Brit.J.

Psychiat. (1977), 530, 397—404

The Plasma Cholinesterase

Variants in Mentally Ill Patients

By MARY WHITTAKER Summary. 1,374

The distribution

mentally

ill patients

and MAUREEN

of the plasma

differs from

cholinesterase

that of a random

BERRY variants control

found in

sample.

The

patients are more likely to have a rare phenotype than an individual from the normal population. None of the diagnostic groups have been shown to differ in the distribution of the E1@gene, but there is strong statistical evidence that Group IV (psychosis) patients have a higher frequency of the E1t gene than the other groups. The overall frequency of the electrophoretic variant C5 + did not differ significantly from that observed in a Caucasian population, with the exception of the increase observed in Group IV c@. Twenty-eight unrelated patients with Huntington's chorea were found to have a signfficantly altered incidence of the C5 + variant and six patients from this group were found to have thc rare E1@gene. Our results indicate that the plasma cholinesterase variants may provide some insight into the inheritance of Hunting ton's chorea.

Germany

INTRODUCTION

The drug suxamethonium, widely used by anaesthetists as a short-acting muscle relaxant, is a choline ester which is rapidly hydrolysed by plasma cholinesterase. A few individuals, how ever, have a prolonged apnoea after an intra venous injection of the drug. It is now accepted that for the majority of these individuals the cause is an unusual plasma cholinesterase which hydrolyses the suxamethonium only slowly (Kalow 1959). Subsequent investigations have shown that this is an oversimplification of the suxamethonium sensitivity, and in fact four genes are now recognized for the control of the biosynthesis of the plasma cholinesterase at this locus. These are the usual, the atypical, the

fluoride-resistent and the silent genes, and these give rise to ten genotypes comprising four homozygotes and six heterozygotes, all of which have been observed. It has been shown, by studying sensitive individuals and their relatives that the four genes are autosomal alleles functioning at the same locus E1. Furthermore, the distribution of the various genotypes amongst suxamethonium sensitive

individuals

in

Canada

(Kalow,

1965),

(Goedde,

1973) and Britain

(Thomp

son and Whittaker, 1966; Lehmann and Liddell, 1969) is remarkably constant. It was therefore somewhat surprising to find a very different distribution of genotypes among the sensitive individuals accumulated over two years during the routine anaesthesia of patients prior to ECT. Moreover, the incidence of suxamethonium sensitivity was much higher than that encountered during anaesthesia for general surgery (Berry and Whittaker, 1975). It was obviously desirable to establish whether this altered distribution of the plasma cholines terase variants was maintained in a large survey of mentally disturbed patients. Accordingly we decided to screen the mentally ill patients of two

large

regional

psychiatric

hospitals

in

the

North East of England. In genetic studies, however, one must have regard to the influence of immigrant ethnic groups modifying the genotype distribution from the usual Caucasian values.

A random

sample

of individuals

from the

same area was therefore genotyped to serve as a comparison. These were mainly surgical patients from a local general hospital whose plasma had been tested. 397

THE PLASMA CHOLINESTERASE

398

VARIANTS

Frequency

NumberE1u

E11Mentally

E1―Phenotypes E1u E1@ E1―E,1E1a

ill patients

Random controls (same area) British students1374

736

7801253

blood

samples

20

75253

2364

(i o ml) were

taken

from consenting patients by venepuncture, and the samples were despatched by first class post to

Exeter

for

genotyping.

The

clinical

diagnosis

of each patient was confirmed by the consultant psychiatrists, to whom we are much indebted. The control samples consisted of plasma collected pathology

for routine laboratory

testing of the

in the general

chemical hospital,

after exclusion of any sample sent for lithium determination or for other investigation from known mentally ill patients. The plasma samples obtained after centri fugation of the heparinized blood were geno typed

immediately

required. assayed

Plasma

or

stored

cholinesterase

by measuring

the

rate

of 5 X I0@ M benzoylcholine metrically

at 240

11111in M/15

frozen

activity

until

was

of hydrolysis

chloride photo phosphate

buffer

pH 7.4at26.5 °Cbythemeth0dofK@owand Lindsay (i955). Dibucaine numbers, i.e. per centage inhibition of enzymic activity produced by io@ M dibucaine, were measured by the method of Kalow and Genest (@7) and flouride numbers (percentage inhibition of enzymic activity produced by 5 x io@ M sodium fluoride) according to Harris and Whittaker (1961).

In addition, most samples were examined electrophoretically, using 13 per cent starch gel with

a Tris-citrate

discontinuous

buffer

i6

700

PROCEDURES

S

ILL PATIENTS

T@nIE I of the plasma cholinesterase variants in mentally ill patients and normal controls

Distribution

Heparinized

IN MENTALLY

system

of Poulik (1957) pH 4@8and stained for plasma cholinesterase following the method of Harris et al, (1963).

E1@Gen

.9755

0

E1@

@oI36

found locus for plasma cholinesterase and E, for the electrophoretic variants which function at a separate locus. The superscripts u, a, f and s indicate the usual, atypical, fluoride resistant and silent genes respectively. The most common electrophoretic variant is designated C5 +, and it differs

from

the

usual

phenotype

The plasma cholinesterase variants occurring in 1374 mentally ill patients are given in Table. I It is customary to use the symbol E1 as the first

by

the

appearance of an additional slow moving component (Harris et al, 1963). The variants found in the clinical laboratory samples from the same area are also tabulated in Table i together with the results from an earlier survey of British students done by Whittaker

(1968).

Table II presents the breakdown of the distribution of the plasma cholinesterase variants found in the mentally ill patients according to their diagnostic , grouping, whilst Table III represents the distribution of the variants according to their, clinical diagnosis as con firmed by the consultant psychiatrists. DISCUSSION

In many psychiatric

disorders,

notably

schizo.

phrenia and the manic-depressive psychoses, there is a raised incidence of similar disorders TABLE II

Distribution of rare cholinesterase phenotypes in mentally ill patients

FrenquencyE,@E,@I

Diagnosis GroupTotal

NumberGene

II53 50@028300094III RESULTS

•¿ C)1@

.9@•()@()7 •¿ oi6o@O247 •¿ oo@

2.9545

34

E1―e

10900.0177 IV226 002110@OI55 0@O27ITotal:1374O@02O7O@0247

MARY WHITTAKER

AND MAUREEN

BERRY

399

T@LE III

Distribution of rare cholinesterasephenotypes and C5+ variants in mentally ill patients

phenotypesGene GroupDiagnosisNo.Rexe

frequencies

C@+E,u E1aE1― E1@ E@s

[email protected]@6@3

E1a

of

E/Percentage

—¿ IIPSYCHOPATHIC 5@0IIIPsyciso@uaosis(a)

STATES50I00O@

Anxiety State (b) Hysterical Disease ‘¿ 0.0IVPSYcHoSIS(a) (c) Neurosis35

8 1833

o

o

4I

50

i0@0429 o•[email protected] o@oI640

72

o

2

0

0

i622

025

I1

00@0193

0@0312I2@4 0O@o218

2!

I

2

0

o'o238

o@o476

i8@g

i

2

0

0o312

00625

133

o3

6I

o0@0329o0@0263 0@I07Iio@8

@.,

@,

Schizophrenia

(b)Affective Disease (i)

Manic-Depressive

(a) Involutional

Melancholia596 2I@4(c) Organic Psychosis

(,) Confusional State (a) Dementia (i) G.P.I.

i6

(ii) Huntington's chorea76 36@4(iii) SenileDementia

a84

io@6

0@OI388

(iv) Arteriosclerotic I9@4(v) Dementia197

0II 00@0355 00@0304 0@0294I2@4 2I 3413 Alcoholic342200@02940@0294I3@3Total1374536440@02070@0247II@9

in

first

evidence,

degree

relatives

indicates

the

which,

existence

with

other

of genetic

factors of some kind (Slater and Cowie, 1971). Indeed, claims have recently been made for

various so-called genetic ‘¿ markers'in schizo phrenia, notably low monoamine oxydase activity in platelets (Wyatt et al, 1973). Also linkage with colour-blindness and the Xg blood group has been claimed for some depressions. Such example,

observations the

have

spectrum

their

limitations

of enzyme

; for

activity

in

cholinesterase variants found in suxamethonium sensitive individuals who are mentally ill. These can be compared

with similar parameters

surgical

showing

patients

amethonium

frequency whereas resistant

(Table

remains the gene,

is associated

It could be that the low activity

with

an enzyme

variant

in the

individual which is part of his genetic comple ment and as such is not influenced by environ mental factors such as nutrition or pathology. Using the data ofour earlier paper (Berry and Whittaker, 1975) WC can calculate the fre quencies of the genes determining the plasma

The

E1U

gene

the same in both surveys,

frequency of the fluoride E1f, has increased significantly TABLE IV

suxamethonium

sensitive individuals

GenefrequenciesNumber

values. These studies can, however, indicate useful areas for the investigation of enzyme polymorphisms.

IV).

from

to sux

Genefrequencies ofplasma cholinesterase variants found in

any population is wide and it is difficult to be rigid about the division between low and high

@

sensitivity

—¿ E1uE,@E1@

General surgery* Mentally ill** patients

..

* Combined

Whittaker

6io 23

data ofKalow

0 4098 o 5! 39 0 .()607 04130

(1966) ; Lehmann

o3261

(1965), Thompson

and

Liddell

02609 and

(I96g),

Whittaker and Vickers (i@'o) and Berry and Whit taker (i@75). ** Berry and Whittaker

(i@@).

400

THE PLASMA

CHOLINESTERASE

VARIANTS

in the ECT patients, with a concomitant decrease in the frequency of the atypical gene. Our

results

observation

are somewhat

reported

‘¿ suxamethonium

time when

seemed

to

it was given

with

act

for

a

to psychiatric

before electroconvulsive was administered

at variance

an

by Rose et al, (1965) that shorter

patients

therapy than when it

before surgery'.

In fact we find

that i •¿per 4 cent psychiatric patients become apnoeic compared to o •¿ i per cent surgical patients when given suxamethonium. In other words, in our experience this muscle relaxant appears

to persist

for a longer

period

in ECT

patients than in surgical patients. Rose et al, (bc

cit)

confirmed

their

hypothesis

that

the

apparent decreased sensitivity to the drug could be accounted for by higher levels of plasma cholinesterase in psychiatric patients than those found in a control group. All individuals were found to have the usual phenotype E1uE1u. It is perhaps unfortunate that neither the I 16 patients nor the 55 controls were examined for the C5+ electrophoretic variant of plasma cholinesterase. This variant is associated with a 30 per cent increase in enzymic activity

(Harris

et a!,

1963).

Higher

levels

of

plasma cholinesterase activity in psychiatric patients than those found in healthy controls have

been

reported

by Richter

and

Both these investigations

of 205 and

atric

patients

were

the

realization

respectively

27 psychi

completed

of the existence

variantsof thisenzyme. The increasedplasma cholinesterase activity was not considered to be

caused by any of the many drugs used in a mental hospital (Plum, ig6o). Antebi and King (1962) found that five in a group of 26 Schizo

@

note we do confirm

an increased

TArn@ V

Statistical analysis of the plasma cholinesterasevariants in mentally ill patients Diagnostic Group

Rare phenotypes Number

withoutI

with

4(7.5%) II

III IV

Mentally Random

I (w%)

ill (Total) controls

British students 752x2

‘¿(6•a%) 4 102 (@•@%) 121 (8.8%) 36 (@@%)

28 (3.8%)

Number

49 4

212 988

1253 700

forgroupIV comparison of patients had a raised plasma cholines terase activity; such a frequency is not widely Mentally Controls Students different in such a small survey from the 10—15 illIII per cent expectation of the C5 + variant with its 1.95* N.T. 0.36* 2.36* associated 30 per cent increase in enzymic IV N.T. 1191** 22.50*** activity. McKerracher et al (1966) have have Mentally ill IO.14** 2o.29*** shown some connection between serum cholin Controls i .26* esterase activities and the severity of psychiatric disorders, but ‘¿ the nature of this relationship * Not significant. remains obscure'. There is, however, some Significant at 2% level. disagreement about the possible relationship Significant at 1% level. of plasma cholinesterase activity and mental Groups I and II are too small for analysis. phrenic

@

this cautionary

plasma cholinesterase activity in our psychiatric patients. Analysis of the cholinesterase phenotypes in the mentally ill patients is complicated by the infrequency with which some diagnoses occur in our sample. However, we see from Table V that an analysis of the data in Table I yields convincing evidence for the hypothesis that a mentally ill patient is more likely to possess a rare phenotype than an individual from the normal population. Further analysis of the data from Table V shows that there is no real

before

of genetic

ILL PATIENTS

disease (reviewed by Domino and Krause, 1972 a). A recent paper by Domino et a!, (1975) continues to report reduced plasma cholines terase activity in chronic (but not acute) schizophrenic patients compared with normals. Studies on enzymic activities are always at a disadvantage since the normal range is very wide and each genetic variant has its own accepted range of activities with considerable overlap between variants. However, in spite of

Lee (1942

a and b), as well as by Ted and Jones (1937).

IN MENTALLY

MARY WHITTAKER

AND MAUREEN

evidence that Group III (psychoneuroses) is statistically different from the controls in pos

genetic component, whereas others, such as hysterical neurosis, may have none or a rela

sessing

tively

one

however

of

the

rare

phenotypes.

very strong evidence

There

is

that Group

IV

(psychoses)differsmarkedlyfrom the reference

@

4°'

BERRY

groups. It appears that psychotic patients are more likely to possess a rare phenotype than the normal population. If one further considers the distribution of two genes E1@and E1@we deduce from the data in Table VI that none of the groups differ in the proportion possessing the E1a gene. Table VI does, however, provide overwhelming evidence that Group IV differs from both the random controls and the students in having a higher frequency of the E,@gene. There is also some evidence that the random control group from the North East have a somewhat higher frequency of the E1f gene than the group of British students. The only subgroups which justify simple CHIZ throughout are schizophrenia (IVa), senile dementia (IVc iii) and neurosis (IIIc). Miner (@7@) has reviewed the evidence for genetic components in the neuroses and concludes from family and twin studies that some neuroses, such as anxiety neurosis, have an important

T@z

minor

genetic

component.

Some support

is given to those conclusions from our results in Table

III.

We

have

found

no rare

plasma

cholinesterase variant in the patients with hysterical neurosis, whereas i per cent of the patients

with anxiety

state had one of the van

ants. But the numbers involved are small and some caution is counselled. There is no real evidence from Table VI that Group III differs from other groups, but once again the number in this group is relatively small. In senile dementia not only the total heterozygotes but both the numbers of the E,a heterozygote and the E1@ heterozygote are very significantly higher. In schizophrenia the significance lies only in the total heterozygotes. Domino and Krause (i 972b) have examined the red cell and plasma cholinesterase activity in 39 drug-free chronic schizophrenic patients. Two of these patients were genotyped as E1uE1a and E1uE15 respectively. The remainder had the usual genotype E1UE1Uwhich gives a gene frequency of E1a = o @oI28and of E,@ = ooooo. These results

are very

different

from

ours.

It is un

VI

Statisticalanalysisof the E1aand E1@Genein mentallyill patients, using datafrom Table 1! Diagnostic Group

Gene E,a Number with

I

Number without

(@.@%)

II

o(o%)

8 (@@%)

III IV

46 (4.2%)

Controls

20 (27%) 25 (32%) 755x2

Students3

Gene E1@

50

IV

218

Controls0.08*

7 (3.1%)

1044

59 (5.4%) i6 (2.2%) 5775x' (o.6%)

716

@ @

Significant at 1% level. Significant at 0.5% level.

219

1031 720

Students1.65* Controls 0.00* 1.02* 0.17*

Groups I and II are too small for analysis * Not significant. ** Significant at a% level.

52 4

groupIV comparison for

Controls 0.17* 2.44*

Number without

I (@•g%) I (20%)

5

groupIVcomparison for StudentsIII

Number with

0.30* Io.8g*@

29.89****

5.44**

THE PLASMA CHOLINESTERASE

402

VARIANTS

fortunate that the genotyping was not done under identical conditions ; not only were different substrates used but the temperature @

used

by

Domino

compared Harris,

and

was

1964;

McComb

and

et al, 1965; and

Whit

ig6g). It is unfortunate

Krause

(1972b)

have

and that

predicted

their flouride and dibucaine numbers for the different phenotypes from a small number of ‘¿ usual' genotype

E1UE,U

an

even

smaller

number of genotype E,uE1a. To our knowledge Domino et al, (1975) have not extended their studies beyond schizophrenia, though they do now distinguish between chronic and acute cases (albeit only 29 of the former and 7 of the latter).

was

of illness. The observed

absent

in

their

difficulty in assessing the duration in Huntington's

chorea

controls.

The

of the disease was reasonably

assumed to account for the lack of a significant

relation

duration ing

between

CSF acid phosphatase

and the

of the illness. It was somewhat surpris

in our

earlier

investigations

(Berry

and

Whittaker, ‘¿ 975)to find that 2/23 of the suxamethonium-sensitive individuals had Hunt ington's chorea, a disease which would be expected

to occur in only about

i in IO,OOO of a

random population. In spite of the few cases it would appear from Table III that patients with Huntington's chorea are significantly different from the remainder of the mentally ill population.

The

gene

frequency

of E1f is very

of obtaining the observed distributions. As regards the total number of heterozygotes, Huntington's chorea showed a highly significant departure from the population sample, and this is entirely

incidence

to the

results

other diseases numbers analysis,

so the exact

in Table

III,

in all

were too small for x2

probability

was

calculated

due to an excess of E,uE1f heterozy

gote. Huntington's chorea is a chronic progressive disease controlled by an autosomal allele with high penetrance for the heterozygote at advanced age (Reed and Ned, I959 Myrianthopoulos ig66; Bruyn, 1968 and Heathfield, 1973). In many cases the age of onset is 25—50.There is to date no technique for detecting clinically healthy carriers of the disease, and the demonstration of close linkage between the genes controlling Huntington's chorea and a polymorphic trait would provide such a technique. Previous investigations to establish such a linkage have @

correlation

much higher, to our knowledge, than any so far reported for ethnic distributions or pathological studies. The significance is, however, obscure and one must await the outcome of further studies; in particular it is very desirable to genotype a very much larger sample of patients with this clinical diagnosis to confirm the high

Returning

@

ILL PATIENTS

related to the duration

37 5 °C process

to our 26 ‘¿ 5 °C (cf. Bamford

taker and Hardisty, Domino

Krause

IN MENTALLY

of E1f. In parenthesis,

it should

be

added that none of the patients are related and that the presence of the flouride-resistant gene has been confirmed by family studies in most cases. It is rather reassuring to learn that in a sample of 13 patients with Huntington's chorea in Denmark four of them were found to have the genotype E,UE1f (Hand, 1974). There are, of course, variations in blood group and

enzyme

polymorphic

distributions

among

Caucasian populations living in different geo graphic areas (Race and Sanger, 1968; Roberts and Sunderland,

1973). The ABO blood

group

distributions in Britain has been assessed from been made by Mohr Leese et al, (I9@a), the extensive data of the emergency blood Yates et al, (1973) and Beckman a al, transfusion service (Kope@, 1970). The ABO The latter investigated 125 individuals in 36 gene frequency distribution showed a highly different sibships for 15 genetic markers. They significant difference between the south-east found an association between Huntington's of Northumberland, and the north part of chorea and the blood group phenotype Fy(a±), County Durham, including Tyne and Wear but no close linkage was apparent. The other County, and the remainder of the country. investigators also drew blank. Yates et al, (,@‘@) Papiha (i@7@) has suggested differences in reported a positive correlation in CSF acid the gene frequencies of some red cell enzymes in phosphatase activity with age in Huntington's 550 subjects born in Northumberland compared chorea patients and suggested that the activity with those found in individuals from the south of this enzyme in CSF in these patients could be of England. But the different frequencies were

MARY WHITTAKER

significant only for adenosine deaminase and adenylic kinase. These findings, together with those reported in this paper, do suggest that we are perhaps investigating an ‘¿ unusualpocket' in the geographic distribution of genetic variants in Britain. A rare gene, such as the fluoride resistant gene E1@,found to have an appreciable frequency . either

@

in genetic

a

restricted drift,

founder

population effect

suggests or

local

selective advantage, but none of these factors are obvious in the present study. Rao and Morton (‘973) have shown that large deviations from the mean gene frequency are not im probable and could very well occur by chance alone. Further genetic studies are very desirable, and these are being pursued. The screening of a similar population in the south-west of England is in progress. During the course of these investi gations we learnt that Propart (i@i@) was also studying

the plasma

cholinesterase

phenotypes

found in mentally ill patients living in Australia. It will be most interesting to compare the results of these independent surveys. The overall frequency of the electrophoretic variant C5 + in mentally ill patients was not significantly different from that found in Caucasian populations. There does, however, appear to be an increased frequency of the C5 + variant in patients having diagnostic code num bers IV c@. which probably merit further investigation. One striking finding was the appearance of a very slow component in the plasma cholinesterase of a schizophrenic patient. Blood samples were taken from this patient many times and the extra band was always apparent. Uncommon electrophoretic patterns have been reported by Van Ros and Druet (1966) in African subjects. Neitlich (1966) has reported a variant with elevated cholinesterase activity which is resistant to suxamethonium. This variant has been shown to have an usual structure by Yoshida and Motulsky (1969). Our variant has different characteristics to any previously described and will be reported elsewhere. In spite of the small sample of patients with Huntington's chorea, the electrophoretic results do indicate an altered incidence of the C5 + variant. Our results indicate that future work on plasma cholinesterase may provide some

AND MAUREEN

insight

BERRY

into

this

403

disease,

and

we

propose

to

investigate the sex-related factor (Bird et a!, i@74) in the inheritance

of Huntington's

chorea.

Aczuowi.anos,aiers Financial

support

from the Medical

Research

Council

is gratefully acknowledged. The spectrophotometer was purchased from a grant from The Royal Society. Postal charges were covered by a grant from the North Eastern Regional Health Authority. ainical laboratory samples were collected at The

Royal Infirmary, Sunderland, and we are grateful to Dr Paul Trinder and Mr Brian Atkins for their enthu

siastic cooperation. The willing assistanceof the nursing staffs of Cherry Knowle Hospital, Winterton Hospital, Stockton-on-Tees,

Sunderland, and is also gratefully

acknowledged. We are indebted to Mr Martin Dyer,

Teesside Polytechnic, Middlesbrough for the statistical analysis. The technical assistance of Mr R. J. Lovell was

indispensable. We are most grateful to Dr C. F. Lascelles, Consultant Psychiatrist, to Dr G.

Cherry Knowle Hospital, Sunderland, and E. Duggan-Keen, .Consultant Psychiatrist,

Winterton diagnoses

Hospital, Stockton-on-Tees

of the mentally

for the clinical

ill patients.

Rnvaanncas ANTEBI,

R.

N.

&

Kiuo,

J.

(I2)

in chronic schizophrenia. BAMPORD,

K.

F. & H@aan,

Serum

enzyme

activity

3. ment. Sri., io8, 75-9. H.

(i@6i@) Studies

on usual

and

atypical serum cholinesterase using x-naphthyl acetate as substrate. Ann. hum. Genet, Land., 27, 417—25. BECKMAN,L., CEDEROREN, B., MAI-I'SSON, B. & OrrossoN (‘974) Association and linkage studies of Hunting ton'schorea in relationto‘¿ fifteen geneticmarkers. Hereditas, 77, 73—80. BERRY,

M.

&

WHITrAKER,

M.

(ig7@)

Incidence

of

suxamethonium apnoea in patients undergoing ECT. Brit. 7. Anaesih., 47, 1195—7.

BIRD,

E.

D.,

CAKo,

A. J.

& PILLINO,

J.

B.

(@97i,)

A sex

related factor in the inheritance of Huntington's chorea.Ann.hum. Genel,Lond.,37,255—60. BRUYN,

G.

W.

clinical

and

(i988)

Huntington's

laboratory

Clinical Neurology, Vol VI G. W. Bruyn), Holland.

pp.

DOMINO, E. F. & Ka@usn,

activity

and

mental

chorea,

synopsis.

historical,

In

Handbook

of

(ed. P. J. Vinken and

298—378. Amsterdam:

North

R. R. (1972a) Cholinesterase

disease:

a literature

review.

MichiganMentalHealthResearchBulletin,5(2), 3—27.

—¿

—¿

(1972b)

Re-examination

of

red

cell

and

plasma

cholinesterase activity in drug-free chronic schizo phrenic patients ‘¿ 7—3'. —¿

—¿

and normals.

THIESSEN,

M.

M.

&

Biological Psychiatry, 4, BATSAKIS,

J.

D.

(,975)

Blood protein fraction comparisons of normal and schizophrenic patients. Arch.gen. Ps,cliiat., 32, 717—21. Goanrnt,

H. W. (I973)

Private

communication,

HANaL,H. K. (1974) Private communication.

THE PLASMA CHOLINESTERASE

404

VARIANTS

M.

(1963)

Genetic

serum cholinesterase

studies

on

detected

a new

variant

of

by electrophoresis.

Ann. hum. Gene:, Lond., 26, 359-82. —¿

&

WHITrAKER,

M.

(1961)

RAcE,

inhibition

lion Symposium on Biochemistry of Human Genetics, Churchill.

Contribution

of

hereditary

factors

to

the

response to drugs. Fed. Proc., 24, I 259-65. —¿

&

Gni@urzr,

K.

(i@@7)

A

method

atypical forms of human determination of dibucaine BiOchem., 35, 339—46. —¿

&

LINDSAY,

H.

A.

(i95@)

for

the

detection

A

comparison

of

KOPEf,

Canad. 3. BiOChem., 33, 568-74.

A. C. (1970)

The Distributions

oft/ze Blood Groups in

the United Kingdom. London: Oxford Univ. Press.

Lansn, S. M., Poim, D. A. & SmELDS,J. (1952) A pedigree

of Huntington's

chorea—with

linkage

data

by

R. R. Race. Ann. Eugen., i7, 92-112. Lnmwos, H. & LIDDELL,J. (‘969) Human cholinesterase (pseudocholinesterase) genetic variants and their

recognition. Brit. 3. Anaerth., 41, 235-44.

McCossn, R. B., L@sorrA, R. V. & WEirroNx, A. (@6@) Procedure for detecting atypical serum cholinesterase using o-nitrophenylbutyrate as substrate. Clin. Qiem.,

6, 645—52.

MCKERRACHER, D. W., McGuntx, W. A., ARONSON,A. & Scoi-r, J. (,966) Pseudocholinesterase and the prediction of stability in subnormal and psycho

—¿

3. med.Genet.,3,298-314.

Study of cholinesterase

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