598 aborted. Fourthly, despite the colossal public-health problem which sickle-cell disease is posing in West Africamany patients are living to adulthood; some are doing very well in university and the professions,7 and genetic counselling and family planning in Ghanaz are more oriented to these adult patients with two abnormal genes than they are to the healthy traits (AS, AC, AThal, AF (highgene)) who form more than 35% of all Ghanaians. Fifth, the State bears the cost of medical care in Ghana while in the U.S.A. couples such as those mentioned above would be financially ruined in seeing their children through several hospital admissions into adulthood. Fortunately, your editorial lays stress on the varying needs of different environments. For our continent, and for the West Indies8 and Saudi Arabia9 where sickle-cell disease is not so severe, antenatal diagnosis with selective abortion could not attract the same excitement as in the developed countries, if even the procedures were entirely free of charge. Ghana Institute of Clinical Genetics, Korle Bu Teaching Hospital, P.O. Box 150, Korle Bu, Ghana

F. I. D. KONOTEY-AHULU

omissions in your editorDr Kan and his colleagues. You the accompanying paper by state that the appearance of Hb A in fetal erythrocytes was first studied by Walker and Turnbull in 1933"’ Using the alkali denaturation method, these investigators noted some non-fetal Hb in some, but not all, fetuses as early as the 13th week. You state that these observations were confirmed by Huehns et al. in 1964’ but in a paper published in 1966 Kaltsoya et al!2 revealed that what had been called Hb A was in fact not adult Hb; and Huehns13later pointed out that this material was probably Hb Portland-1, which was shown to constitute as much as 10% of fetal Hb up until the fourth month of fetal life. In that article Huehns stated that the position with regard to the appearance of Hb A was, therefore, obscure. The first observation of the synthesis of humanchains in fetal erythrocytes was reported by Hollenberg et al. in 1971’4 These investigators observed that Hb A was synthesised at a rate of about 10% that of Hb F in the reticulocytes of fetuses as early as 4.5 cm, or 8-9 weeks of gestation. The amount of Hb’ A in such cells was negligible, and methods such as alkali denaturation would have missed it altogether. Because the method of Hollenberg et al. could be carried out on very few erythrocytes and because it surmounted the problem of maternal contamination, these workers predicted its use for antechains were undoubtnatal diagnosis, suggesting that since edly being synthesised, their absence in the p-thalassxmia syndromes and the presence of (3S chains should be detectable by this method. As you state that Kan et al. reported the fulfilment of this prediction in 1972P but this observation was reported independently by Pataryas and Stamatoyannopoulos’6 and by Kazazian et all both in 1972. These observations are intended only to fill in what your editorial missed. They are not intended to, and indeed could

SiR,—Iwish

to comment on some

ial

pA

5.

Konotey-Ahulu, F. I. D. in Proceedings of the Fifth International Congress of Christian Physicians (Christian Medical Fellowship); p. 43. Singapore,

1975. 6. Henrickse, R. G. Ghana med. J. 1963, 2, 14. 7. Konotey-Ahulu, F. I. D. Archs intern. med. 1974, 133, 611. 8. Serjeant, G. R. in Sickle Cell Disease: Clinical Features in the West Indies. Amsterdam, 1974. 9. Pembrey, M. Personal communication. 10. Walker, J., Turnbull, E. P. N. Archs Dis. Childh. 1955, 30, 111. 11. Huehns, E. R., Dance, N., Beaven, G. H., Keil, J. V., Hecht, F., Motulsky, A. G. Nature, 1964, 201, 1095. 12. Kaltsoya, A., Fessas, P., Stavropoulos, A. Science, 1966, 153, 1417. 13. Huehns, E. R., Beaven, G. H. Clins devel. Med. 1971, 37, 1975. 14. Hollenberg, M. D., Kaback, M. M., Kazazian, H. H., Jr, Science, 1971, 174, 698. 15. Kan, Y. W., Dozy, M. T., Alter, B. P., Frigoletto, F. D., Nathan, D. G. New

Engl. J. Med. 1972, 287, 1. 16. Pataryas, H. A., Stamatoyannopoulos, G. Blood, 1972, 39, 688. 17. Kazazian, H. H., Jr, Kaback, M. M., Woodhead, A. P., Leonard, C. O., Nersessian, W. S. in Hemoglobin and Red Cell Structure and Function (edited by G. J. Brewer); p. 337. New York, 1972.

not, detract from the his colleagues.

high quality of the

Department of Pediatrics, Johns Hopkins Hospital, Baltimore, Maryland 21205, U.S.A.

work of Dr Kan and

BARTON CHILDS

PAIN INSENSITIVITY A METABOLIC DISEASE

SIR,-Congenital pain insensitivity is a rare inborn incapato feel superficial or profound pain, with normal tactile

city

and thermal sensations. It occurs in families with consanguineous marriages, and in some cases more than one member of the family is affected, suggesting that it is transmitted by an autosomal recessive gene.1 There are no morphological defects in the central or peripheral nervous systems, and congenital analgesia has been considered to be a functional defect similar to congenital verbal blindness or deafness.3 Several small-molecular-weight compounds have been proposed as pain mediators. Studies by our group of a few cases found in the State of São Paulo, Brazil, have shown that paininducing substances such as acetylcholine, serotonin, histamine, and bradykinin injected under the skin produce hypersemia and oedema, but that there is no accompanying pain. Neurokinin activity in the blister fluid and in subcutaneous perfusate after faradic stimulation is normal.4 We have detected, in the urine of a patient with congenital pain insensitivity concentrated in vacuon to one tenth of its volume, a dark material insoluble in 1 mol/1 hydrochloric acid, but soluble in 1 mol/1 sodium hydroxide. This material is bleached when reduced by hydrosulphide and re-oxidised when treated with ferricyanide, as melanin is.’ The ultraviolet spectra of the sodium-borohydrate-reduced solution has a band around 300 nm, and is identical to the spectra described for the borohydrate-reduced melanin produced by enzymatic oxidation of dopamine by rat brain homogenate.6 The urine of three unrelated patients with congenital pain insensitivity gives a positive melanin test with ferric chloride in hydrochloric acid (Jaksch-Pollak test)sodium nitroprussate (Thormahlen test),8 and hydrosulphide reduction.5 The skin of these patients, who are White, have in the basal layer an accumulation of an apparent colourless compound that gives the histochemical reactions of melanin.9 In their urine we found an abnormal metabolite’O which after acid hydrolysis gives a yellow colour with Erhlich reagent. The product of hydrolysis seems to be an aromatic amine with a molecular weight of 220. It is absent in normal urine, and in the analgesic patients it increases after the sterilisation of the intestinal flora with neomycin. Although paper chromatography does not reveal any major defect in the metabolism of tyrosine, it is possible that the metabolite arises from a minor pathway as a result of an inborn error of metabolism. It seems likely that the melanin-like compound originates as a result of this metabolic defect. A melanin-like compound is normally present as an inclusion in some neurons in the central nervous system, and seems present in some sensory nerve ganglia, where it is sometimes classified as lipofucsin.11 Neuromelanin is thought to have a ’

Saldanha, P. H., Schmidt, B. J., Leon, N. Acta genet. Basel. 1969, 14, 143. Baxter, D. M., Olazewski, V. Brain, 1960, 83, 301. Armstrong, D. Handbk exp. Pharmacol. 1970, 25, 434. Ramos, A. O., Schmidt, B. J. Arch. Neurol. 1964, 10, 42. 5. Figge, F. H. Proc. Soc. exp. Biol. Med. 1939, 41, 127. 6. Das, K. C., Abramson, M. B., Katzman, R. J. Neurochem. 1976, 26, 695. 7. Oser, B. L. (editor) Hawk’s Physiological Chemistry. New York, 1965. 8. Rothman, S.J. Lab. clin. Med. 1942, 27, 687. 9. Merzel, H. Blumen, F., Schmidt, B. J., Raw, I., Castro, N. N. Nucl. Med. 1969, 7, 83. 10. Costa Maia, J. C., Pudles, J., Raw, I., Sihmidt, B. J. Clin. chim Acta, 1974, 54, 225. 11. Lillie, R. D., Fillmer, H. M. Histopathologic Technique and Practical Histochemistry. New York, 1976. 1. 2. 3. 4.

599 functional role in dopamine metabolism, and melanin formation has been described in a decrease in Parkinson’s disease." Developments in the isolation of opium receptors and endorphins call attention to their possible role in the perception of pain. E prostaglandins elicit pain and hyperalgia that is lessened by opiates.14 It seems that the E prostaglandins act at the same level as the opium receptors, which does not exclude still another pain mediator that acts at a lower level before the signal reaches the thalamus. This research was supported by the German Goldman Institute for Human Biology.

Sophie Davis Center for Biomedical Education, City College, New York 10031 City University of New York, New York, N.Y.

10031, U.S.A.

TIEN LAU ISAIAS RAW

Department of Pediatrics, Escola Pulista de Medicina, S. Paulo, Brazil

BENJAMIN J. SCHMIDT

Department of Immunology, University of S. Paulo,

SERGIO PIVA

FOLATES AND THE FETUS

SIR,-Your editorial (Feb. 26, p. 462) refers to our prospective study’ of folate status in pregnancy in relation to neuraltube defects and concludes that the next step will be "preconceptional vitamin supplementation in mothers at high risk of neural-tube defect". As explained in our paper, such a study is now under way. Four other centres are collaborating with Leeds in this work, and we hope to reach a conclusion within two years. Women who have previously given birth to one or more infants with anencephaly or spina bifida, who are planning another pregnancy but who are not yet pregnant, are eligible for the vitamin-supplementation trial. If any doctor has a patient who would like to be included in the study, we should be happy to put them in touch with the most convenient partici-

pating centre. Paediatrics and Child Health,

Department of

R. W. SMITHELLS SHEILA SHEPPARD C. J. SCHORAH

University of Leeds, Leeds LSI 3ET

VACCINATION AGAINST WHOOPING-COUGH

SIRy Your readers will

not

derive any

reassurance

either

from Dr Melchior’s

paperon the relation between pertussis vaccine and neurological illness in infants, or from your ’note on it (Feb. 26, p. 495). It has never been suggested that pertussis immunisation accounts for more than a very small proportion of cases of infantile spasms and hypsarrhythmia, so failure to demonstrate a statistically significant change in the age of onset of this form of infantile epilepsy with changing immunisation practice in Denmark is hardly surprising. This type of study is quite unsuitable for seeking to prove or disprove such an association. Dr Melchior’s paper and the cases mentioned by Dr Stephenson (Feb. 12, p. 357) and Dr Ounsted (Feb. 19, p. 419) may be held to emphasise the hazard of administering pertussis vaccine to infants with pre-existing neurological abnormalities. Hospital for Sick Children, London EC1N 3JH 12

JOHN WILSON

Curson, G. in Biochemical Aspects of Nervous Diseases (edited by C. N. Cunnings); p. 151. New York, 1972. 13 Max, T. E. Science, 1976, 193, 1227. 14 Collier, H. O. J., Roym, A. C. Nature, 1974, 248, 24. 1 Smithells, R. W., Sheppard, S., Schorah, C. J. Archs Dis. Childh. 1976, 51,

ESCHERICHIA COLI MENINGITIS AND CONGENITAL TUBERCULOSIS IN THE SAME INFANT

SIR,-Although congenital tuberculosis is rare in Britain, the increase in tuberculosis in the adult immigrant population is a reminder that we should not forget this disease in neonates with an unusual respiratory or general illness. When it occurs in combination with another serious infection it presents a bizarre diagnostic problem, but it is unwise to neglect the possibility of simultaneous infection with two organisms where there is inadequate response to chemotherapy. A girl, the first child of Kenyan Asians who had been in the U.K. for 12 years, was delivered by Kielland’s forceps for fetal distress at 38 weeks’ gestation, weighing 2.46 kg. Her mother had been unwell with a low-grade fever in the week before delivery, and continued to be febrile in the puerperium. The cause of this illness was not apparent, but a chest X-ray was normal. The infant was in fair condition at birth and needed no special resuscitation. She became jaundiced, and her serum-bilirubin rose to 380 mol/1 on the 6th day. Preparations were made for an exchange transfusion, but the bilirubin level fell thereafter and the transfusion was not done. No cause for the jaundice was found. She was discharged home on the 14th day, apparently well and gaining weight, only to be readmitted 2 days later with a 24 h history of pyrexia, listlessness, and poor feeding. Her white-blood-cell count was 11 900/ple with 55% neutrophils, showing toxic granulations and a left shift. The cerebrospinal fluid (c.s.F.) which was obtained easily, contained 6 polymorphs/.1, 110 mg/dl protein, and 3-3mmol/l glucose. Culture yielded a pure growth of Escherichia coli. She was treated with gentamicin and ampicillin, and chloramphenicol was substituted for the ampicillin when the culture results were known. Shortly after admission tachypnoea and some respiratory difficulty developed. Chest X-ray showed diffuse miliary mottling and the suggested radiological diagnosis was miliary tuberculosis. This was rejected at the time on the grounds that the mother’s chest X-ray was clear, that there was already an alternative diagnosis (E. coli meningitis and probably septicsemia, with haematogenous spread to the lungs), and that the infant was so young. After a day of slight improvement she developed signs of acute water intoxication, with convulsions, a bulging fontanelle, hypothermia, and a plasma-sodium of 101 mmol/l (a fall of 40 mmol/l in 2 days). Lumbar c.s.F. was sterile. Since the plasma-potassium was normal, this clinical picture was attributed to inappropriate antidiuretic hormone secretion, a well-described complication of neonatal meningitis. The infant improved with water restriction and anticonvulsants but her respiratory difficulty subsequently became more severe, and there was deterioration in the chest X-ray appearances, with bilateral confluent pneumonia. At this stage, aged 23 days, she was started on isoniazid and rifampicin, but she died the next day. Full necropsy was refused, but lung tissue taken post mortem showed large numbers of acid-fast bacilli throughout the tissue. The infant’s mother was subsequently investigated and uterine curettings were found to contain tubercle bacilli. This case is a reminder that genital tuberculosis in women need not be associated with infertility, and that coincidental pathogenic bacteria may occur in immunologically incompetent individuals, which includes neonates. Congenital tuberculosis may be rapidly fatal, and Hughesdon’ in 1946 listed ten published cases in which death from tuberculosis had occurred before 30 days of age. Four of these infants had birth-weights exceeding 2000 g, and in five birth-weight was not recorded. We should be continually on the look-out for this disease in persons of all ages, particularly Asian immigrants. infections with different

Departments of Child Health and Radiology, St. George’s Hospital, London SW17 0QT

944.

2. Melchior, J. C. ibid. 1977, 52, 134.

1.

Hughesdon, M.

R. Archs Dis Childh.

1946, 21, 121.

O. G. BROOKE JEAN DOW T. K. HAND