24

is not used as an excuse to further inflate the high rate of surgical interventions. 1. Black N. Surgery for glue ear-a modem epidemic. Lancet 1984; i: 835-37. 2. Maw AR, Herod F. Otoscopic, impedance, and audiometric findings in glue ear treated by adenoidectomy and tonsillectomy. Lancet 1986; i: 1399-402. 3. Black NA, Sanderson CFB, Freeland AP, Vessey MP. A randomised controlled trial of surgery for glue ear. Br Med J 1990; 300: 1551-56. 4. Chalmers DC, Stewart I, Silva P, Mulvena A. Otitis media with effusion in children-the Dunedin study. Clin Dev Med 1989; 108.

NEW EVIDENCE ON XAMOTEROL

Eighteen months ago we gave the newly launched beta-1selective adrenoceptor partial agonist xamoterol a guarded welcome as a potentially useful additional treatment for at least some types of heart failure.! Since then further work has confirmed that xamoterol therapy gives modest improvements in haemodynamic function, symptoms, and exercise tolerance in patients with mild to moderate chronic heart failure (CHF).2-6 This week, however (see p 1), we publish a placebo-controlled trial involving patients with severe CHF in whom treatment with xamoterol was associated with an increase in mortality. This comes at a time when concern has been expressed in the British press (both lay and medical) about the use of xamoterol. Clearly the role of this agent in the treatment of heart failure needs to be reassessed in the light of the new study and other recent evidence. Two points about the present study should be reiterated. Firstly, it was not originally designed to examine the effect of xamoterol on mortality. Because of this, details of the mode of death and its temporal relation to initiation of xamoterol treatment are not well defined. Secondly, this study was conducted in a group of patients with severe CHF, most of whom have coronary artery disease. An increase in death due to pump failure soon after the introduction of xamoterol would suggest a detrimental effect of beta-blockade (xamoterol reduced daytime heart rate in these patients). Alternatively, an increase in myocardial infarction or ventricular arrhythmias would support a detrimental effect of the beta-agonist effect of xamoterol (nocturnal heart rate was increased). These possibilities have very different implications for future use of the drug. Restriction of prescribing to those with mild heart failure, in whom beta-blockade is not seen at rest, should greatly reduce the hazard of acute myocardial depression. However, it has also been suggested that mild heart failure progressses to severe heart failure and in the process the patient becomes increasingly dependent on the sympathetic nervous system for inotropic support. Consequently xamoterol, while initially exerting a beneficial positive inotropic action, could eventually exert a detrimental negative inotropic one. Whether CHF does progress in this way is not at all clear. Nor is it certain that sympathetic activation is good rather than bad. It is also possible that xamoterol could prevent deterioration (long-term beta-blockade may augment rather than diminish catecholamine responsiveness in CHF). Either way, if the original premise is held, the drug can be stopped if CHF does worsen. The second possibility, that increased mortality reflects an effect of beta agonism rather than antagonism, should also apply to patients with milder forms of CHF and is therefore a greater worry. The limited evidence does not

concern. Ambulatory electrocardiography in a of patients in the present study did not show an increase in ventricular arrhythmias, and in previous studies xamoterol has not been found to aggravate myocardial ischaemia. Furthermore, four-year follow-up data are available on 221 UK patients with mild CHF initially randomised to a three-month comparison of xamoterol and placebo (on completion, "open label" xamoterol was continued in responders). Survival, by "intention to treat" analysis, was 80% in the xamoterol group and 75% in the placebo group.s Thus, while the verdict on efficacy is good, that on safety is "not proven"; a prospective mortality study in mild CHF is needed to clear xamoterol. For the moment at least, the British Committee on Safety of Medicines has judged that the risk-benefit ratio for xamoterol, used carefully, in mild CHF is acceptable. How can xamoterol be prescribed safely? Only patients with mild heart failure should receive the drug. Post-marketing surveillance by the Drug Safety Research Unit in Southampton has shown that xamoterol, despite advice to the contrary, has frequently been prescribed to patients with severe CHF.99 Consequently it is now mandatory that patients undergo full investigative and functional evaluation (ECG, chest radiograph, echocardiogram, and exercise test). If indicated xamoterol should then be started-in hospital, under supervision. These precautions could be more widely applied. Heart failure is a complex syndrome of multiple aetiologies requiring precise diagnosis and tailored therapy. For good management of this common and disabling condition, patients need to be assessed individually; for some, the treatment may still include xamoterol.

support this

subgroup

1. Editorial. Xamoterol: stabilising the cardiac beta receptor? Lancet 1988; ii: 1401-02. 2. The European ’Corwin’ Study Group. Xamoterol in mild to moderate

heart failure: a subgroup analysis of patients with cardiomegaly but no concomitant angina pectoris. Br J Clin Pharmacol 1989; 28 (suppl 1): 675-95. 3. Bostraom PA, Johansson BW, Lecerof H, Lilja B, Torp A. Effect of xamoterol on exercise capacity and left ventricular function in angina pectoris and in dilated cardiomyopathy. J Intern Med 1989; 226: 331-35. 4. Waller DG, Webster J, Sykes CA, Bhalla KK, Wray R. Clinical efficacy of xamoterol, a &bgr;1-adrenoceptor partial agonist, in mild to moderate heart failure. Eur Heart J 1989; 10: 1003-10. 5. Virk SJS., Anfiologoff NH, Lawson N, et al. The acute effects of intravenous xamoterol on resting and exercise haemodynamics in patients with mild to moderate heart failure. Eur Heart J 1989; 10: 227-34. 6. Vigholt-Sorensen E, Faergeman O, Snow HM. Effects of xamoterol, a &bgr;1 adrenoceptor partial agonist, in patients with ischaemic dysfunction of the left ventricle. Br Heart J 1989; 62: 335-41. 7. Heilbrunn SM, Shah P, Bristow MR, Valantine HA, Ginsburg R, Fowler MB. Increased &bgr;-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy. Circulation 1989; 79: 483-90. 8. Marlow HF, Lewis JA. Effects of xamoterol on mortality in mild to moderate heart failure (abstr). Eur Heart J (in press). 9. PEM News 1990, no 6.

ANDERSON-FABRY DISEASE

Anderson-Fabry disease (angiokeratoma corporis diffusum) is a pleotropic genetic disorder. Deficiency of the lysosomal enzyme a-galactosidase results in widespread tissue accumulation of uncleaved glycosphingolipids, chiefly trihexosyl ceramide. The gene for this enzyme has been mapped to the middle of the long arm of the X chromosome. As might be expected with a slowly progressive storage disorder, the clinical manifestations are

25

so it is not too surprising that the is often delayed or missed.2 In childhood diagnosis is characterised disease the by the appearance of ectatic in the vascular skin lesions bathing-trunk area, episodic pain most commonly affecting the limbs, and a subtle and symptomless corneal dystrophy. Abdominal pain may be mistaken for appendicitis. In adult males virtually no system is spared, with vascular disease of the kidneys, heart, and brain contributing to progressive disability. Vertigo with

protean and non-specific, correct

sensorineural hearing loss,3 arthropathy,4 and, rarely, lymphadenopathy5 are additional complications. Without dialysis or transplantation most affected males will succumb to renal failure by the age of 50. Treatment is far from satisfactory. Antiplatelet therapy may help to prevent the atherosclerotic and thromboembolic effects of damage to the vascular epithelium 36but experience of this approach is limited. The painful crises and constant burning acroparaesthesiae, which are probably caused by axonal neuropathy, are helped in many patients by phenytoin and/or carbamazepine, although carbamazepine may sometimes exacerbate autonomic dysfunction.7 Renal transplantation will correct renal function provided care is taken to ensure that the donor kidney does not originate from a heterozygote;8 transplantation may also prevent other disease manifestations by providing a source of normal enzyme for release into the circulation. However, a report of progressive cardiac involvement despite successful renal allotransplantation9 emphasises the importance of longterm follow-up studies. Rapid progress at the genetic level during the past few years means that genetic counselling should now be offered to all families in whom this condition has been diagnosed. Prenatal diagnosis based on enzyme assay in amniocytes and chorionic villi is well established.1O Carrier detection by use of conventional clinical and biochemical criteria is less reliable. A small proportion of carrier females are clinically affected and about 70% show signs of corneal dystrophy. Measurement of the a-galactosidase to 0-galactosidase activity ratio in leucocytes, plasma, fibroblasts, and hair follicles provides reasonable but not total discrimination between carriers and non-carriers." Consequently, localisation of the gene and subsequent identification of closely linked polymorphic DNA markers12 has been especially welcomed by the possible carriers in whom conventional testing has given equivocal results. This development was followed closely by isolation and characterisation of the a-galactosidase gene itself.13 The gene is about 12 kb

long and contains 7 exons encoding a protein of 429 aminoacids. The basic molecular defect has been studied in 130 patients and identified in 7, 5 of whom showed a partial deletion, 1 a duplication, and 1 a point mutation.14 Only the patient with the point mutation showed any residual a-galactosidase activity. The breakpoint junction for four of the five partial gene deletions was in an exon containing multiple Alu repeats, an observation consistent with the hypothesis that these may be hot spots for the generation of deletions and duplications as a consequence of misalignment and unequal crossing over in

precursor

meiosis. Demonstration of the basic molecular defect in a family with Anderson-Fabry disease is a major advance, not only for those scientists and clinicians with a keen interest in genotype-phenotype correlation, but also for close female relatives of patients who seek precise carrier detection. For

the patients themselves, who are sometimes driven to suicide by intractable pain and behavioural disturbance, identification and characterisation of the a-galactosidase gene greatly enhances short-term prospects for direct enzyme replacement and long-term hopes of somatic gene

therapy. 1. Desnick RJ, Bishop DF. Fabry disease: &agr;-galactosidase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. 6th ed. New York: McGraw-Hill, 1989: 1751-96. 2. Morgan SH, Crawfurd M d’A. Anderson-Fabry disease. A commonly missed diagnosis. Br Med J 1988; 297: 872-73. 3. Morgan SH, Rudge P, Smith SJM, et al. The neurological complications of Anderson-Fabry disease (&agr;-galactosidase A deficiency)— investigation of symptomatic and presymptomatic patients. Q J Med 1990; 75: 491-504. 4. Sheth KJ, Bernhard GC. The arthropathy of Fabry disease. Arthritis Rheum 1979; 22: 781-83. 5. Mayou SC, Kirby JD, Morgan SH. Anderson-Fabry disease: an unusual presentation with lymphadenopathy. J R Soc Med 1989; 82: 555-56. 6. Sakuraba H, Igasrashi T, Shibata T, Suzuki Y. Effect of vitamin E and ticlopidine on platelet aggregation in Fabry’s disease. Clin Genet 1987; 31: 349-54. 7. Filling-Katz MR, Merrick HF, Fink JK, Miles RB, Sokol J, Barton NW. Carbamazepine in Fabry’s disease: effective analgesia with dosedependent exacerbation of autonomic dysfunction. Neurology 1989; 39: 598-600. 8. Popli S, Molnar ZV, Leehey DJ, et al. Involvement of renal allograft by Fabry’s disease. Am J Nephrol 1987; 7: 316-18. 9. Kramer W, Thormann J, Mueller K, Frenzel H. Progressive cardiac involvement by Fabry’s disease despite successful renal allotransplantation. Int J Cardiol 1985; 7: 72-75. 10. Kleijer WJ, Hussaarts-Odijk LM, Sachs ES, Jahoda MGJ, Niermeijer MF. Prenatal diagnosis of Fabry’s disease by direct analysis of chorionic villi. Prenat Diagn 1987; 7: 283-87. 11. Spence MW, Goldbloom AL, Burgess JK, D’Entremont D, Ripley BA, Weldon KL. Heterozygote detection in angiokeratoma corporis diffusum (Anderson-Fabry disease) J Med Genet 1977; 14: 91-99. 12. MacDermot KD, Morgan SH, Cheshire JK, Wilson TM. AndersonFabry disease, a close linkage with highly polymorphic DNA markers DXS17, DXS87 and DXS88. Hum Genet 1987; 77: 263-66. 13. Bishop DF, Calhoun DH, Bernstein HS, Hantsopoulos P, Quinn M, Desnick RJ. Human &agr;-galactosidase A: nucleotide sequence of a cDNA clone encoding the mature enzyme. Proc Natl Acad Sci 1986; 83: 4859-63. 14. Bernstein HS, Bishop DF, Astrin KH, et al. Fabry disease: six gene rearrangements and an exonic point mutation in the &agr;-galactosidase gene. J Clin Invest 1989; 83: 1390-99.

LIPIDS AND MULTIPLE SCLEROSIS In this issue (p 37) we publish a paper by Dr R. L. Swank that marks forty years of study into the relation between dietary fat and the prevalence of multiple sclerosis (MS). Some essential questions remain. Is there a relation? What is the mechanism? Does dietary modification confer any

benefit? The initial suggestion of a link between MS and diet was made on the basis of epidemiology / elaborated by analogy,22 and received support from subsequent epidemiological studies during the next twenty years.3 Coincidental evidence of a possible relation between polyunsaturated fatty acids and MS was provided by the observation that the

proportions of the omega-6 fatty acids (arachidonic and linoleic acids) in the lecithin fraction of cerebral myelin differed in MS patients from those in normal controls 4 This suggestion of a lipid abnormality of MS was strengthened by subsequent reports of low levels of linoleic acid in patients’ serum, platelets, and red cells.5-7 Although these observations have been reproduceds,9 they have not been found consistently and some workers have suggested that they are merely a feature of chronic neurological disease.10,11