Clouds still gathering over galactosaemia

especially if an epidemic is unlikely to last for more than a few months, as was the case in Peru 1991.4 Immunisation would mainly protect individuals from death or serious illness and only to a lesser degree control the spread of cholera since the protective efficacy against symptomless infections was only 42%. Cholera vaccination is unlikely to be integrated in the WHO Expanded Programme on Immunization because the target age group and the sequence of boosters differ from those of other vaccines. What about travellers, who are least at risk? As many as 75% of those going to affected areas receive cholera vaccine, Australian visitors to Bali being a case in point.5 According to surveys based on reported and imported cases of cholera, the risk is usually far less than 1 per 100000 travellers, with a case-fatality rate of less than 2%. Even if we acknowledge that additional very mild or symptomless cholera infections occur, cholera is one of the lesser risks among vaccine-preventable infections in travellers.8 Except for frequent travellers or long-term residents in developing countries, no pre-travel vaccination is cost-effective.9 Whilst protection against a frequent risk, mainly hepatitis A, may well be worth the additional costs to the individual, cholera vaccination would result in an extremely high cost-benefit ratio. WHO is right to discourage vaccination as a means of personal protection for foreign travel." Robert Steffen Division of Epidemiology and Prevention of Communicable Diseases, Institute of Social and Preventive Medicine, University of Zurich, Zurich, Switzerland 1

2

3 4 5 6

Clemens JD, Sack DA, Harris JR, et al. Field trial of oral cholera vaccines in Bangladesh: results from three-year follow-up. Lancet 1990; 335: 270-73. Levine MM, Kaper JB. Live oral vaccines against cholera: an update. Vaccine 1993; 11: 207-12. Sack DA. Cholera control. Lancet 1994; 344: 616-17. Gotuzzo E, Cieza J, Estremadoyro L, Seas C. Cholera-lessons from the epidemic in Peru. Infect Dis Clin N Am 1994; 8: 183-205. Grayson ML, McNeil JJ. Preventive health advice for Australian travellers to Bali. Med J Aust 1988; 149: 462-66. Morger H, Steffen R, Schär M. Epidemiology of cholera in travellers, and conclusions for vaccination recommendations. BMJ 1983; 286: 184-86.

Weber JT, Levine WC, Hopkins DP, Tauxe RV. Cholera in the United States, 1965-1991. Arch Intern Med 1994; 154: 551-56. 8 Steffen R, Kane MA, Shapiro CN, Billo N, Schoellhorn KJ, van Damme P. Epidemiology and prevention of hepatitis A in travelers. JAMA 1994; 272: 885-89. 9 Behrens RH, Roberts JA. Is travel prophylaxis worth while? Economic appraisal of prophylactic measures against malaria, hepatitis A, and typhoid in travellers. BMJ 1994; 309: 918-22. 10 World Health Organization. International travel and health. Geneva: WHO, 1994. 7

Clouds still

gathering over galactosaemia

The main message of a 1984 Lancet editoriaP on galactosaemia was that the long-term outcome of patients with the classical form of the disorder was poor and that this fact was being ignored. Subsequent retrospective studies confirmed fears about the complications of the disease 10 years on we now know far more about the genetic basis of galactosaemia,5-’ but what progress has been made towards understanding the complications and preventing them? Classical galactosaemia is an autosomal recessively inherited disorder of galactose metabolism, caused by a deficiency of the enzyme galactose-1-phosphate uridyl

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transferase (transferase). The disorder usually presents in the first weeks of life with liver dysfunction and sepsis, which are life threatening and associated with other abnormalities including a Fanconi syndrome, cataracts, and cerebral oedema. After identification of the enzyme defect 40 years ago, simple biochemical methods of confirming the diagnosis were soon developed. Introduction of galactose-restricted diets led to resolution of the acute disorder in most cases, and the accepted view, until publication of the Lancet editorial, was that the outcome was excellent. It subsequently transpired that about 50% of patients aged over 6 years were developmentally delayed, and that learning difficulties increased with age. One possible reason for the deterioration is progressive neurological disease; another that brain damage sustained at an undetermined time becomes increasingly apparent with age as more complex tests can be applied. More recently, about 13% of patients aged 3 years and over were noted to have impaired motor function and balance.3,9This figure may be an underestimate, since three times as many children were thought by their parents to have difficulties with running, balance, and handwriting.9 In addition, about 60% of patients have a speech disorder, 80% of females have primary gonadal failure, and 20% of patients have some growth retardation.2 Paediatricians have also noted severe personality disorders, with timidity and lack of drive in many of their patients.

Surprisingly, the age at which treatment begins and the severity of the neonatal disorder do not seem to affect the long-term outcome. Since the metabolic disturbance is expressed in the galactosaemic fetus, 10 several of the clinical abnormalities may have a prenatal origin. The ovarian disorder in particular is thought to arise in this way." The possibility of prenatal damage is the rationale for restriction of milk intake during a pregnancy at risk, but this strategy has not been shown to have any beneficial effect. Nevertheless, this lack of benefit does not exclude prenatal damage because galactose metabolites still accumulate abnormally to the same degree despite the dietary restriction.12 These metabolites probably originate from metabolic pathways in the mother or the fetus or both. The other possibility is that some damage occurs postnatally, since blood and urine concentrations of galactose metabolites remain slightly raised despite the galactose-restricted diet. Galactose-1phosphate has always been regarded as an important toxic metabolite, but in one study, mean concentrations in individual patients between 6 and 24 months did not correlate with their IQ.2 However, the biochemical and developmental measurements in this study were made in many centres and may have been inaccurate. In 1989, Ng and colleagues13 in Los Angeles reported deficiency of uridine diphosphate galactose (UDPGal) in red blood cells, cultured skin fibroblasts, and liver of treated galactosaemic patients and showed a possible correlation between this metabolic abnormality and ovarian failure. The suggestion was that deficiency of UDPGal, a product of the transferase reaction and the galactosyl donor for the synthesis of galacto-proteins and galacto-lipids, could be the cause of some of the longterm complications. In addition, the finding that UDPGal concentrations could be increased to normal by giving uridine to patients held out the promise of an additional

for the disease. Unfortunately, other studies, with different analytical techniques, have cast doubt on the original observations.’4 A small reduction in mean red blood cell UDPGal in galactosaemic individuals was confirmed but the large overlap with the concentrations in matched controls calls into question the biological significance of the results. The UDPGal deficiency has not been confirmed in cultured fibrobla1?ts,15 and there is no convincing evidence of the clinical benefit of uridine therapy.16 However, there is independent and convincing evidence of abnormalities of galactoconjugate synthesis in treatment

reproductive failure: prenatal and In: Donnell GN, ed. Galactosemia: new frontiers in research. Bethesda: National Institutes of Health, 1993: 109-21. 12 Jacobs C, Kleijer WJ, Bakker HD, et al. Dietary restriction of maternal galactose intake does not prevent accumulation of galactitol in the amniotic fluid of fetuses affected with galactosaemia. Prenat Diagn

postnatal ovarian toxicity.

1988; 8: 641-45. 13

Ng WG, Xu YK, Kaufman FR, Donnell GN. Deficit of uridine diphosphate galactose in galactosaemia. J Inher Metab Dis 1989;

12:

257-66. 14 Holton JB, de la Cruz

F, Levy HL. Galactosemia: the uridine diphosphate galactose deficiency-uridine treatment controversy. J Pediatr 1993; 123: 1009-14.

15 Keevill

galactosaemia.17 The transferase gene, which has now been isolated and cloned, codes for a polypeptide of 379 aminoacids, the active enzyme being a homodimer.5 Nine polymorphisms fulfilling the criteria for a disease mutation have been recorded and the prevalence of one of these, Q188R, is about 70% in the Caucasian galactosaemic populations of North America and the UK.5,6 Preliminary studies suggested that homozygotes for this common mutation generally do worse than other patientsbut in other studies the outcome has not been different from that of compound heterozygotes.7 Although this work may already have applications in diagnosis, the obvious goal of gene therapy is probably going to be more difficult to achieve in galactosaemia than in many other metabolic conditions since transferase is active in many organs, including the brain. We still have much to learn about galactosaemia. Carefully planned prospective studies are essential for collection of accurate clinical and laboratory data, and standard protocols for patient investigation and management need to be introduced, with patient registers to collect longitudinal data. These plans and new research initiatives-eg, study of the defect in cultured cellsshould see the clouds over galactosaemia beginning to clear. J B Holton, J V Leonard Department of Child Health, University of Bristol, and Metabolic Unit, London Centre for Paediatric Endocrinology and Metabolism, Institute

11 Mattison DR. Galactosemia and

of

Child Health, London, UK

1 Editorial. Clouds over galactosaemia. Lancet 1984; ii: 1379-80. 2 Waggoner DD, Buist NRM, Donnell GN. Long-term prognosis in galactosaemia: results of a survey of 350 cases. J Inher Metab Dis 1990; 13: 802-18. 3 Schweitzer S, Shin Y, Jacobs C, Brodehl J. Long-term outcome in 134 patients with galactosaemia. Eur J Pediatr 1993; 152: 36-43. 4 Bakker HD, Boelen CCA. Clinical and biochemical study in 69 cases of classical galactosemia from the Netherlands. Int Pediatr 1993; 8: 135-36. 5 Elsas LJ II, Fridovich-Keil JL, Leslie ND. Galactosemia: a molecular approach to the enigma. Int Pediatr 1993; 8: 101-09. 6 Holton JB, Tyfield LA, Heptinstall L, Mann RJ. Prevalence of the Q188R mutation at the galactose-1-phosphate gene locus in galactosaemia patients from England and Scotland. 32nd Annual Symposium of the Society for the Study of Inborn Errors of Metabolism, 1994. 7 Kaufman FR, Reichardt JKV, Ng WG, et al. Correlation of cognitive, neurological and ovarian outcome with Q188R mutation of the galactose-1-phosphate uridyl transferase gene. J Pediatr 1994; 125: 225-27. 8 Segal S. Disorders of galactose metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease, 6th ed. New York: McGraw-Hill, 1989: 453-80. 9 Waggoner DD, Buist NRN. Long-term complications in treated galactosemia: 175 US cases. Int Pediatr 1993; 8: 97-100. 10 Allen JT, Gillett MG, Holton JB, King GS, Pettit BR. Evidence of galactosaemia in utero. Lancet 1980: i: 603.

NJ, Holton JB, Allen JT. UDPGlucose and UDPGalactose concentrations in cultured skin fibroblasts of patients with classical galactosaemia. J Inher Metab Dis 1994; 17: 23-26. 16 Segal S. The challenge of galactosemia. Int Pediatr 1993; 8: 125-32. 17 Ornstein KS, McGuire EJ, Berry GT, et al. Abnormal galactosylation of complex carbohydrates in cultured fibroblasts from patients with galactose-1-phosphate uridyl transferase deficiency. Pediatr Res 1992; 31: 508-11.

Eschewing the predictable Marshall Marinker said of general practice research that, for the most part, it provided predictable answers to banal questions. I was reminded of this sentiment when I came across a paper by Roberts and Norton’ in the New Zealand Medical Journal entitled "Auckland children’s exposure to risk as pedestrians". The conclusion goes as follows: "The increased pedestrian injury rates for poor children and for Maori and Pacific Island children may be explained, in part, by the increased pedestrian exposure of these children. Increased pedestrian exposure is likely to reflect social and economic constraints, rather than differences in perceptions of the danger to children as pedestrians. Efforts to address the safety of children as pedestrians are urgently required". In brief, and without the academic caution of "may" and "likely", if your parents do not have a car you walk to school, and if you walk to school you are more likely to be knocked down. Among many examples of research of this kind the problem lies not in the techniques, which are usually sound, or in the results, which if predictable are at least true, but in the questions. Surely it would have been far more interesting to plot the places at which poor New Zealand children get knocked down. If a few "black spots" were identified something might well be done to reduce the toll of accidents. Research is a shibboleth of our culture, and as a result many are obliged to "do research" not because of any burning desire to answer important questions but to meet perceived requirements for a career. For most of us research is an added and usually irrelevant burden, the immediate consequence being that research ideas are generated mainly on grounds of feasibility. This could be done rather than this should be done; sometimes, this could be funded rather than this should be funded. And with a little persistence by the authors, almost anything can see itself in print. Banality is by no means confined to general practice research. Epidemiological research, for example, has unearthed something like 300 risk markers for coronary heart disease; they are mostly derived from case-control studies and virtually none illuminates in any useful way the aetiology of this complex process. Questions that derive from non-tenable hypotheses lead to trivial or misleading answers. Feinsteinlately restated his plea that

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