1102 EARLY DIAGNOSIS OF DUCHENNE MUSCULAR DYSTROPHY
SIR,-By the time Duchenne muscular dystrophy (D.M.D.) is diagnosed further males may have been born or conceived, and of them will be affected. If the parents and the mother’s sisters and nieces are to be alerted in time the diagnosis of D.M.D. must be made as early as possible. In Germany newborn males are screened for increases in serum-creatine-kinase (c.K.),’ but diagnosis of an incurable disease before the onset of symptoms may distress the parents.2 We suggest an alternative-namely, C.K. measurement on all boys who are not walking at 18 months. This would be about 3% ofboys,3 and in the U.K. would mean some 9000 tests a year. Such screening could be done by arranging a routine developmental check at 18 months, and if the Department of Health’s proposals4 following the Court report are implemented it could be put into operation immediately using existing services. Experience in Newcastle (see figure) shows that about half of Duchenne patients would be detected in this way. This would be a worthwhile improvement because the average age at diagnosis of D.M.D. in Birmingham is 5.7 years5 and in first-affected cases born in North-East England in 1955-69 the average was 5.8 years and none were diagnosed before the age of 2 years. some
of D.M.D. were born in North-East England. The births of 16 (13. 1%) might have been prevented by the neonatal díagnosis of an older affected relative; 10 of them were conceived after the onset of symptoms in the relative (8.2%). Thus, screening at 18 months would be less effective than neonatal screening in preventing the births of secondary cases of D.M.D., but still worthwhile, and the interpretation and explanation of an abnormal result would be easier. Moreover it would allow those couples who have no family history of the disease to enjoy wholeheartedly the first 18 months of their affected son’s life. cases
Regional Neurological Centre, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE
Infant Development Unit, Queen Elizabeth Medical Centre,
Birmingham Children’s Hospital, Birmingham
DAVID GARDNER-MEDWIN SARAH BUNDEY STUART GREEN
CHLORAMPHENICOL-RESISTANT PNEUMOCOCCI IN WEST AFRICA
Ages at which 130 Newcastle patients with D.M.D. began independent walking, compared with normal3 range. How many further cases might be conceived before the index patient reaches 18 months, and therefore be not "preventable" if diagnosis were at 18 months instead of birth? In the Birmingham study,’ of 22 brothers conceived after the index patient and before the diagnosis was made in him, 5 also had D.M.D., giving a recurrence risk of 1 in 4 to 1 in 5 for brothers. This accords with earlier reports that the proportion of affected brothers of index patients is 022-028.6-’o Incidence figures obtained in North-East England" suggest that about 100 infants with D.M.D. are born in England and Wales every year. Of the next 100 sibs born in these families 10-12 might be males with D.M.D., and 5 or 6 are likely to be conceived before the index patient reaches 18 months.12 In 1952-67 122 1. Beckman, R.,
Scheuerbrandt, G., Antonik, A. Mschr. Kinderheilk. 1976,
124, 658. 2. Gardner-Medwin, D. Archs Dis. Childh. 1976, 51, 982. 3. Neligan, G., Prudham, D. Devel. Med. Child Neurol. 1969, 11, 413. 4. Prevention in the Child Health Services: D.H.S.S. consultation document, annex A p. 2. January, 1978. 5. Bundey, S., Edwards, J. H., Insley, J. Unpublished. 6. Stevenson, A. C. Ann. hum. Genet. 1953, 18, 50. 7. Stevenson, A. C. ibid. 1955, 19, 15. 8. Blyth, H., Pugh, R. J. ibid. 1955, 23, 127. 9. Thompson, M. W., Hutton, E. M. in Vth International Congress of Human Genetics (edited by S. Armenclares and R. Liska); abstr. p. 195. Amster-
dam, 1976. 10. Zatz, M., Lange, K., Spence, M. A. Lancet, 1977, i, 759. 11. Gardner-Medwin, D. J. med. Genet. 1970, 7, 334. 12.
Registrar General’s
Stationery Office.
Statistical Review of
England
and Wales 1972. H.M.
SIR,-First described from Poland in 1970, by Cybulska and her colleagues,’ chloramphenicol-resistant (C.R.) pneumocci have subsequently been met with in Australia,2 Britain,3 and South Africa.4 It is noteworthy that most C.R. pneumococci reported to date have also been resistant to tetracycline (T). The degree of resistance to chloramphenicol has been moderate, with a minimal inhibitory concentration (M.t.c.) of 10-20 }jLg chloramphenicol per ml (M.iC. normally 1-2 flg per ml). This level of resistance has led to the failure of chloramphenicol therapy in pneumococcal meningitis.4 Chloramphenicol resistance has been encountered in serotypes 6, 9, 19, and 23, all of which are common types among carriers and patients with pneumococcal disease. In November, 1977, nasal swabs were collected from 149 children and 59 adults at the University College Hospital, Ibadan, Nigeria. A single swab was used to sample both anterior nares and then promptly plated on blood agar. Cultures were incubated in an atmosphere containing added carbon dioxide. Pneumococci were typed by the specific capsular reaction with sera from the Statens Serum Institut, Copenhagen. Antibiotic sensitivity tests were done by the flood-plate method on blood agar using ’Mastrings’ and all isolates were also tested for sensitivity to chloramphenicol, penicillin, and tetracycline by an agar dilution method using an inoculum of about 1000 viable (colony-forming) units. Among 99 sick children attending the outpatients department, 44 yielded smooth (typeable) pneumocci, which is a high carrier-rate. Of 50 pneumococci isolated in all, 7 (14%) were resistant to both c and T, and 3 (6%) were resistant to T alone. A single strain (type 6) was relatively resistant to penicillin, M.LC. 0-2 g penicillin G per ml, but sensitive to the other antibiotics tested. Resistance to erythromycin or lincomycin was not encountered. The T.R. strains showed a high degree of resistance—M.i.c. 50 g tetracycline hydrochloride per ml. For the c.R. strains the m.i.c.s ranged from 10 to 20 g c per ml. The C.R. isolates, all of which were also resistant to T, belonged to types 6, 9, 11, 12, 13 and 19. Chloramphenicol resistance has not been previously reported in types 11, 12, or 13; serotype 12 may cause
epidemic pneumonia. Serious pneumococcal infections, including fatal meningitis, caused by pneumococci resistant to both c and p have recently 1.
Cybulska, J., Jeljaszewicz, J., Lund, E., Munksgaard, 1970, 15, 304. 2. Hansman, D. Proc. int. Cong. Chemother. (in the press). 3. Howard, A. J., Hince, C. J. ibid. 4. Appelbaum, P. C., Scragg, J. N., Bowen, A. J., Cooper, R. C. Lancet, 1977, ii, 995.
A.
Chemotherapy,
Bhamjee, A., Hallett,
A.
F.,
1103 occurred in Durban4and Johannesburg,5 South Africa. Some of the isolates from Johannesburg were also resistant to erythromycin, lincomycin, and clindamycin. Pneumococcal meningitis is common in West Africa, especially in the rain-forest belt.6 It is therefore important to test the sensitivity of isolates from patients, especially now that chloramphenicol resistance has been found to be common in strains from carriers. It has been our experience in Australia and New Guinea that the isolation of drug-resistant strains from carriers may precede the appearance of infections caused by resistant pneumococci. I thank David Montefiore and Mr C. N. Anong, department of medical microbiology, and Prof. J. B. Familusi, department of paediatrics, University College Hospital, Ibadan, for invaluable assistance. Prof. C. Eric Stroud, department of child health, King’s College Hospital, London, helped to arrange my visit to Nigeria.
Department of Microbiology, Adelaide Children’s Hospital, North Adelaide, South Australia, 5006
DAVID HANSMAN
THE &agr;1-ANTITRYPSIN PHENOTYPE MZ IN ACUTE ANTERIOR UVEITIS with
anterior uveitis (A.A.U.) SIR,-When patients attend eye clinics, 15-25% are found to have clinical and radiographic evidence of ankylosing spondylitis (A.s.); and 30-40% of patients with classic A.s. have attacks of A.A.u. at some time in their lives. An explanation for this overlap has been discovered in studies of the inherited antigen HLA-B27.’ Present in 7% of the population, this antigen has been found in 85-95% of patients with A.S., in 43% of patients with A.A.U. without rheumatic disease, and in almost all patients with both A.s. and A.A.u. Thus, these two clinical features seem to occur together owing to an overlap of genetic factors, sharing B27 as a marker. But this is not the whole answer: A.A.U. occurs in only 1% of the entire B27 population, compared with one-third of patients with B27and classic A.s. We have previously reported an increased frequency of the al-antitrypsin phenotype MZ in fibrosing alveolitis, and of both MS and MZ in patients with rheumatoid arthritis and fibrosing alveolitis.2 We now report a study in which the phenotype MZ was found in 20 of 80 patients with A.A.U., compared with 6 of 200 controls (P=0-000001) (see accompanying table). 47 patients with A.A.u. had been investigated thoroughly and found to have no evidence of rheumatic disease; 38 of them had been tissue-typed, and MZ was present in 6 of 17 without B27 and 2 of 21 with B27. In all, 10 of the 47 patients without rheumatic disease had MZ. This suggests a previously unrecognised inherited susceptibility to A.A.u. capable of operating in the absence of B27 or any tendency to rheumatic disacute
ease.
We also compared A.S. patients, with and without A.A.u. 5 patients without B27 and 10 who also had peripheral arthritis were
included, approximately equally divided between the two
groups: all of these patients had the phenotype M and therefore did not bias the results. MZ was present in only 2 of 30 patients with A.s. and no history A.A.u. Buisseret et a1.3 reported MZ in 6 of 175 patients with A.S. without specifying the clinical features. Taken together, these results suggest that a major association of MZ with A.s. alone is unlikely. By cofitrast, we found MZ in 10 of 33 patients with both A.s. and A.A.u. Even when B27 or "spondylitis susceptibility genes" are present, the phenotype MZ seems to increase the risk of A.A.U. more than tenfold. Dr Arnason and his colleagues (Feb. 11, p. 339) reported a 5.
Koornhof, H. J., Jacobs, M., Robins-Browne, R., Isaacson, M. Morbid. Mortal. wkly Rep. 1977, 26, 285. 6. Tugwell, P., Greenwood, B. M., Warrell, D. A. Q. J. Med. 1976, 45, 583. 1. Brewerton, D. A. Arthritis Rheum. 1976, 19, 656 2. Geddes, D. M., Webley, M., Brewerton, D. A., Turton, C. W., Turner-Warwick, M., Murphy, A. H., Milford Ward, A. Lancet, 1977, ii, 1049. 3. Buisseret, P. D., Pembrey, M. E., Lessof, M. H. ibid. p. 1358.
PHENOTYPE
Statistical
MZ
IN PATIENTS AND CONTROLS
comparisons with controls tp
SIR,-By the time Duchenne muscular dystrophy (D.M.D.) is diagnosed further males may have been born or conceived, and of them will be affected. If the parents and the mother’s sisters and nieces are to be alerted in time the diagnosis of D.M.D. must be made as early as possible. In Germany newborn males are screened for increases in serum-creatine-kinase (c.K.),’ but diagnosis of an incurable disease before the onset of symptoms may distress the parents.2 We suggest an alternative-namely, C.K. measurement on all boys who are not walking at 18 months. This would be about 3% ofboys,3 and in the U.K. would mean some 9000 tests a year. Such screening could be done by arranging a routine developmental check at 18 months, and if the Department of Health’s proposals4 following the Court report are implemented it could be put into operation immediately using existing services. Experience in Newcastle (see figure) shows that about half of Duchenne patients would be detected in this way. This would be a worthwhile improvement because the average age at diagnosis of D.M.D. in Birmingham is 5.7 years5 and in first-affected cases born in North-East England in 1955-69 the average was 5.8 years and none were diagnosed before the age of 2 years. some
of D.M.D. were born in North-East England. The births of 16 (13. 1%) might have been prevented by the neonatal díagnosis of an older affected relative; 10 of them were conceived after the onset of symptoms in the relative (8.2%). Thus, screening at 18 months would be less effective than neonatal screening in preventing the births of secondary cases of D.M.D., but still worthwhile, and the interpretation and explanation of an abnormal result would be easier. Moreover it would allow those couples who have no family history of the disease to enjoy wholeheartedly the first 18 months of their affected son’s life. cases
Regional Neurological Centre, Newcastle General Hospital, Newcastle upon Tyne NE4 6BE
Infant Development Unit, Queen Elizabeth Medical Centre,
Birmingham Children’s Hospital, Birmingham
DAVID GARDNER-MEDWIN SARAH BUNDEY STUART GREEN
CHLORAMPHENICOL-RESISTANT PNEUMOCOCCI IN WEST AFRICA
Ages at which 130 Newcastle patients with D.M.D. began independent walking, compared with normal3 range. How many further cases might be conceived before the index patient reaches 18 months, and therefore be not "preventable" if diagnosis were at 18 months instead of birth? In the Birmingham study,’ of 22 brothers conceived after the index patient and before the diagnosis was made in him, 5 also had D.M.D., giving a recurrence risk of 1 in 4 to 1 in 5 for brothers. This accords with earlier reports that the proportion of affected brothers of index patients is 022-028.6-’o Incidence figures obtained in North-East England" suggest that about 100 infants with D.M.D. are born in England and Wales every year. Of the next 100 sibs born in these families 10-12 might be males with D.M.D., and 5 or 6 are likely to be conceived before the index patient reaches 18 months.12 In 1952-67 122 1. Beckman, R.,
Scheuerbrandt, G., Antonik, A. Mschr. Kinderheilk. 1976,
124, 658. 2. Gardner-Medwin, D. Archs Dis. Childh. 1976, 51, 982. 3. Neligan, G., Prudham, D. Devel. Med. Child Neurol. 1969, 11, 413. 4. Prevention in the Child Health Services: D.H.S.S. consultation document, annex A p. 2. January, 1978. 5. Bundey, S., Edwards, J. H., Insley, J. Unpublished. 6. Stevenson, A. C. Ann. hum. Genet. 1953, 18, 50. 7. Stevenson, A. C. ibid. 1955, 19, 15. 8. Blyth, H., Pugh, R. J. ibid. 1955, 23, 127. 9. Thompson, M. W., Hutton, E. M. in Vth International Congress of Human Genetics (edited by S. Armenclares and R. Liska); abstr. p. 195. Amster-
dam, 1976. 10. Zatz, M., Lange, K., Spence, M. A. Lancet, 1977, i, 759. 11. Gardner-Medwin, D. J. med. Genet. 1970, 7, 334. 12.
Registrar General’s
Stationery Office.
Statistical Review of
England
and Wales 1972. H.M.
SIR,-First described from Poland in 1970, by Cybulska and her colleagues,’ chloramphenicol-resistant (C.R.) pneumocci have subsequently been met with in Australia,2 Britain,3 and South Africa.4 It is noteworthy that most C.R. pneumococci reported to date have also been resistant to tetracycline (T). The degree of resistance to chloramphenicol has been moderate, with a minimal inhibitory concentration (M.t.c.) of 10-20 }jLg chloramphenicol per ml (M.iC. normally 1-2 flg per ml). This level of resistance has led to the failure of chloramphenicol therapy in pneumococcal meningitis.4 Chloramphenicol resistance has been encountered in serotypes 6, 9, 19, and 23, all of which are common types among carriers and patients with pneumococcal disease. In November, 1977, nasal swabs were collected from 149 children and 59 adults at the University College Hospital, Ibadan, Nigeria. A single swab was used to sample both anterior nares and then promptly plated on blood agar. Cultures were incubated in an atmosphere containing added carbon dioxide. Pneumococci were typed by the specific capsular reaction with sera from the Statens Serum Institut, Copenhagen. Antibiotic sensitivity tests were done by the flood-plate method on blood agar using ’Mastrings’ and all isolates were also tested for sensitivity to chloramphenicol, penicillin, and tetracycline by an agar dilution method using an inoculum of about 1000 viable (colony-forming) units. Among 99 sick children attending the outpatients department, 44 yielded smooth (typeable) pneumocci, which is a high carrier-rate. Of 50 pneumococci isolated in all, 7 (14%) were resistant to both c and T, and 3 (6%) were resistant to T alone. A single strain (type 6) was relatively resistant to penicillin, M.LC. 0-2 g penicillin G per ml, but sensitive to the other antibiotics tested. Resistance to erythromycin or lincomycin was not encountered. The T.R. strains showed a high degree of resistance—M.i.c. 50 g tetracycline hydrochloride per ml. For the c.R. strains the m.i.c.s ranged from 10 to 20 g c per ml. The C.R. isolates, all of which were also resistant to T, belonged to types 6, 9, 11, 12, 13 and 19. Chloramphenicol resistance has not been previously reported in types 11, 12, or 13; serotype 12 may cause
epidemic pneumonia. Serious pneumococcal infections, including fatal meningitis, caused by pneumococci resistant to both c and p have recently 1.
Cybulska, J., Jeljaszewicz, J., Lund, E., Munksgaard, 1970, 15, 304. 2. Hansman, D. Proc. int. Cong. Chemother. (in the press). 3. Howard, A. J., Hince, C. J. ibid. 4. Appelbaum, P. C., Scragg, J. N., Bowen, A. J., Cooper, R. C. Lancet, 1977, ii, 995.
A.
Chemotherapy,
Bhamjee, A., Hallett,
A.
F.,
1103 occurred in Durban4and Johannesburg,5 South Africa. Some of the isolates from Johannesburg were also resistant to erythromycin, lincomycin, and clindamycin. Pneumococcal meningitis is common in West Africa, especially in the rain-forest belt.6 It is therefore important to test the sensitivity of isolates from patients, especially now that chloramphenicol resistance has been found to be common in strains from carriers. It has been our experience in Australia and New Guinea that the isolation of drug-resistant strains from carriers may precede the appearance of infections caused by resistant pneumococci. I thank David Montefiore and Mr C. N. Anong, department of medical microbiology, and Prof. J. B. Familusi, department of paediatrics, University College Hospital, Ibadan, for invaluable assistance. Prof. C. Eric Stroud, department of child health, King’s College Hospital, London, helped to arrange my visit to Nigeria.
Department of Microbiology, Adelaide Children’s Hospital, North Adelaide, South Australia, 5006
DAVID HANSMAN
THE &agr;1-ANTITRYPSIN PHENOTYPE MZ IN ACUTE ANTERIOR UVEITIS with
anterior uveitis (A.A.U.) SIR,-When patients attend eye clinics, 15-25% are found to have clinical and radiographic evidence of ankylosing spondylitis (A.s.); and 30-40% of patients with classic A.s. have attacks of A.A.u. at some time in their lives. An explanation for this overlap has been discovered in studies of the inherited antigen HLA-B27.’ Present in 7% of the population, this antigen has been found in 85-95% of patients with A.S., in 43% of patients with A.A.U. without rheumatic disease, and in almost all patients with both A.s. and A.A.u. Thus, these two clinical features seem to occur together owing to an overlap of genetic factors, sharing B27 as a marker. But this is not the whole answer: A.A.U. occurs in only 1% of the entire B27 population, compared with one-third of patients with B27and classic A.s. We have previously reported an increased frequency of the al-antitrypsin phenotype MZ in fibrosing alveolitis, and of both MS and MZ in patients with rheumatoid arthritis and fibrosing alveolitis.2 We now report a study in which the phenotype MZ was found in 20 of 80 patients with A.A.U., compared with 6 of 200 controls (P=0-000001) (see accompanying table). 47 patients with A.A.u. had been investigated thoroughly and found to have no evidence of rheumatic disease; 38 of them had been tissue-typed, and MZ was present in 6 of 17 without B27 and 2 of 21 with B27. In all, 10 of the 47 patients without rheumatic disease had MZ. This suggests a previously unrecognised inherited susceptibility to A.A.u. capable of operating in the absence of B27 or any tendency to rheumatic disacute
ease.
We also compared A.S. patients, with and without A.A.u. 5 patients without B27 and 10 who also had peripheral arthritis were
included, approximately equally divided between the two
groups: all of these patients had the phenotype M and therefore did not bias the results. MZ was present in only 2 of 30 patients with A.s. and no history A.A.u. Buisseret et a1.3 reported MZ in 6 of 175 patients with A.S. without specifying the clinical features. Taken together, these results suggest that a major association of MZ with A.s. alone is unlikely. By cofitrast, we found MZ in 10 of 33 patients with both A.s. and A.A.u. Even when B27 or "spondylitis susceptibility genes" are present, the phenotype MZ seems to increase the risk of A.A.U. more than tenfold. Dr Arnason and his colleagues (Feb. 11, p. 339) reported a 5.
Koornhof, H. J., Jacobs, M., Robins-Browne, R., Isaacson, M. Morbid. Mortal. wkly Rep. 1977, 26, 285. 6. Tugwell, P., Greenwood, B. M., Warrell, D. A. Q. J. Med. 1976, 45, 583. 1. Brewerton, D. A. Arthritis Rheum. 1976, 19, 656 2. Geddes, D. M., Webley, M., Brewerton, D. A., Turton, C. W., Turner-Warwick, M., Murphy, A. H., Milford Ward, A. Lancet, 1977, ii, 1049. 3. Buisseret, P. D., Pembrey, M. E., Lessof, M. H. ibid. p. 1358.
PHENOTYPE
Statistical
MZ
IN PATIENTS AND CONTROLS
comparisons with controls tp
