ABC of Clinical Genetics

DNA ANALYSIS IN GENETIC DISORDERSHelen M Kingston

Examples of mapped autosomal genes

ciDisorder

Porphyria cutanea tardaGaucher's diseasevon Hippel-Lindau diseaseHuntington's choreaPolyposis coliHaemochromatosis21-Hydroxylase deficiencyOsteogenesis imperfecta(some forms)

Cystic fibrosisGalactosaemiaMultiple endocrine neoplasia IlaSickle cell anaemia and

a thalassaemiaAcute intermittent porphyriaPhenylketonuria (classic)Wilson's diseaseRetinoblastomaa,-Antitrypsin deficiencyTay-Sachs disease(x ThalassaemiaAdult polycystic kidney

diseaseNeurofibromatosis

(peripheral)Osteogenesis imperfecta(some forms)

Familialhypercholesterolaem ia

Myotonic dystrophyAlzheimer's disease (familial)HomocystinuriaHurler's syndrome(mucopolysaccharidosis 1)

Neurofibromatosis (central)

hromosomeNo

1

1

34566

779

10

1 111121313141516

16

17

17

19192121

2222

The ability to analyse DNA has had an important impact on ourunderstanding of genetic disorders. Many genes have now been cloned andsequenced and the mutations that cause disease identified. Many othergenetic disorders, for which the genes are not yet isolated, have beenmapped to particular chromosomal locations, and this permits predictivetesting with linked DNA markers. It has been estimated that the entirehuman genome will be mapped and all the important genes sequenced bythe end of the century. This is not unrealistic and promises to be ofenormous benefit to families with genetic disorders and to potential genecarriers.

International meetings on human gene mapping, inaugurated in 1973,are held every two years and mark current progress. At the first meeting thetotal number of autosomal genes whose chromosomal location had beenidentified was 64. The corresponding number ofmapped genes had risen to928 by the ninth meeting in 1987. This tremendous increase reflects theaddition of various molecular biological approaches to those of moretraditional somatic cell genetics. The total number of mapped X linked locihas also risen, from 155 in 1973 to 308 in 1987. Single copy anonymousDNA segments, which may be used as DNA markers for genetic disorders,number more than 1500 for autosomes and over 300 for the X chromosome.Many of these are clinically useful probes that can be applied both todetecting carriers and to prenatal diagnosis.

In this concluding article some of the ways in which moleculartechniques can be applied clinically are illustrated with selected geneticdisorders as examples. In most genetic conditions amenable to prenataldiagnosis by DNA analysis studies must be performed on the family first todetermine whether there is a DNA variation that gives an informativepattern, and certain key relatives must be available for testing to makeprediction possible. Because chorionic villus sampling is performed at eightto nine weeks of gestation counselling and investigating a family beforepregnancy is important to ensure that a couple have time to make fullyinformed decisions.

Haemoglobinopathies

41;t a ce2 cal5'{I I} m

Chromosome 16

Embryonic Fetal Adulthaemoglobin haemoglobin haemoglobin

4f32 - GY A'Y 4,t31 b 35'11C711_UU

Chromosome 1 1

Globin gene clusters on chromosomes 1 1 and 16. (ipdenotes pseudogenes.)

The haemoglobinopathies constitute the most common autosomaldisorders world wide and have profound effects on the provision of healthcare in some developing countries. They were among the first disorders tobe analysed at a molecular DNA level, partly because the structure ofhaemoglobin was already well defined and also because fairly puremessenger RNA could be extracted from reticulocytes and used to producecomplementary DNA probes. The globin gene clusters on chromosome 16include two cc globin genes and on chromosome 11 a i globin gene.

Various mutations in the P3 globin gene cause structural alterations inhaemoglobin, the most important being the point mutation that produceshaemoglobin S and causes sickle cell anaemia. Direct detection of the pointmutation (described in the previous chapter) permits early prenataldiagnosis by analysis ofDNA extracted from chorionic villus material.

BMJ VOLUME 299 15 JULY 1989170

Normal o0+ trait

trait

a+ thalassemia

^ Comp>hetero(haemH dise;

cO thalassemia(haemoglobin Bart'shydrops)

Normal gene-{ }l Gene deletion or mutation

Representation of globin genes in various formsof a thalassaemia.

Cystic fibrosis

Kq"" 1-21-1

A R C D

Allele 1

Allele 2

Autoradiographic bands detected byprobe pJ311 in DNA digested with Msp Irestriction endonuclease in family withcystic fibrosis. Affected child (lane B) ishomozygous for allele 1, identifying theparental chromosomes that carry thecystic fibrosis gene. The fetus (lane C) hasinherited one normal chromosome andone carrying the cystic fibrosis gene andis predicted to be a healthy carrier.

The thalassaemias are due to a reduced rate of production of one or moreglobin chains, leading to an imbalance in their production. In athalassaemia production of a globin chains may be absent (aO) or reduced(a+). In the &° thalassaemia trait both a globin genes are deleted from onechromosome and in the homozygous state all four genes are deleted. In theca thalassaemia trait only one a globin gene is inactivated, either by deletionor mutation, and the other is intact. Deleted genes can be detected directlyin the homozygous state by failure of hybridisation with a globin geneprobes.

n

In 13 thalassaemia over 30 different mutations causing the disorder havebeen identified, which result in ,13 and ,+ types depending on whether theproduction of 13 globin chains is absent or reduced. Major gene deletions areunusual in ,B thalassaemia, and most mutations entail point mutations orsmall deletions or insertions. To offer prenatal diagnosis by DNA analysiseach individual family must be studied to determine the nature of themutation. Particular mutations are common in certain populations, andspecific oligonucleotide probes are available for prenatal diagnosis in manycases.

Cystic fibrosis is the commonest autosomal recessive disorder in northernEuropeans and remains incurable, although survival is improved withsupportive treatment. Detection of carriers in the population may soon bepossible, but at present prevention depends largely on prenatal diagnosisbeing offered to couples who already have an affected child. The Brock testhas been available for several years and predicts the likelihood of cysticfibrosis in a fetus at high risk by measuring enzyme activities of themicrovilli in amniotic fluid. Early prenatal diagnosis is now possible byDNA analysis of chorionic villus material.

The cystic fibrosis gene has not yet been isolated, but family studieslocalised it to chromosome 7 in 1985. Several identified DNA probes thatare closely linked to the cystic fibrosis locus on either side of the gene can beused clinically. An informative DNA pattern in a family is one in which theparental chromosomes carrying the cystic fibrosis gene can be identifiedfrom the DNA pattern in the affected child. The genetic state of a fetusdepends on whether it shares one, two, or no haplotypes with the affectedsibling. With currently available probes most families are informative forthis type of prenatal diagnosis with a high degree of accuracy (99%). DNAanalysis can similarly be used in families with cystic fibrosis to assess carrierstate in healthy siblings. The likelihood of an unrelated spouse being acarrier can also be calculated because most chromosomes carrying the cysticfibrosis gene in northern Europeans carry a particular set of marker typesthat are uncommon in normal chromosomes. This linkage disequilibriumbetween the marker haplotype and the cystic fibrosis gene has no directconnection with the cystic fibrosis mutation but probably reflects the factthat most chromosomes carrying the gene are descended from a singleancestral mutant.

A healthy sibling of a patient with cystic fibrosis with an unrelated spousehas a fairly low risk of cystic fibrosis occurring in his or her children(2/3X 1/2OX V4_ 1/12o) and may find this reassuring. Analysis ofDNAhaplotypes might change the risk such that it becomes particularly high orparticularly low, and this might influence decisions about reproduction andprenatal diagnosis. If the risk increases, however, but not to a level at whichprenatal diagnosis becomes sufficiently reliable, parental anxiety will onlybe heightened. More certain detection of gene carriers in the generalpopulation will probably become feasible once the gene for cystic fibrosishas been isolated, and such couples may choose to defer tests until this ispossible.

BMJ VOLUME 299 15 JULY 1989 171

Huntington's chorea

G8 typing

17kb-15kb-

4 9kb*

3-7kb-

Inheritance of G8 haplotypes in DNA digested withHind /II restriction endonuclease (A= 17, 3-7 kilobases(kb); B=17, 4-9 kb (not shown); C=15, 3-7 kb; andD=15, 4-9 kb).

AA BC

AC BD

/AD

AA BC

AC BD

ECD

AB AC

AA BD

/'AD

Examples of fetal exclusion test results inHuntington's chorea.

Duchenne muscular dystrophy

Xp

Xq

U

High risk Low risk

Huntington's chorea is an autosomal dominant condition and is one ofthemost devastating genetic disorders, with the onset of involuntarymovements and dementia being variable but commonly occurring betweenthe ages of 35 and 55. The gene has not yet been cloned but was found to belinked to a probe called G8 in family studies in 1983, which localised thegene to the short arm of chromosome 4. The G8 probe detectspolymorphisms with the restriction enzyme Hind III, and the fourhaplotypes, designated A, B, C, and D, can be tracked through affectedfamilies. Other linked probes are also now available and predictive testingfor a person at risk is possible if the family structure is suitable and themarker pattern in the family is informative. People at risk, however, maynot want predictive testing in the absence of any effective treatment. Thepotential for predictive testing raises many important ethical issues. Carefulcounselling before and after such tests is essential to ensure that the patientcan cope with possible bad news from a test.

A major concern ofmany people at risk of developing the disease is thatthey may transmit the disorder to their children. A prenatal test can beperformed that indicates the risk to a fetus without predicting the geneticstate ofthe parent. The principle ofthe test is that it determines whether thefetus has inherited a chromosome from the affected or unaffectedgrandparent through the parent at risk. A chromosome from the affectedgrandparent confers a 50% risk (the same as the risk to the parent). Achromosome inherited from the unaffected grandparent reduces the risk tothat associated with the chance of recombination having occurred betweenthe gene for the;disease and the probe being used. One potential problemwith this type of test is that if a pregnancy identified as being at 50% riskcontinues to term and the parent subsequently develops Huntington'schorea this indicates that the child has probably also inherited the gene andwill develop the disorder.

Uninformative

Xp 21.2 Duchenne muscular dystrophy-O*Xp Id 1.. Becker's muscular dystrophy

Location of genefor Duchenne andBecker's musculardystrophy on Xchromosome.

Duchenne muscular dystrophy was first described in 1861 and theX linked pattern ofinheritance reported in 1943. A milder form ofX linkedmuscular dystrophy identified by Becker in 1955 is now known to be due toa defect in the same gene. Duchenne muscular dystrophy has been reportedin girls who have one X chromosome disrupted by a translocation between itand an autosome, with the normal X chromosome being preferentiallyinactivated. The site of the breakpoint in the cases of the chromosomaltranslocation is always located in the Xp2 1 band, which suggested thatthis was the location of the Duchenne gene. DNA probes identified fromthis region were shown to be linked to Duchenne muscular dystrophy infamily studies in 1983, confirming this localisation. Other probes showingcloser linkage have subsequently been identified and used in detectingcarriers. Strategies were then devised to obtain DNA probes from within-the gene by using DNA from a patient with a chromosomal deletion andfrom another with a chromosomal translocation. The gene that causesDuchenne and Becker's muscular dystrophy when it is defective has sincebeen cloned and the gene product, dystrophin, identified. Several genomicand complementary DNA probes are now available for use in carrierdetection and prenatal diagnosis.

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172

Restriction fragment lengthpolymorphism (alleles 1 and 2) onX chromosom'e detected by probepERT 87-15 in DNA digested with Xmn Irestriction endonuclease. Dystrophygene segregates with maternal allele 1,indicating that one daughter (lane D) isat high risk of being a carrier and theother (lane E) is at low risk.

Autoradiographic bandscorresponding to exons of dystrophingene detected by probe Cf56 in DNAdigested with Pst I restrictionendonuclease from boys withDuchenne muscular dystrophy. LaneA: five exons with no deletion; lanesB-F: various exons deleted; lane D:also shows alteration in size of largestexon.

?*; 1-2 :>1-

A-^ B C

Several probes detect restriction fragment length polymorphisms(RFLPs) within the dystrophin gene. The variant bands identified onautoradiography can be used to track the disease gene through a family andmake predictions about genetic state in female relatives and male fetuses atrisk. As the dystrophin gene is so large (consisting oftwo million base pairs)and mutations causing muscular dystrophy may occur throughout the genethe gene mutation in a particular family may be a considerable distance fromthe RFLP site detected by the probe. Recombination between the two sitesduring gametogenesis may separate the loci so that absolute predictionabout transmission of the mutation from parent to child cannot be madefrom RFLP studies. In family studies 5% recombination is observed andthe prediction of genetic state can therefore be made with 95% accuracy.

About 60-70% ofmales with Duchenne and Becker's muscular dystrophyhave deletions ofcoding sequences in the dystrophin gene as shown byhybridisation with complementary DNA probes. This not only confirmsthe clinical diagnosis, which can be difficult in mild, sporadic cases, but alsoprovides a definitive prenatal diagnostic test in families in which an affectedboy has a gene deletion. Chorionic villus sampling in pregnancies at riskallows fetal sexing to be performed by chromosomal and DNA analysis andin male fetuses the presence or absence of a deletion can be determined.This allows unaffected male pregnancies to continue to term, which was notpossible when only fetal sexing was available. Different deletions are seen indifferent families, and patterns are emerging that correspond to theDuchenne and Becker's forms of muscular dystrophy; this helps todistinguish between the two disorders in sporadic cases in young boys.Deletions causing a frame shift completely disrupt dystrophin productionor function and cause Duchenne muscular dystrophy whereas deletions thatdo not disrupt the reading frame allow a modified protein to be produced,resulting in the milder Becker's form.

A deletion in the dystrophin gene does not help to identify gene carriersas on autoradiography the bands corresponding to the normal gene on oneX chromosome mask the presence of a deleted gene on the other. Dosagestudies (determining whether one or two copies of the relevant exons arepresent) are not generally reliable enough to permit prediction. If a probethat detects a deletion in a family also, however, identifies an associatedRFLP this can be used in determining carrier state, as shown by theautoradiograph opposite. DNA from the affected boy (lane A) shows nobands with probe p20, indicating a gene deletion. His mother (lane B) isheterozygous for the associated RFLP (one allele being present on eachchromosome), indicating that neither of her X chromosomes carries thisgene deletion in the cells studied. Her carrier risk is not, however,negligible as she may carry a germline mutation which would not bedetected by analysing leucocyte DNA. The boy's sister (lane C) is alsoheterozygous for the RFLP (one band inherited from her father and theother from her mother), indicating that she has not inherited a deleted genefrom her mother. An inherited mutation would be present in all somaticcells and heterozygosity for the RFLP in leucocyte DNA confirms that sheis not a carrier.Restriction fragment length polymorphism and deletion detected, with probe p20 inDNA digested with Msp / restriction.endonuclease. (See text for interpretation.)V = Deletion.

BMJ VOLUME 299 15 JULY 1989 173

1-2 1-V7A B C D E

Allele 2 - J_

Restriction fragment length polymorphism anddeletion detected with probe p20 in DNA digestedwith Msp / restriction endonuclease. (See text forinterpretation.) V=Deletion.

Another example of deletion and RFLP analysis is shown in theautoradiograph opposite. The affected boy again has a gene deletiondetected by probe p20 (lane C). His mother (lane A) is apparentlyhomozygous for allele 2. One of the boy's sisters (lane E) has inherited anX chromosomal band from her father (lane B) but not her mother. Theexplanation of this apparent "non-maternity" is that the daughter hasinherited a deleted gene from her mother, and this indicates that they areboth carriers. The other sister (lane D) has inherited a paternal and amaternal band. The maternal band corresponds to the non-deleted gene,and this sister is therefore not a carrier.DNA analysis has proved to be extremely valuable in investigating

families with Duchenne and Becker's muscular dystrophy. Not only canmany carriers be identified and offered definitive prenatal diagnosis butfemale relatives at low risk can commonly be identified and reassured.Several difficulties are still encountered: family studies are required andpredictive tests may not be possible if the affected boy is no longer living;occasional families have uninformative DNA patterns with the currentlyavailable probes; and calculations are often complex. In sporadic cases themother of an affected boy cannot be given a negligible risk because of thepossibility of germline mosaicism, and even if population screening forcarriers becomes possible the disorder will not be eradicated because of thefrequency with which new mutations occur.

Dr HelenM Kingston is consultant clinical geneticist at St Mary's Hospital, Manchester.The autoradiograph of cystic fibrosis was reproduced by kind permission ofMr A Ivinson,

that of the G8 haplotypes by Dr A Read, and that of Duchenne muscular dystrophy by Mr RMountford, St Mary's Hospital, Manchester.

This article concludes the series.

BOOKS RECEIVED

Cardiovascular diseases

Thrombolysis in Cardiovascular Disease.Ed D G Julian, W Kubler, R MMorris, et al. (Pp xii+458; figs; pricenot stated.) New York: Dekker, 1989.ISBN 0-8247-8147-3.World Health Organisation TechnicalReport Series 772. "Appropriate Diag-nostic Technology in the ManagementofCardiovascular Diseases." Report ofa WHO Expert Committee. (Pp 41:Sw frs 6.) Geneva: World HealthOrganisation, 1988. ISBN 92-4-120772-8.

Child welfareChild Abuse: the Scottish Experience.Ed F Stone. (Pp 88; £6.99 paperback.)London: British Agencies for Adop-tion and Fostering, 1989. ISBN 0-903534-83-5.Responses to Cleveland: ImprovingServices for Child Sexual Abuse. Ed PRiches. (Pp vi+94; £7.95 paperback.)London: Whiting and Burch on behalfof the National Children's Bureau,1989. ISBN 1-871177-01-4.Sexual Abuse: Giving Help to Children.A Practical Guidefor Concerned Profes-sionals. C Doyle. (Pp 16; £1.95 paper-back.) London: Whiting and Burch onbehalf of the National Children'sBureau, 1988. ISBN 1-871177-00-6.

DentistryClinical Densistry in Health and Disease.Vol 2. "The Mouth and PerioralTissues." Ed C Scully. Coordinatingeditor D K Mason, (Pp ix+413; figs;£60.) London: Heinemann Medical,1989. ISBN 0-433-00055-4.

DermatologyDifferential Diagnosis in Dermatopath-ologyI. A B Ackerman, J L Troy, L BRosen, et al. (Pp xiii+202; colourplates £63.73.) Philadelphia: Lea andFebiger, 1988. ISBN 0-8121-1053-6.Skin Cancer: an Illustrated Guide to theAetiology, Clinical Features, Pathologyand Management of Benign andMalignant Cutaneous Tumours. R MMacKie. (Pp vi+346; colour plates;

£59.95.) London: Dunitz, 1989. ISBN0-948269-59-6.

Disabled/handicapped people

Able Lives: Women's Experience ofParalysis. Ed J Morris. Illustrated byA Martin. (Pp ix+227; figs; £5.95paperback.) London: Women's Press,1989. ISBN 0-7043-4155-7.

EndocrinologyEXS 56: Experientia Supplementum.Vol 56. "Regulatory Peptides." EdJ M Polak. (Pp xii+406; figs; Sw frs168.) Basel: Birkhauser, 1989. ISBN3-7643-1976-3.

Environmental and public health

IPCS International Programme onChemical Safety: Environmental HealthCriteria. No 78. "DithiocarbamatePesticides, Ethylenethiourea, andPropylenethiourea: a General Intro-duction." United Nations Environ-ment Programme/InternationalLabour Organisation/World HealthOrganisation. (Pp 140) Sw frs 15paperback.) Geneva: World HealthOrganisation, 1988. ISBN 92-4-154278-0.

HaematologyHaematology. Vol 10. "Disorders ofthe Spleen: Pathophysiology andManagement." Ed C Pochedly, R HSills, A D Schwartz. Series editor KMBrinkhous. (Pp xvii+464; figs; $150.)New York: Dekker, 1989. ISBN 0-8247-7933-9.

Health care issues

Changing the Public Health. ResearchUnit in Health and BehaviouralChange, University of Edinburgh.(Pp xxi+ 199; £14.95 paperback.)Chichester: Wiley, 1989. ISBN0-471-91976-4.

Contemporary Issues in Health.Medicine, and Social Policy. "Successand Crisis in National Health Systems:a Comparative Approach." Ed M GField. General editor J B McKinlay.

(Pp viii+296; figs; £13.95 paperback.)London: Routledge, 1989. ISBN 0-415-01290-2.The Homeless Mentally Ill: a Task ForceReport ofthe American Psychiatric Asso-ciation. Ed H R Lamb. (Pp xix+320;£22.50.) Washington: AmericanPsychiatric Association, 1989. Distri-buted by Cambridge University Press.ISBN 0-89042-200-1.

History of medicine

The Irish School ofMedicine: Outstand-ing Practitioners of the 19th Century. DCoakley. (Pp vi+ 170; figs; colourplates; IR £14.95.) Dublin: TownHouse, 1988. ISBN 0-948524-08-1.Multiple Exposures: Chronicles of theRadiation Age. C Caufield. (Pp xii+304; figs; £12.95.) London: Seckerand Warburg, 1989. ISBN 0-436-09478-9.A Peculiar Place. The AdelaideHospital, Dublin: Its Times, Places andPersonalities 1839 to 1939. D Mitchell(Pp 336; figs; £18 including postage.)Dublin: Blackwater Press, 1989.Available from The Adelaide Hospital,Peter Street, Dublin 8, Eire; chequespayable to 'History account'. ISBN 0-905471-16-4.The Royal Berkshire Hospital 1839-1989. M Railton, M Barr. (Pp ix+ 355;figs; £12.95.) Reading: RoyalBerkshire Hospital, 1989. ISBN 0-9514373-0-5.Scientific Revolutionaries: a Biograph-ical Series. "Robert Koch: a Lifein Medicine and Bacteriology." T DBrock. (Pp ix+365; figs; DM 48.)Wisconsin: Science Tech Publishers/Berlin: Springer, 1988. ISBN 3-540-19344-8.SirFrederick Treves: theExtra-OrdinaryEdwardian. S Trombley. (Pp ix+218;£19.95.) London: Routledge, 1989.ISBN 0415-03423-X.

Human reproductionHuman Embryos: the Debate on AssistedReproduction. C R Austin. (Pp x+ 163;figs; £6.95 paperback.) Oxford:Oxford University Press, 1989. ISBN0-19-261758-3.

Immunology

Immunization in Practice: a Guide forHealth Workers Who Give Vacctnes.World Health Organisation. (Pp vix+361; £3.50 paperback.) Oxford:Oxford University Press, 1989. ISBN0-19-261545-9.Immunology Series. Vol 43. "HumanImmunogenetics: Basic Principles andClinical Relevance." Ed S D Litwin.Editor in chief N R Rose. (Pp xvi+828; figs; $180.) New York: Dekker,1989. ISBN 0-8247-7899-5.Immunology Series 45. "Cell SurfaceAntigen Thy-l: Immunology, Neuro-logy, and Therapeutic Applications."Ed A E Reif, M Schlesinger. Editor inchief N R Rose. (Pp xxiv+618; figs;$119.50.) New York: Dekker, 1989.ISBN 0-8247-7925-8.The Year in Immunology. Vol 4. "TheYear in Immunology 1988: CellularMolecular and Clinical Aspects."Volume and Series editors J M Cruse,R E Lewis Jr. (Pp viii+311; figs;£115.90.) Basel: Karger, 1989. Distri-buted by John Wiley and Sons. ISBN3-80554808-7.The Year in Immunology. Vol 5."The Year in Immunology 1988:Immunoregulatory Cytokines and CellGrowth." Volume and series editorsj M Cruse. R E Lewis Jr. (Pp viii+224; figs; £90.) Basel: Karger, 1989.Distributed by John Wiley and Sons.ISBN 3-80554895-8.

Infection

Hydrocephalus Shunt Infections. RBayston. (Pp ix+ 160; figs; £22.50.)London: Chapman and Hall, 1989.ISBN 0412-31240-9.

Medical ethics

Birthrights: Law and Ethics at theBeginnings of Life. Ed R Lee, DMorgan. (Pp x+222; £30.) London:Roudledge, 1989. ISBN 0415-00301-6.

NeurologyAdvances in Contemporary Neurology. FPlum. (Pp xvii+211; figs; £29.12.)

Philadelphia: Davis, 1988. ISBN 0-8036-6971-2.Diagnostic Neuropathology: a PracticalManual. M M Esiri, D R Oppen-heimer. (Pp xi+403; figs; £59.50.)Oxford: Blackwell Scientific, 1989.ISBN 0-632-01951-4.Frontiers of Clinical Neuroscience. Vol6. "Neural Regeneration and Trans-plantation." Ed F J Seil. Series editorsI Bodis-Wollner, E A Zimmerman.(Pp ix+294; figs; $75.) New York:Liss, 1988. Distributed by John Wileyand Sons. ISBN 0-8451-4505-3.

MisceilaneousAIDS and its Metaphors. S Sontag. (Pp95; £9.95.) London: Allen Lane ThePenguin Press, 1989. ISBN 0-7139-9025-2.Alive and Kicking: Towards a PracticalTheology of Illness and Healing. SPattison. (Pp ix+ 192; £8.50 paper-back.) London: SCM Press, 1989.ISBN 0-334-01871-4.Debates in Medicine. Vol 1. G Gitnick,H V Barnes, T P Duffy, N J Fortuin.(Pp xiv+277; £34.) Chicago; YearBookMedical Publishers, 1988. Distri-buted by Wolfe Medical Publications.ISBN 0-8151-3600-5.Forces ofChange: Why We Are the WayWe Are Now. H Hobhouse. (Pp viii+264; figs; £17.95.) London: Sidgwickand Jackson, 1989. ISBN 0-283-99828-8.HealthandDevelopment. ReprintedfromFinance & Development. A Measham,N Birdsall, F Sai, et al. (Pp 25; figs;$3.95 paperback.) 1989. Availablefrom The World Bank, PublicationsDepartment J2190, 1818 H StreetNW, Washington DC 20433, USA.Stock number IB-1 106.Inside Time. K Smith. (Pp 237;£12.95.) London: Harrap, 1989. ISBN0-245-54720-7.The KC Factor. D H S Reid. (Pp ix+280; figs; £5.95 paperback.) StAndrews: Napier Press, 1988. Avail-able from D H S Reid, Step RockHouse, St Andrews, KYl16 9AT, Fife,Scotland. ISBN 1-871479-01-0.

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