1095

that a proportion of the autistic children and of those with otherkinds of childhood psychoses had chromosomal fragile sites at

(XXp22). This chromosomal marker was seen in one girl and sevenboys, which means that 12% of the autistic/psychotic children inour study had the fra(X) (p22) abnormality (in 1-3/0 of cells).

Rett’s syndrome is characterised by autism, dementia, ataxia andloss of purposeful hand movements. It appears to afflict girls onlyland is often diagnosed as autism/childhood psychosis long beforethe neurological symptoms come to dominate the clinical picture.We have so far examined fifteen girls with Rett’s syndromechromosomally and found the fra(X) (p22) abnormality in six (in1-8% of the cells).So far, we have not identified a unique clinical subsyndrome or

core symptom group of autistic/psychotic children with frag(X)(p22). However, the affected children are usually very severelypsychiatrically disturbed, regardless of intellectual level, even

within this very severely deviant group, and they are possibly ratherthinner than other autistic/psychotic children.Could the fra(X) (p22) abnormality seen in some cases of infantile

autism/other childhood psychoses and in Rett’s syndromepredispose to the same kind of psychiatric abnormality? We urgeother researchers to focus on this point. However, no generalconclusion can be drawn because the proportion (if any) of normalchildren who have this chromosomal marker is not known.

Institute of Handicap Researchand Child and Youth Psychiatry,

University of Göteborg,402 35 Göteborg, Sweden CHRISTOPHER GILLBERG

Department of Clinical Geneticsand Psychiatry III,

University of Göteborg JAN WAHLSTRÖMInstitute of Paediatrics II,University of Göteborg BENGT HAGBERG

1 Brown WT, Jenkins EC, Friedman E, et al. Autism is associated with the fragile Xsyndrome J Autism Devel Disorders 1982, 12: 303-08.

2 Meryash DL, Szumanski LS, Gerald PS. Infantile autism associated with the fragile Xsyndrome J Autism Devel Disorders 1982; 12: 295-301.

3 Gillberg C. Identical triplets with infantile autism and the fragile X syndrome Br JPsychiatry 1983; 143: 256-60.

4 American Psychiatric Association. Diagnostic and statistical manual of mental

disorders, DSM-III, 3rd ed Washington DC: APA, 19805 Gillberg C, Wahlström J. Chromosome abnormalities in infantile autism and other

childhood psychoses population study of 66 cases Devel Med Child Neurol (inpress)

6 Hagberg B, Aicardi J, Dias K, Ramos D. A progressive syndrome of autism, dementia,ataxia and loss of purposeful hand use in girls. Rett’s syndrome: report of 35 cases.Ann Neurol 1983, 14: 471-79.

FREE RADICALS, LIPID PEROXIDATION,AND CELL DAMAGE

SIR,-We are pleased that our review has provoked somediscussion in your columns. Mr Ryle’s data (Aug 25, p 461) supportthe view that lipid peroxidation is an important component ofethanol hepatotoxicity, although they do not show whetheraccelerated peroxidation is a mechanism by which ethanol initiallycauses damage or a consequence of cell damage by anothermechanism’ (eg, acetaldehyde formation causing glutathionedepletion). In any case, the action of cytotoxic end-products of lipidperoxidation will potentiate liver injury.We agree with Dr Garcia-Bunuel (Sept 8, p 577) that vitamin E

reduces the severity of retrolental fibroplasia in premature babiesand, we too believe that this disorder is caused by increased oxygenradical formation.3 However, there is no proof for this hypothesis;vitamin E is not only an antioxidant but also a stabiliser ofmembranes.4 As Slater pointed out, "before concluding that a freeradical scavenger is attenuating a type of cell injury by a free radicalscavenging mechanism, it is necessary to study in depth the manyother possible influences that such a scavenger may have underconditions in vivo". For example, the antioxidant promethazinereduces the toxic effects of carbon tetracholoride but it also haseffects on respiration rate, body temperature, and the absorption ofcarbon tetrachloride from the gut.2 Glutathione has manyfunctions, including aminoacid transport, drug detoxification,prostaglandin synthesis, and protection against radiation damage,and it may be the lack of these, in addition to glutathione’s radical-

scavenging role, that produces the major symptoms seen in inbornerrors of glutathione synthesis.We challenge Mr Singh and Professor Ghosh (Sept 8, p 577) to

prove that "in most cases, pre-cell-damage lipid peroxidationinitiates the damage". We know of few casesl in which there is hardevidence to support this belief. Indeed that was the point of ourarticle. We do not understand what their statement that there are

"qualitative as well as quantitative differences in free radicalformation vis-a-vis lipid peroxidation states in the pre and postdamaged conditions in the cell" is intended to convey. The lucidwriting of Dr Dormandy should be an example to us all.Department of Biochemistry,King’s College,London WC2R 2LS

National Institute for

Biological Standards and Control,London NW3

B. HALLIWELL

J. M. C. GUTTERIDGE1 Halliwell B, Gutteridge JMC Lipid peroxidation, oxygen radicals, cell damage, and

antioxidant therapy. Lancet 1984; i: 1396-97.2. Slater TF Free-radical mechanisms in tissue injury. Biochem J 1984; 222 1-15.3. Halliwell B Oxygen is poisonous: the nature and medical importance of oxygen

radicals Med Lab Sci 1984; 41: 157-71.4. Lucy JA. Functional and structural aspects of biological membranes, a suggested

structural role for vitamin E in the control of membrane permeability and stability.Ann NY Acad Sci 1972; 203: 4-11.

5. Dormandy TL. An approach to free radicals Lancet 1983; n: 1010-14

INTERPRETATION OF CLOFIBRATE TRIAL

SIR,-The last sentence of the WHO clofibrate trial follow-upreport (Sept 15, p 600) pointed out that the significant differencebetween groups in mortality from causes other than ischaemic heartdisease (IHD) remained unexplained. However, the paper is writtenfrom the assumption that the difference represented an increase inthe treatment group I, while the evidence suggests the strongpossibility of a chance low incidence of mortality from non-cardiovascular disease (CVD) in the high cholesterol controls

(group II). 1,2After the earlier reports on the trial many doctors, somewhat

uneasily, continued with clofibrate in high-risk individuals whoselipids had responded well. They felt justified in this because the trialhad shown that such men had a greater than 30% reduction in

mortality from IHD and in non-fatal heart attacks. For theadditional peace of mind of these doctors, it seems worthwhile tosummarise the evidence that the adverse findings were due tochance. The latest report draws attention to the fact that the

mortality difference between groups was virtually restricted to thein-trial period. Figures for that time should therefore be looked atparticularly.

(1) Mortality for diseases other than CVD and cancer appear tohave been unrealistically low for group II in the in-trial period. Weexpected much lower than usual figures for all non-CVD causesexcept accidents and violence in all three groups, because we startedwith a healthy population of volunteers and those in whom seriousillnesses developed were withdrawn or dropped out, to die usuallylong after the 6-12 months time-lag specified for in-trial deaths inthe trial design. The table shows that we were largely correct if ourtrial figures are compared with those calculated to have beenexpected from the Registrar General’s figures for England andWales in 1971, which was roughly the mid-point of the trial.

However, the trial figure for diseases other than CVD and cancer ingroup II is only one-twelfth of that expected, and seems

unaccountably low.(2) There was no difference between groups I and II in the

numbers of withdrawals from the trial because of non-CVD (ie, onlymortality and not disease incidence was involved).

NON-CVD DEATHS COMPARED WITH NUMBERS EXPECTED FROM

NATIONAL FIGURES IN CLOFIBRATE TRIAL GROUPS I, II, AND III