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PUBERTAL FAILURE IN CONGENITAL ADRENOCORTICAL HYPOPLASIA
1035
high firing frequency were found. In supraspinatus muscles big potentials were noted. In extensor brevis muscles, instead of a few polyphasic potentials, the pattern was almost one of interference. A 40-year-old woman, 2 years before admission, had fasciculations in abdominal wall and limb muscles. Climbing stairs became more difficult. 7 months later she could not squat and rise without support. Muscle wasting and shoulder-girdle weakness developed followed by hand weakness after she had been admitted to hospital. On admission she could sew with big needle: 2 months later she could not even feed herself. She used to work as a clerk in a car-repair shop with a high degree of air pollution. The rationale for penicillamine therapy was again the possibility of chronic latent lead intoxication,
although no laboratory indicators were found. in hand and lower arm muscles showed: extreme loss. In the shoulder-girdle there was moderate, similar, or even pathological, findings in leg muscles. c.s.F. and blood studies all normal; no evidence of lead toxicity. Treatment with penicillamine 3 x 300 mg/day began 5 weeks ago. After a week she already felt stronger. She did not tire so easily. Climbing stairs became easier. Her disease seems to have stopped progressing and may even have improved slightly. Some days ago basophilic punctated erythrocytes (46% of red blood-cells) and reticulocytes (14%) appeared. Park et aLl described favourable results with penicillamine in the treatment of dystrophic chickens. Their rationale for using penicillamine, a sulphydryl compound with reducing properties, was to attempt to protect essential thiol groups of enzymes and structural proteins against oxidation and to reduce collagen cross-linking and synthesis. E.M.G.
motor-neurone
Centre for Neuromuscular
Diseases,
Department of Neurology, Medical School,
University of Zagreb, Zagreb, Yugoslavia
ANICA JUŠIĆ M. ŠOŠTARKO
COMPLICATION OF CERVICAL CIRCLAGE
SIR,—We read with interest your editorial (Oct. 1, p. 691) on
cervical
to report an
circlage for cervical incompetence and would like unusual complication.
A 34-year-old woman presented at outpatients complaining of increasing incontinence of urine for 4 years since her confinement. Incontinence was present at night but not after voluntary bladder emptying. She had also had recurrent urinary infections and severe stress incontinence. She had a history of a 12-week miscarriage treated by diagnostic curettage, and a subsequent painless labour at 24 weeks, the baby dying after 11 h. Subepithelial cervical sutures had been inserted in her succeeding three pregnancies using ’Mersilene’ tape, all tied anteriorly. The last suture had been removed under general
anaesthetic, with some difficulty, 4 years previously. The patient had an extensively scarred cervix, a moderate cystourethrocele with free stress incontinence, and a small vaginal pool of urine. With intravesical methylene-blue, a pinhole fistula high on the anterior vaginal wall on the right side was found. Cystoscopy showed extensive inflammation and a hnear groove in the bladder wall medial to the right ureteric orifice. At operation a small vesicovaginal fistula with a 1 cm scar of the bladder, presumably caused either at insertion or removal of the last cervical suture, was excised and repaired, together with an anterior colporrhaphy. The patient is now continent. Department of Obstetrics and Gynæcology, B M Stanley Hospital, St Asaph, Clwydd LL17 0RS 1
J. L. BATES T. CROPLEY
Park, J. H, Chon, T. H., Hill, E. J., Pinson, R., Bartle, E., Connally, J., Lequire, V., Roelofa, R., Olson, W. in Recent Advances in Myology edited by W G Bradley, D. Gardner-Medwin, and J. N. Walton); p. 401. Amsterdam, 1975.
PUBERTAL FAILURE IN CONGENITAL ADRENOCORTICAL HYPOPLASIA
SIR,-Some twenty-seven cases of the cytomegalic type of congenital adrenocortical hypoplasia (C.A.H.) have been described.l,2 Twelve were sporadic and fifteen familial. Of the six surviving patients the three oldest boys, now aged between 17 and 19 years, live in Scotland. Since 1974, when he presented at the age of 14 with short stature and a lack of pubertal development, the second oldest boy3 with cytomegalic C.A.H. has attended Glasgow Royal Infirmary. After hypothyroidism and growth-hormone deficiency had been excluded he was put on a course of human chorionic gonadotrophin (H.C.G.) therapy in 1975. Although pubertal grading was only marginally advanced the patient had a definite growth spurt and his plasma-testosterone on H.c.G. was 36 nmol!l (normal adult male range 11-36). However, when H.c.G. therapy was discontinued the plasma-testosterone fell to 1-2 nmol/1 and no further progress into puberty was clinically detectable. Since May, 1976, the patient has been periodically investigated and it has been established that he has secondary (hypogonadotrophic) hypogonadism. His testes respond to exogenous gonadotrophin but both single and repeated injections of gonadotrophin-releasing hormone (G.R.H.) do not cause significant release of pituitary gonadotrophin, either luteinising hormone (L.H.) or follicle-stimulating hormone (F.s.H.). In 1975 Prader et al.4 reported L.H. deficiency in an 18-yearold boy with C.A.H. During the past 4 months two further sporadic cases of C.A.H.5,6 have been described where, at the ages of 14 and 21, the coexistence of hypogonadotrophic hypogonadism has been demonstrable. Since 1976 I have followed up all the reported cases’,’,’ of the cytomegalic type of familial C.A.H. who are of pubertal years (i.e., at least 13 years of age). With the cooperation of the patients’ physicians, to whom I am indebted, I have monitored the pubertal progress of these five patients, now aged 13-19.- Moreover I also have current information on two surviving brothers who were unique in the c.A.H. literature9 in having, in 1971, at the ages of 11 and 13 years, easily measurable serum L.H. levels considered "appropriate for age and stage of sexual development". All seven patients show a lack of pubertal development and all seven have very low testosterone values in the face of low L.H. and F.S.H. values. In those five patients where a G.R.H. test has been performed there were no significant increases in the concentrations of either serum L.H. or F.S.H.
the question posed by Prader at al.4 it appears is regularly associated with gonadotrophin deficiency which results in lack of pubertal development. The two endocrine defects might be unrelated, but this seems unlikely because there is now some evidence that, in both rat and man,10, 11 the adrenal sex steroids, dehydroepiandrosterone and androstenedione, may play a role in triggering the hypothalamic-pituitary-gonadal axis by hastening the onset of maturation of the central-nervous-system mechanisms leading to To that
answer
c.A.H.
puberty. Since cases,
puberty has not happened spontaneously in the ten by the age of 21, some form of therapeutic inter-
even
vention is indicated. So far testosterone4
or
H.C.G.5,6 have been
Mamelle, J-C., David, M., Riou, D., Gilly, J., Trouillas, J., Dutruge, J., Gilly, R. Archs fr. Pédiat. 1975, 32, 139. 2. Laverty, C. R. A., Fortuhe, D. W., Beischer, N. A. Obstet. Gynec. 1973, 41, 1.
655.
Uttley, W. S. Archs Dis. Childh. 1968, 43, 724. 4. Prader, A., Zachmann, M., Illig, R. J. Pediat. 1975, 86, 421. 5. Kelly, W. F., Joplin, G. F., Pearson, G. W. Br. med. J. 1977, ii, 98. 6. Black, S., Brook, C. G. D., Cox, P. J. N. ibid. p. 996. 7. Mitchell, R. G., Rhaney, K. Lancet, 1959, i, 488. 8. Weiss, L., Mellinger, R. C. J. med. Genet. 1970, 7, 27. 9. Sperling, M. A., Wolfsen, A. R., Fisher, D. A. J. Pediat. 1973, 82, 444. 10. Gorski, M. E., Lawton, I. E. Endocrinol. 1973, 93, 1232. 11. Ducharme, J. R., Forrest, M. G., De Peretti, E., Sempe, M., Collu, R., trand, J. J clin Endocr. Metab 1976, 42, 468. 3.
Ber-
1036 tried. It seems likely that these treatments will dampen the presumed functionally immature hypothalamic-pituitary-gonadal axis, and in the latest reported case6 there has certainly been no improvement in G.R.H. response despite pubertal advancement with exogenous gonadotrophin. It would, therefore, seem worthwhile to try adrenal androgens in patients with familial C.A.H. Although the mechanism responsible for the onset of puberty may be sensitive to adrenal androgens for only a limited period, which may be past at the time of diagnosis of hypogonadism, there is no definite information to confirm this and a trial of dehydroepiandrosterone is being planned in the three Scottish cases of familial cytomegalic adrenocortical hypoplasia and hypogonadotrophic hypogonadism. The endocrine investigations of these patients will be published in full elsewhere. I thank Dr J. A. Thomson for allowing me to study the patient under his care.
University Department of Medicine, Royal Infirmary, Glasgow G4 OSF
IAN D. HAY
In 1976 Dr M. B. Bhide of the Haffkine Institute showed that case 5 was D.D.S.-resistant in the mouse-foot-pad test. 100 mg D.D.S. per day was continued till May 1977 when our test showed complete resistance to D.D.S. but sensitivity to rifampicin. This patient has now shown excellent clinical response to
rifampicin. This work has been supported by the United Kingdom Ministry of Overseas Development and the World Health Organisation, Geneva. Foundation for Medical Research, Worli, Bombay—400 018, India
Acworth Leprosy Hospital,
Wadala, Bombay
LEPROSY on
purified suspensions of leprosy bacilli under conditions where the bacterial population is similar to that of the original biopsy, and before the emergence of contaminants.’ Tritium (3H)-labelled thymidine and dihydroxyphenylalanine (dopa) have been used to estimate growth potential and bacterial integrity (dopa, a species-specific label, becomes trapped within the high-permeability barrier of the plasma membrane and is then oxidised in situ; this barrier is absent in tissue contaminants2 and dead bacilli). Replicate cultures in suitable medium3’s are incubated with pulse-labelled thymidine for 24 h and labelled dopa for 6 h. Ratios of scintillation counts at days 6 or 9 to counts on day 0 are calculated. The range of dapsone (D.D.s.) concentrations studied covers the range found in serum of D.D.s.-resistant patients. With untreated cases, we also observed responses with a range of lower concentrations of D.D.s., some samples showing a sensitivity of 100 times greater than that shown by any known contaminant. Our first D.D.s. resistance tests using labelled dopa showed that untreated cases gave a ratio at 6 days of 2.08±0.24 (s.E.); D.D.S: treated cases gave a ratio at 6 days of 1.58±0.22 (s.E.). 11 relapsed cases gave highly variable ratios, some appearing to respond, others appearing resistant, but recent results with Ambrose, E. J., Antia, N. H., Khanolkar, S. R. Nature, 1976, 47, 267. Krishnaswamy, P. R., Shetty, K. T. Personal communication. Bapt, C. V., Modak, M. S. Bombay University, M. SC. thesis, 1977. Nakamura, M. J. Microbiol. 1976, 82, 385. Murohashi, T., Yoshida, K. Acta leprol. 1975, 58, 21.
N. H. ANTIA R. G. CHULAWALLA K. K. KOTICHA
SIR,-The paper by Dr Brodie and colleagues (Oct. 1, 699) contains several discrepancies and errors.
p.
Congenital porphyria is considered to be "a deficiency of [uroporphyrinogen cosynthetase] activity". There is sufficient evidence to doubt the deficiency of URO. Cos;1-3 excess of URO. s. [synthetase] may be the defect.1,2 The difference between "relative deficiency"4 and "deficiency"2 is very signiURO. cos.
ficant because similar symptoms will be encountered with URO. s. excess and URO. cos. deficiency.3 Brodie et al. state that URo. cos. "converts uroporphyrinogen i to the metabolically useful uroporphyrinogen m". This is wrong: uroporphyrinogenI is not converted to uropor-
phyrinogen III by URO. cos. or by URO. s./URO. cos. systems.’-10 Writing on acute and non-acute porphyria, Brodie et al. implicate 8-aminolsevulinic acid (A.L.A.) as the cause of the neurological symptoms in acute porphyrias. The evidence is controversial. Our experiments disprove A.L.A. toxicity in rats," and a review of the problem12 leaves the question open, Miyagi, K., and others. Am. J. Hemat. 1976, 1, 3. Petryka, Z. J. Ann. N.Y. Acad. Sci. 1975, 244, 493. 3. Tschudy, D. P., Bonkowsky, H. L. Mol. cell. Biochem. 1973, 2, 55. 4. Levin, E. Y. Ann. N.Y. Acad. Sci. 1975, 244, 481. 5. Smith, K. M. (editor). Porphyrins and Metalloporphyrins. Amsterdam, 1. 2.
1975.
Bogorad, L. Science 1955, 121, 878. 7. Bogorad, L. J. biol. Chem. 1958, 233, 510, 510. 8. Granick, S., Mauzerall, D. ibid. 1958, 232, 1119. 9. Bogorad, L., Marks, G. S. Biochim. biophys. Acta, 1960, 41, 356. 10. Levin, E. Y. Biochemistry, 1971, 10, 4669. 11. Pierach, C. A., and others. Experientia, 1977, 33, 873. 12. Becker, D. M., Kramer, S. Medicine, 1977, 56, 411. 6.
1. 2. 3. 4. 5.
E. J. AMBROSE SAROJ R. KHANOLKAR
ENZYME ABNORMALITIES IN THE PORPHYRIAS
RAPID TEST FOR DRUG RESISTANCE IN
SIR,—We have investigated the in-vitro effect of drugs
improved methods and using ratios at day 9 are shown in the table. Untreated case 2, on whom parallel tests with thymidine and dopa were carried out, shows sensitivity to D.D.S. and rifampicin. Relapsed case 3 has responded well in the clinic to rifampicin. Relapsed case 4 has received no regular treatment.
high firing frequency were found. In supraspinatus muscles big potentials were noted. In extensor brevis muscles, instead of a few polyphasic potentials, the pattern was almost one of interference. A 40-year-old woman, 2 years before admission, had fasciculations in abdominal wall and limb muscles. Climbing stairs became more difficult. 7 months later she could not squat and rise without support. Muscle wasting and shoulder-girdle weakness developed followed by hand weakness after she had been admitted to hospital. On admission she could sew with big needle: 2 months later she could not even feed herself. She used to work as a clerk in a car-repair shop with a high degree of air pollution. The rationale for penicillamine therapy was again the possibility of chronic latent lead intoxication,
although no laboratory indicators were found. in hand and lower arm muscles showed: extreme loss. In the shoulder-girdle there was moderate, similar, or even pathological, findings in leg muscles. c.s.F. and blood studies all normal; no evidence of lead toxicity. Treatment with penicillamine 3 x 300 mg/day began 5 weeks ago. After a week she already felt stronger. She did not tire so easily. Climbing stairs became easier. Her disease seems to have stopped progressing and may even have improved slightly. Some days ago basophilic punctated erythrocytes (46% of red blood-cells) and reticulocytes (14%) appeared. Park et aLl described favourable results with penicillamine in the treatment of dystrophic chickens. Their rationale for using penicillamine, a sulphydryl compound with reducing properties, was to attempt to protect essential thiol groups of enzymes and structural proteins against oxidation and to reduce collagen cross-linking and synthesis. E.M.G.
motor-neurone
Centre for Neuromuscular
Diseases,
Department of Neurology, Medical School,
University of Zagreb, Zagreb, Yugoslavia
ANICA JUŠIĆ M. ŠOŠTARKO
COMPLICATION OF CERVICAL CIRCLAGE
SIR,—We read with interest your editorial (Oct. 1, p. 691) on
cervical
to report an
circlage for cervical incompetence and would like unusual complication.
A 34-year-old woman presented at outpatients complaining of increasing incontinence of urine for 4 years since her confinement. Incontinence was present at night but not after voluntary bladder emptying. She had also had recurrent urinary infections and severe stress incontinence. She had a history of a 12-week miscarriage treated by diagnostic curettage, and a subsequent painless labour at 24 weeks, the baby dying after 11 h. Subepithelial cervical sutures had been inserted in her succeeding three pregnancies using ’Mersilene’ tape, all tied anteriorly. The last suture had been removed under general
anaesthetic, with some difficulty, 4 years previously. The patient had an extensively scarred cervix, a moderate cystourethrocele with free stress incontinence, and a small vaginal pool of urine. With intravesical methylene-blue, a pinhole fistula high on the anterior vaginal wall on the right side was found. Cystoscopy showed extensive inflammation and a hnear groove in the bladder wall medial to the right ureteric orifice. At operation a small vesicovaginal fistula with a 1 cm scar of the bladder, presumably caused either at insertion or removal of the last cervical suture, was excised and repaired, together with an anterior colporrhaphy. The patient is now continent. Department of Obstetrics and Gynæcology, B M Stanley Hospital, St Asaph, Clwydd LL17 0RS 1
J. L. BATES T. CROPLEY
Park, J. H, Chon, T. H., Hill, E. J., Pinson, R., Bartle, E., Connally, J., Lequire, V., Roelofa, R., Olson, W. in Recent Advances in Myology edited by W G Bradley, D. Gardner-Medwin, and J. N. Walton); p. 401. Amsterdam, 1975.
PUBERTAL FAILURE IN CONGENITAL ADRENOCORTICAL HYPOPLASIA
SIR,-Some twenty-seven cases of the cytomegalic type of congenital adrenocortical hypoplasia (C.A.H.) have been described.l,2 Twelve were sporadic and fifteen familial. Of the six surviving patients the three oldest boys, now aged between 17 and 19 years, live in Scotland. Since 1974, when he presented at the age of 14 with short stature and a lack of pubertal development, the second oldest boy3 with cytomegalic C.A.H. has attended Glasgow Royal Infirmary. After hypothyroidism and growth-hormone deficiency had been excluded he was put on a course of human chorionic gonadotrophin (H.C.G.) therapy in 1975. Although pubertal grading was only marginally advanced the patient had a definite growth spurt and his plasma-testosterone on H.c.G. was 36 nmol!l (normal adult male range 11-36). However, when H.c.G. therapy was discontinued the plasma-testosterone fell to 1-2 nmol/1 and no further progress into puberty was clinically detectable. Since May, 1976, the patient has been periodically investigated and it has been established that he has secondary (hypogonadotrophic) hypogonadism. His testes respond to exogenous gonadotrophin but both single and repeated injections of gonadotrophin-releasing hormone (G.R.H.) do not cause significant release of pituitary gonadotrophin, either luteinising hormone (L.H.) or follicle-stimulating hormone (F.s.H.). In 1975 Prader et al.4 reported L.H. deficiency in an 18-yearold boy with C.A.H. During the past 4 months two further sporadic cases of C.A.H.5,6 have been described where, at the ages of 14 and 21, the coexistence of hypogonadotrophic hypogonadism has been demonstrable. Since 1976 I have followed up all the reported cases’,’,’ of the cytomegalic type of familial C.A.H. who are of pubertal years (i.e., at least 13 years of age). With the cooperation of the patients’ physicians, to whom I am indebted, I have monitored the pubertal progress of these five patients, now aged 13-19.- Moreover I also have current information on two surviving brothers who were unique in the c.A.H. literature9 in having, in 1971, at the ages of 11 and 13 years, easily measurable serum L.H. levels considered "appropriate for age and stage of sexual development". All seven patients show a lack of pubertal development and all seven have very low testosterone values in the face of low L.H. and F.S.H. values. In those five patients where a G.R.H. test has been performed there were no significant increases in the concentrations of either serum L.H. or F.S.H.
the question posed by Prader at al.4 it appears is regularly associated with gonadotrophin deficiency which results in lack of pubertal development. The two endocrine defects might be unrelated, but this seems unlikely because there is now some evidence that, in both rat and man,10, 11 the adrenal sex steroids, dehydroepiandrosterone and androstenedione, may play a role in triggering the hypothalamic-pituitary-gonadal axis by hastening the onset of maturation of the central-nervous-system mechanisms leading to To that
answer
c.A.H.
puberty. Since cases,
puberty has not happened spontaneously in the ten by the age of 21, some form of therapeutic inter-
even
vention is indicated. So far testosterone4
or
H.C.G.5,6 have been
Mamelle, J-C., David, M., Riou, D., Gilly, J., Trouillas, J., Dutruge, J., Gilly, R. Archs fr. Pédiat. 1975, 32, 139. 2. Laverty, C. R. A., Fortuhe, D. W., Beischer, N. A. Obstet. Gynec. 1973, 41, 1.
655.
Uttley, W. S. Archs Dis. Childh. 1968, 43, 724. 4. Prader, A., Zachmann, M., Illig, R. J. Pediat. 1975, 86, 421. 5. Kelly, W. F., Joplin, G. F., Pearson, G. W. Br. med. J. 1977, ii, 98. 6. Black, S., Brook, C. G. D., Cox, P. J. N. ibid. p. 996. 7. Mitchell, R. G., Rhaney, K. Lancet, 1959, i, 488. 8. Weiss, L., Mellinger, R. C. J. med. Genet. 1970, 7, 27. 9. Sperling, M. A., Wolfsen, A. R., Fisher, D. A. J. Pediat. 1973, 82, 444. 10. Gorski, M. E., Lawton, I. E. Endocrinol. 1973, 93, 1232. 11. Ducharme, J. R., Forrest, M. G., De Peretti, E., Sempe, M., Collu, R., trand, J. J clin Endocr. Metab 1976, 42, 468. 3.
Ber-
1036 tried. It seems likely that these treatments will dampen the presumed functionally immature hypothalamic-pituitary-gonadal axis, and in the latest reported case6 there has certainly been no improvement in G.R.H. response despite pubertal advancement with exogenous gonadotrophin. It would, therefore, seem worthwhile to try adrenal androgens in patients with familial C.A.H. Although the mechanism responsible for the onset of puberty may be sensitive to adrenal androgens for only a limited period, which may be past at the time of diagnosis of hypogonadism, there is no definite information to confirm this and a trial of dehydroepiandrosterone is being planned in the three Scottish cases of familial cytomegalic adrenocortical hypoplasia and hypogonadotrophic hypogonadism. The endocrine investigations of these patients will be published in full elsewhere. I thank Dr J. A. Thomson for allowing me to study the patient under his care.
University Department of Medicine, Royal Infirmary, Glasgow G4 OSF
IAN D. HAY
In 1976 Dr M. B. Bhide of the Haffkine Institute showed that case 5 was D.D.S.-resistant in the mouse-foot-pad test. 100 mg D.D.S. per day was continued till May 1977 when our test showed complete resistance to D.D.S. but sensitivity to rifampicin. This patient has now shown excellent clinical response to
rifampicin. This work has been supported by the United Kingdom Ministry of Overseas Development and the World Health Organisation, Geneva. Foundation for Medical Research, Worli, Bombay—400 018, India
Acworth Leprosy Hospital,
Wadala, Bombay
LEPROSY on
purified suspensions of leprosy bacilli under conditions where the bacterial population is similar to that of the original biopsy, and before the emergence of contaminants.’ Tritium (3H)-labelled thymidine and dihydroxyphenylalanine (dopa) have been used to estimate growth potential and bacterial integrity (dopa, a species-specific label, becomes trapped within the high-permeability barrier of the plasma membrane and is then oxidised in situ; this barrier is absent in tissue contaminants2 and dead bacilli). Replicate cultures in suitable medium3’s are incubated with pulse-labelled thymidine for 24 h and labelled dopa for 6 h. Ratios of scintillation counts at days 6 or 9 to counts on day 0 are calculated. The range of dapsone (D.D.s.) concentrations studied covers the range found in serum of D.D.s.-resistant patients. With untreated cases, we also observed responses with a range of lower concentrations of D.D.s., some samples showing a sensitivity of 100 times greater than that shown by any known contaminant. Our first D.D.s. resistance tests using labelled dopa showed that untreated cases gave a ratio at 6 days of 2.08±0.24 (s.E.); D.D.S: treated cases gave a ratio at 6 days of 1.58±0.22 (s.E.). 11 relapsed cases gave highly variable ratios, some appearing to respond, others appearing resistant, but recent results with Ambrose, E. J., Antia, N. H., Khanolkar, S. R. Nature, 1976, 47, 267. Krishnaswamy, P. R., Shetty, K. T. Personal communication. Bapt, C. V., Modak, M. S. Bombay University, M. SC. thesis, 1977. Nakamura, M. J. Microbiol. 1976, 82, 385. Murohashi, T., Yoshida, K. Acta leprol. 1975, 58, 21.
N. H. ANTIA R. G. CHULAWALLA K. K. KOTICHA
SIR,-The paper by Dr Brodie and colleagues (Oct. 1, 699) contains several discrepancies and errors.
p.
Congenital porphyria is considered to be "a deficiency of [uroporphyrinogen cosynthetase] activity". There is sufficient evidence to doubt the deficiency of URO. Cos;1-3 excess of URO. s. [synthetase] may be the defect.1,2 The difference between "relative deficiency"4 and "deficiency"2 is very signiURO. cos.
ficant because similar symptoms will be encountered with URO. s. excess and URO. cos. deficiency.3 Brodie et al. state that URo. cos. "converts uroporphyrinogen i to the metabolically useful uroporphyrinogen m". This is wrong: uroporphyrinogenI is not converted to uropor-
phyrinogen III by URO. cos. or by URO. s./URO. cos. systems.’-10 Writing on acute and non-acute porphyria, Brodie et al. implicate 8-aminolsevulinic acid (A.L.A.) as the cause of the neurological symptoms in acute porphyrias. The evidence is controversial. Our experiments disprove A.L.A. toxicity in rats," and a review of the problem12 leaves the question open, Miyagi, K., and others. Am. J. Hemat. 1976, 1, 3. Petryka, Z. J. Ann. N.Y. Acad. Sci. 1975, 244, 493. 3. Tschudy, D. P., Bonkowsky, H. L. Mol. cell. Biochem. 1973, 2, 55. 4. Levin, E. Y. Ann. N.Y. Acad. Sci. 1975, 244, 481. 5. Smith, K. M. (editor). Porphyrins and Metalloporphyrins. Amsterdam, 1. 2.
1975.
Bogorad, L. Science 1955, 121, 878. 7. Bogorad, L. J. biol. Chem. 1958, 233, 510, 510. 8. Granick, S., Mauzerall, D. ibid. 1958, 232, 1119. 9. Bogorad, L., Marks, G. S. Biochim. biophys. Acta, 1960, 41, 356. 10. Levin, E. Y. Biochemistry, 1971, 10, 4669. 11. Pierach, C. A., and others. Experientia, 1977, 33, 873. 12. Becker, D. M., Kramer, S. Medicine, 1977, 56, 411. 6.
1. 2. 3. 4. 5.
E. J. AMBROSE SAROJ R. KHANOLKAR
ENZYME ABNORMALITIES IN THE PORPHYRIAS
RAPID TEST FOR DRUG RESISTANCE IN
SIR,—We have investigated the in-vitro effect of drugs
improved methods and using ratios at day 9 are shown in the table. Untreated case 2, on whom parallel tests with thymidine and dopa were carried out, shows sensitivity to D.D.S. and rifampicin. Relapsed case 3 has responded well in the clinic to rifampicin. Relapsed case 4 has received no regular treatment.