552

stage cancer to frequencies similar to those in controls and the rise inwomen with advanced disease may reflect the natural history ofdisease-namely, an immune response to CIN, selection of

non-responders who progress to early stage invasive cancer, andantibody production late in the disease in response to prolongedpresence of large amounts of HPV antigens. Conversely antibodymay reflect host response to HPV antigens during vegetativeexpression of genome in CIN and of selected transformation-associated antigens in large tumours.

Viral Exanthems and Herpesvirus Branch,Divison of Viral and Rickettsial Diseases,Center for Infectious Diseases,Centers for Disease Control,Atlanta, Georgia 30333, USA

Institute for Molecular Virology,St Louis University Medical Center,St Louis, Missouri

Molecular Virology and Immunology Program,Department of Pathology,McMaster University,Hamilton, Ontario, Canada

WILLIAM C. REEVES

J. ALAN RAWLSMAURICE GREEN

WILLIAM E. RAWLS

1. Reeves WC, Rawls WE, Brinton LA. Epidemiology of HPV and cervical cancer. RevInfect Dis 1989; 11: 426-39.

2. Dillner J, Dillner L, Robb J, et al. A synthetic peptide defines a serologic IgA responseto a human papillomavirus-encoded nuclear antigen expressed in virus-carryingcervical neoplasia. Proc Natl Acad Sci USA 1989; 86: 3838-41.

3. Phelps WC, Yee CL, Munger K, Howley PM. The human papillomavirus type 16 E7gene encodes transactivation and transformation functions similar to those ofadenovirus E1A. Cell 1988; 53: 539-47.

4. Smotkin D, Wettstein FO. Transcription of human papillomavirus type 16 early genesin a cervical cancer and a cancer-derived cell line and identification of the E7

protein. Proc Natl Acad Sci USA 1986; 83: 4680-84.5. Prakash SS, Reeves WC, Sisson GR, et al. Herpex simplex type 2 and human

papillomavirus type 16 in cervicitis, dysplasia and invasive cervical carcinoma. Int JCancer 1985; 35: 51-57.

Meconium ileus equivalent in associationwith nebulised ipratropium bromide in

cystic fibrosisSIR,-About 15% of adults with cystic fibrosis are prone to"meconium ileus equivalent" (MIE), a partial or completeintestinal obstruction resulting from abnormally viscid faeculentmaterial in the distal intestine. Precipitating factors may includewithdrawal of pancreatic supplements, inactivity, dietaryindiscretion, and respiratory infection.1,2 For some time, we havehad the impression that drug therapy may be a precipitating cause,and since 1986 the policy at our adult cystic fibrosis centre has beento avoid drugs that might impair intestinal motility—eg, codeinephosphate, parasympatholytic drugs, and even nebulised

ipratropium bromide, on the basis that most of it is swallowed andreaches the intestinal tract in active form. We report here severeMIE in a patient with cystic fibrosis who was inadvertently givenipratropium.

In September, 1989, a 28-year-old man with cystic fibrosis wasadmitted with a respiratory infection. He had had one previousadmission (in 1985), with a respiratory infection and MIE. On thatoccasion be had been using ipratropium bromide by metered doseinhaler but this was subsequently discontinued in view of the MIE.On the 1989 admission his treatment in hospital included,inadvertently, nebulised ipratropium bromide solution at a dose of500 Jlg every 6 h. After 10 days, his respiratory status was muchimproved, but severe MIE developed with abdominal pain anddistension. The ipratropium was discontinued but his MIE wasrefractory to intensive therapy over the next 5 days. Finally heresponded to polyethyleneglycol in solution by mouth.3

This was the most severe case of MIE seen on our unit for manyyears. The patient has had only two episodes of MIE, both timeswhile on ipratropium bromide by inhalation. Nebulised

ipratropium bromide is predominantly deposited in the oropharynxand swallowed and so may act on cholinergic receptors in theintestinal tract in the same way that it produces bronchodilation inthe respiratory tract.4 In most patients, this is of little consequencebecause the dose is small, but in patients with CF it may precipitate

MIE by impairing intestinal transit at a time when other factorssuch as inactivity and respiratory infection make them vulnerable tothis pharmacological effect.

Adult Cystic Fibrosis Centre,Medical Professorial Unit,St Vincent’s Hospital,Dublin 4, Ireland

D. MULHERINM. X. FITZGERALD

1. Hanly JG, FitzGerald MX. Meconium ileus equivalent in older patients with cysticfibrosis. Br Med J 1983; 286: 1411-13.

2. di Sant’Agnese PA, Davis PB. Cystic fibrosis in adults: 75 cases and a review of 232cases in the literature. Am J Med 1979; 66: 121-32.

3. Davidson AC, Harrison K, Steinfort CL, Geddes DM. Distal intestinal obstructionsyndrome in cystic fibrosis treated by oral intestinal lavage, and a case of recurrentobstruction despite normal pancreatic function. Thorax 1987; 42: 538-41.

4. Gross NJ. Ipratropium bromide. N Engl J Med 1988; 319: 486-94.

Gene/energy interaction in cystic fibrosisSiR,—The basis for the energy requiring defect in cystic fibrosis(CF) remains unclear.1,2 Significant increases in levels of energyexpenditure are documented in patients with normal pulmonaryfunction and nutritional status. This fmding would be consistentwith those of Feigal et al3 and others,l,4 suggesting that the primarydefect in CF might be associated with an energy requiringmechanism at the cellular level, possibly within the mitochondria.CF is now established as a heterogeneous condition with most

patients showing the F508 mutation.s The CF gene product hasbeen named cystic fibrosis transmembrane conductance regulator(CFTR), having properties consistent with membrane associationand nucleotide binding.’ The deletion of a phenylalanine residuemay affect cellular bioenergetics by upsetting the normal cycle ofmitochondrial respiration. We report an association between themain CF gene mutation and raised energy expenditure in CF.During a study of basal metabolic rate (BMR) in CF, with

indirect calorimetry under standardised conditions, we examinedthe possibility that BMR is correlated with the &Dgr;F508 mutation.Blood samples were collected from 38 unrelated patients in Belfast,randomly coded, and sent to the Human Genetics Unit, Edinburgh,for genomic DNA analysis.7 There were similar numbers ofpatients with high and low metabolic rates. The &Dgr;F508 mutation wasseen on 55 % of chromosomes in this group of patients. This findingis somewhat different from that previously reported for the Scottishpopulation,8 but is in good agreement with that in another study inNorthern Ireland (N. Nevin, personal communication). Thedifference probably reflects racial admixture in the two populations.On the basis of DNA analysis, patients were divided into threegroups: (1) those homozygous for AF (n=12), (2) those

heterozygous for AF511 (18); and (3) those who did not carry &Dgr;F508(8). Group 1 had a median BMR of 25% above predicted (95%

Distribution of BMR deviation in groups 1. 2, and 3, as

interquartile range (box).

Medians shown as horizontal lines within box Extensions denote

group range.

553

confidence intervals [CI] about the median, 6-36%), in group 2 itwas + 10% (95% CI,3-18%),andingroup3 +2% (95% CI, - 14to + 19%). BMR values differed between group 1 and group 3

(Mann Whitney U test, p=00124; figure). Decline in pulmonaryfunction did not explain the raised energy requirement, there beingno correlation between pulmonary function score and BMR.We speculate that the effect of an abnormal ATP binding domain

in the &Dgr;F508 allele of CFTR may prevent the proper binding of ATPrequired oxidative phosphorylation, thus providing a cellular basisfor heightened metabolism by blocking movement of a high energyphosphate bond within the cell.

Department of Child Health,Queen’s University of Belfast,Belfast BT12 6BJ, UK

Royal Belfast Hospital for Sick Children,Belfast

Human Genetics Unit,University of Edinburgh,Western General Hospital,Edinburgh

A. O’RAWE

J. A. DODGE

A. O. B. REDMOND

I. MCINTOSHD. J. H. BROCK

1. Shepherd RH, Vasques-Velasquel L, Prentice A, et al. Increased energy expenditurein children with cystic fibrosis. Lancet 1988; i: 1300-03.

2. Vaisman N, Pencharz PB, Corey M, et al. Energy expenditure of patients with cysticfibrosis. J Pediatrics 1987; 111: 496-500.

3. Feigel RJ, Shapiro BL. Mitochondrial calcium uptake of patients with cystic fibrosis.Nature 1979; 178: 267-77.

4. Stutts MJ, Knowles MR, Gatzy JT, Boucher RC. Oxygen consumption and ouabainbinding sites in cystic fibrosis nasal epithelium. Paediatr Res 1986; 20: 1316-20.

5. Kerem B-S, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosisgene: genetic analysis. Science 1989; 245: 1073-80.

6. Riordan JR, Rommens JM, Kerem B-S, et al. Identification of the cystic fibrosis gene:cloning and characterisation of the complementary DNA. Science 1989; 245:1066-73.

7 McIntosh I, Raeburn JA, Curtis A, Brock DJH. First-trimester prenatal diagnosis ofcystic fibrosis by direct gene probing. Lancet 1989; ii: 972-73.

8. McIntosh I, Lorenzo M-L, Brock DJH. Frequency of &Dgr;F508 mutation on cysticfibrosis chromosomes in UK. Lancet 1989; ii: 1404-05.

Testing for Huntington’s disease withsupport for all parties

SIR,-Reports of experience with presymptomatic DNA testing forHuntington’s disease (HD) have focused on the reactions ofidentified gene-carriers" and less attention has been paid tonon-carriers and the partners of carriers or to the impact on families.In formerly at-risk individuals found not to be carrying the gene wehave unexpectly found long-term emotional numbing and survivorguilt and partners of gene-carriers were reluctant to seek help orsympathy for fear of appearing selfish.One year after presymptomatic diagnosis for HD we followed up

18 people who had a definitive test result. 9 were gene-carriers (7men and 2 women, mean age 33 years, range 22-45) and 9 werenon-carriers (4 men and 5 women, mean age 36, range 24-43).Planning for the future, including the desire for children, was themost common reason for seeking the test. All but 2 had stablerelationships. 3 gene-carriers have children (total 7) and 8

non-gene-carriers have children (total 14), 3 of whom were bornafter the test result. In separate interviews with the testedindividuals and their partners, feelings, cognition, defence

mechanisms, coping strategies, and family dynamics were

evaluated.Gene-carriers seemed to cope well with the unfavourable

result." The initial shock was followed by a fairly rapid recovery.They are shown sympathy and receive follow-up and aftercare.This is understandable since the incidence of suicide among peoplewith HD is believed to be 5-11 times higher than the populationaverage.4 However, gene-carriers have yet to show an increase insuicidal tendency.1-3

In 8 non-carriers the expected relief on learning the result wassoon replaced by persistent guilt feelings and depression. 6 haveavoided contact with siblings, and members of their families seemindifferent to their results. 2 of them did not even tell their brothersand sisters (total 10) what the result was. 5 remained preoccupiedwith their involuntary movements and the threat of the disease. Notone, however, regretted having the test.

Previously, those at risk of HD lived with the fear of the diseasedeveloping and for years had struggled to master that threat. Theyhad shaped their lives against a background of possible HD. Ourfindings suggest that most of them are not equipped to assimilate thenotion that adjusting to the possibility of this fearful disease was,after all, unnecessary. The emotional numbing, which may beprolonged, can be seen as an adjustment to the loss of this lifescenario and to the need to adjust to the new reality. Survivor’sguiltS too is understandable.Non-gene cariers may find it hard to answer the question "why

have I escaped?" and sometimes they may even think "Because Ihave not inherited the gene, my siblings are more at risk". Thedesired relief from the threat of the HD gene has not been

experienced. Some may feel obliged to be continuously available tosupport affected or at-risk relatives, and it is hard to find the balancebetween relief and availability.The threat of HD affects families, often over more than one

generation. It either induces close scrutiny for early symptoms orthe denial of them in relatives. A conspiracy of silence is broken oncea family member seeks presymptomatic testing. 4 non-gene-carriersin our study found that relatives reacted to their "privileged"position by "banning" them from the family because the HD tie hadbeen severed.

Partners of the gene-carriers deserve attention too. They tend notto discuss their feelings about the possibility of an unfavourable testresult before disclosure: attention focuses on the at-risk individualand for the partner to explore his or her feelings might seemself-centered. As soon as a partner’s positive-gene carrier status isrevealed the reaction is one of sorrow, anger, and despair about afuture that will be overshadowed by HD. Carriers themselves maynot appreciate their partners’ feelings. The partners of gene carriersdo need professional support but may be reluctant to ask, seeing it assomehow disloyal to do so.Our findings have important implications for presymptomatic

testing of HD and other late-onset genetic diseases. All thoseinvolved-gene carriers, non-gene-carriers, and partners-need tohave their specific problems paid attention to, at least for the firstyear after testing.

Supported by grants from the Prinses Beatrix Fonds.

Clinical Genetics Centreand Departments of Psychiatry and Neurology,

Academic Hospital Leiden,2300 RC Leiden, Netherlands;Department of Medical Psychologyand Psychotherapy,

Erasmus University, Rotterdam,and Department of Clinical Genetics,

Erasmus Universityand University Hospital Dijkzigt,

Rotterdam

A. TIBBENM. VEGTER-V.D. VLISM. F. NIERMEIJERJ. J. P. V.D. KAMPR. A. C. RoosH. G. M. ROOIJMANSP. G. FRETSF. VERHAGE

1. Craufurd D, Dodge A, Kerzin-Storrar L, et al. Uptake of presymptomatic predictivetesting for Huntington’s disease. Lancet 1989; ii: 603-05.

2. Meissen GJ, Myers RH, Mastromauro CA, et al. Predictive testing for Huntington’sdisease with use of a linked DNA marker. N Engl J Med 1988; 318: 535-42.

3. Brandt J, Quaid KA, Folstein SE, et al. Presymptomatic diagnosis of delayed-onsetdisease with linked DNA markers: the experience in Huntington’s disease. JAMA1989; 261: 3108-14.

4. Kessler S, Bloch M. Social system responses to Huntington disease. Fam Proc 1989;28: 59-68.

5. Lifton RJ. The broken connection: on death and the continuity of life. New York:Simon and Schuster, 1979.

Childhood cancer in Zaire

SIR,-Dr Lucas and Dr Fisher (Jan 13, p 115) in their comments onDr Miller (Oct 21, p 978) and Professor Massabi and colleagues’(Aug 26, p 501) reports of the apparently low frequency ofneuroblastoma in Zaire and some other African countries refer tothe suggestion that another embryonic tumour, nephroblastoma(Wilms’ tumour), has a uniform frequency worldwide. FollowingInnis" report it has often been assumed that this is the case andtherefore that nephroblastoma can be used as an "index" tumouragainst which to measure the frequencies of other tumours.However, more data have since become available, particularly those