Specific Activity-Time Curves for Unesterified
and Esterified Cholesterol in the Whole Plasma of the Pa-
tient and Her Parents after an Intravenous injection of :‘ H-
DI -Movalonic Acid.
Table 1. Cholesterol and Triglyceride Content of Lipoprotein Fractions Derived from Whole Plasma.
--
SUUECI AGE (Y R) CHOLESTEROLCONTENT (Mc/lOO ML) TRIGLYCERIDE
CONTENT (MoilOO ML)
WHOLE PLASMA HDL LDL VLDL WHOLEPLASM.4 HDL LDL “LDL
Father 47 167 (75 % csterilied) 31 I13 23 86 14. 30 42
Mother 38 200 (71 % esterified) 26 I51 23 31 12
Ihghter (patient) IS 59 (70 % eslerified) 7 47 5 2 7 49 2
Mde conlrol 31 166 60 98 8 56 16 23 17
m;lte of the turnover rate* of the esterified choles- low value of 1.7 wg was also obtained for the pa-
tel.01 pool in question. A measure of the turnover tient when plasma from a normal person was used
rate and turnover of the plasma esterified cholester- as substrate, indicating that the additional Iipopro-
01 pool can be obtained by means of the method of tein substrate provided did not enhance the rate of’
calculation used by Nestel and Monger’ J and ester&&ion.
Xloutafis and Myant. 2o The values are shown in
Post-Heparin Lipoprotein Lip&e Activity
Tahle 2 for the whole-plasma esterified cholesterol
pool and for individual plasma lipoprotein pools. The results are shown in Table 4. Xlasimum \.a]-
Since a direct measure of the turnover rate of ues for lipoprotein lipase were seen in each case at
Table 2. Turnover of Esterified Cholesterol in Vivo.
SUBJECT ESTERIFIEDCHOLwrEROL POOL TURNOVER RATE TURNOVER
WG) )
(Hit-‘ Wc/Hd
“HOLE “LDL LDL HDI. WHOLE “LDL l.DL HDL WHOLE “LDL LDL “DL
PLASMA PLASM* PLASMA
Father 2913 I89 1872 558 0.015 0.022 0.026 0.024 44 4 49
Mother 4213 229 3218 465 0.022 0.02 1 0.029 0.022 93 5 93 I
Patient 639 90 537 120 0.075 0.039 0.043 I .750’ 48 4 23 ‘L
Estimate.
‘ , .
esterified cholesterol in HDL could not be obtained the first sampIing time, 10 minutes after the injec-
in the patient with Tangier disease, an estimate was tion of heparin. with both assay methods, the acti\--
made by subtracting the values for the turnover for ity of the patient’s plasma was consider&l>. less
LDL and VLDL from that of,whole plasma.15 Turn- than the activity s
obtained with her father’ plasma
over rate for 1lDL was then calculated by division or with the plasma of a normal person.
of turnover by the pool size.
Table 2 shows that the turnover rates for DISCUSSION
esterified ch:;iesterol in the patient’s whole plasma The case reported satisfies the requirements for
and in the individual lipopr&eins were higher than
the corresp:: iding values for her parents. The FATHER
difference is i)articularly striking for the HDL, in 20 o UNESTERIFIED CHOLESTERO
which the tu. !:over rate for the Tangier patient was . ESTERIFIED CHOLESTEROL
estimated at I.750 per hour. However, the turnover II) 1500
of esterified c~~olesterol in whole plasma, 48 mg per
hour, was similar to values reported by NesteP in
normal persons. The turnover for the patient’ HDL s
esterified chc!esterol appears higher than for her
parents, but it should he emphasized thqt this value
was calculated indirectly and that the true magni- MOTHER
tude of difleerc;nce between the parents and the pa-
tient is uncertain. On the other hand, the turnover
in the daughter’ s LDL is considerably less than that
in her parents.
LCAT Activity
The results are shown in Table 3. The value of
25 bg of cholesterol esterified per milliliter of ac- I
tive plasma I>,:” hour of incubation was obtained for 10 20 30 40 50 60 70
the patient W~:EII her own plasma was used as sub- TIME-HOURS
strate: this VX.; much lower than the values ob-
Figure 2. Specific Activity-Time Curves for Unesterified
tained for her parents and for a normal person. A and Esterified Cholesterol in the HDL of the Parents of
the Patient after an Intravenous injection of 3H-Mevalontc
*Turnover rate is the fraction of the plasma pool replaced per hour. Acid.
570 l-HE
‘ NEW EN(;l.AKD ,]C)UKNAI. 01; ~IEDI<:INE Mar. llj r’
l’ ;:!
Table 3. LCAT Activity (in Vitro Cholesterol Esterification One of the factors thought to regulate ~IIC tliiI,.
Rate) over of esterified cholesterol in plasma is the C~IX! I,,(’
LCA’ , I’ the activity of which has been x+soci,i$c,(]
ACTIVE PLASMA SOURCE OF ~TERlFlCATlON
SUBSTRATE RATE’
with the presence of HDL in the plasm;~.~~~’ P.,.
A: tients with genetic deficiency of LCAT ;!]so il.:\ c
Normal person Normal pcrson 4.5 f 0.4
low plasma HDL concentrations.2s.2fi The activit\ of
Father Father 4.1 rf: 0.1
Mother Mother 7.0 * 0.3 LCAT has been positively correlated with the WI,-
Patient Patient 2.5 f 0.2 centration of unesterified cholesterol in the p];,+
B: ma.*’ In our patient, low HDL concentration or lo\\.
Father Normal person 4.5 rt 0.1 unesterified cholesterol concentration, or both, ma!.
Mother Normal person 6.1 _+ 0.3
Patient (Tangier disease) Normal person 1.7 + 0.3 have contributed to the low LCAT activity. Ijo\v-
ever, the LCAT activity in the patient’ s plasma did
l pg -of cholesterol esterified/ml of fresh test plasmajhr of incubation
(mean 91 SD). not rise when additional substrate was provided I)!-
use of normal plasma, suggesting that the enz)mc
the diagno$s of Tangier disease in the following concentration itself was diminished. Because in vi\-o
respects: -a low total plasma cholesterol in the pa- turnover of total plasma esterified cholesterol uxs
tient with a normal proportion esterified; near ab- normal, it seems likely that factors in addition to
sence of IIDL from the plasma as assessed by ultra- LCAT are responsible for the turnover of esterified
centrifugal, electrophoretic and immunologic tech- cholesterol in the plasma.
nics; a high plasma triglyceride concentration but The postheparin lipoprotein lipaqe activity of our
an absence of pre-beta migrating \‘LDL on electro- patient’ s plasma was found to be much lower than
phoresis; and a low HDL cholesterol concentration that in her father and in a normal person. LOW ill:,+
in the plasma of both parents. ma postheparin lipase activity has previousl\, 1:: r‘ .!
In the present case lymphoid tissue was not di- described in a patient with LCAT and 1 ;. ,
rectly analyzed for esterified cholesterol content. deficiency. 2fi Lipoprotein lipase appears to rz.! .i:’
However, tissue of a yellow-orange color observed HDL, or at least one apoprotein common to I-: i;!
in the pharynx of our patient was similar in nppear- and \‘ LDL as a cofactor, to achieve maximal a~:~.~
ante to lesions in the pharynx described in other ity,28-33
and the low enzyme activity in the plasma of
tonsillectomized patients \vitl> Tangier disease.3*5 our patient with Tangier disease is consistent with
Also, microscopical examination of adenoidal tissue this view. The frequently observed increase in the
in our patient showed large numbers of pale macro- plasma triglycerides in patients with Tangier dis-
phages with foamy cytoplasm assumed to contain ease may be related to diminished lipoprotein li-
lipid material hut not proved to be esterified choles- pase activity.
terol. The patient had a low platelet count on two
We are indebted to blrs. C. Foxman. Mrs. A. Lynch and
occasions, as previously described by Hoffman and Xlrs. G. Porter for technical assistance.
Fredrickson3 and by Kummer et al.6 in this disease.
The-explanation for her episodes of unusual bleed-
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