- Email: [email protected]
NEONATAL AND PRENATAL DIAGNOSIS OF HEREDITARY TYROSINAEMIA
1279 twice daily doses with sustained-release the plasma concentration 12 h post dosing is an important indicator. In our study these concentrations were higher after the evening dose (8 -. 0±11 8 mg/1 for infusion and 7 -9±211 mg/1 for the tablets) than after the morning dose (6 - 6--t I -6 mg/l and 6-1±2’00 mg/1) (p<0 01 for both routes of administration). Thus pharmacokinetically theophylline behaves differently during the night and the day. The prolonged half-life of the drug at night-time might contribute to a better prevention of bronchial obstruction in the morning ("morning dip"). The characteristics of a particular sustained-release preparation could have a major influence on the plasma-concentration/time profiles at night, either
With long-term
theophylline,
or by exaggerating these differences. Primrose’s data are inconclusive because the mean curve of the nocturnal plasma concentrations was highly influenced by data from one of the three patients. Such pharmacokinetic studies should take food intake into account: this factor was controlled in our trial but not in Primrose’s pilot study, and this might explain the differences. We agree with Primrose that more data on nocturnal plasma theophylline concentrations are needed, especially for slowrelease theophylline preparations.
by smoothing out
Department of Biopharmaceutics and Clinical Pharmacokinetics, Laboratory for Drug Analysis, 9400 AC Assen, Netherlands
Laboratory investigations were: haemoglobin of 8 - 5 g/dl, white blood cells 2508 8 x 109/1, platelets 368 x 109/1, prothrombin time more than 200 s, and kaolin partial thromboplastin time 178 s. She was resuscitated with packed cell blood transfusion and fresh frozen plasma. Vitamin K 1 mg was given. Repeat coagulation studies were normal and the baby has since progressed well. Over the last 2 years, we have seen several other, milder cases of haemorrhagic disease of the newborn presenting with bruising, oozing from the cord, or passage of blood in the stool, all in breast fed babies, all of whom responded to vitamin KI. Over 85% of babies born in our district are breast fed. The severity of the above case illustrates the importance of recognising the condition promptly and of reconsidering the use of prophylactic vitamin KI. ’
St John’s
Hospital, Chelmsford, Essex CM2 9BG
GAIL C. BRIDGMAN
NEONATAL AND PRENATAL DIAGNOSIS OF HEREDITARY TYROSINAEMIA
SIR,-Lindblad and co-workers,l
in
1977,
were
the first
to
indicate the
JAN H. G. JONKMAN WIM J. V. VAN DER BOON
VITAMIN D BY MOUTH
SiR,-Dr Fraser (April 30, p 971) concludes that "The oral route of supplying vitamin D is ineffective, unnatural, and potentially dangerous". K. T. Koshy, in a 1982 review (J Pharm Sci 71: 137-51), concludes that "dietary vitamin Dis efficiently as a means
mobilised to 25 (OH) D3" and thus is an effective source. As to whether dietary vitamin D is natural, surely it makes more sense to question the "naturalness" of wearing clothes and living in temperate/sub-Arctic zones. Large sections of the UK population do not get enough ultraviolet to satisfy the needs of their bodies for vitamin D and its metabolites. The tragedy of rickets in immigrant communities, and the incidence of femoral neck fractures demonstrate this. As a natural source of vitamin D 33 codliver oil contains a high enough vitamin D3 level to be active (10-20 pig per dose), is acceptable as a food to most vegetarians, and yet is not likely to be taken in doses capable of producing toxicity, a daily dose estimated by Koshy as 2500 J.lg. Indeed the efficacy of codliver oil as an antirachitic agent has recently been acknowledged by the chief medical officer at the Department of Health.1I Seven Seas Health Care Ltd, Marfleet, Kingston-upon-Hull, HU9 5NJ
R. D. RICE
probability of a deficiency of fumarylacetoacetase (EC 3.7.12) in hereditary tyrosinaemia type I. Since then there have been several reports of this deficiency and of the excretion of the accumulating succinylacetone in urine. 2,3Progress has been reviewed by Goldsmith.4 In regions where the incidence of the disorder justifies such an approach, mass to screening has been undertaken, based upon the measurement of succinylacetone in neonatal urine.Prenatal diagnosis has been based upon the measurement of succinylacetone in amniotic fluid.6 This is an important development for there is no effective treatment for hereditary tyrosinaemia. We have established a precise gas-chromatography/massspectrometric assay for succinylacetone, which is measured as its isoxazole-pentafluorobenzyl derivative, using- the homologue glutarylacetone as an internal standard. We have found less than 6 nmol/l of succinylacetone in the amniotic fluid from unaffected pregnancies. Amniotic fluid from pregnancies associated with hereditary tyrosinaemia type I have been reported to contain greater than 100 nmol/l.6 Urine samples from ten patients who were suspected of having hereditary tyrosinaemia have been examined; four had concentrations above 5 mmol/mol creatinine and the remaining six had less than 0 - 4 mmol/mol, a value consistent with those observed for non-pathological samples. Two prenatal tests, with our method, have been done for pregnancies at risk for the disease. The Quebec groupagreed to do their assay in parallel with us. Both laboratories obtained negative results and both mothers have subsequently delivered apparently normal, healthy children. The parents knew that the assays were
experimental. PROPHYLACTIC VITAMIN K AND HAEMORRHAGIC DISEASE OF THE NEWBORN
SiR,-Like Dr McNinch and colleagues (May 14, p 1089) we have been considering returning to a policy of giving vitamin K routinely after birth, following a recent admission to our special care baby unit. The baby had been born at 40 weeks weighing 2380 g. Delivery was uneventful and the baby cried immediately. Examination after birth and again before discharge was satisfactory, and she was allowed home on the tenth day fully breast fed. 3 days later her parents brought her to the special care baby unit with a 36 h history of oozing blood from the umbilicus. She had been seen by a health visitor on the previous day and by a doctor on the morning of admission, but no investigations were requested or treatment given, apart from cord powder. The umbilical oozing of blood had continued all day, and on the night of admission the bleeding had become heavy. On arrival in the unit, she was shocked and pale with continuous bleeding from the cord but no bruising or bleeding from any other site. She had tachypnoea (64/min) and tachycardia (180/min). 1 Rickets and osteomalacia
(Rep Health Soc Subj no 19).
London: HMSO, 1980.
The measurement of succinylacetone in neonatal urine is of value in the differential diagnosis of hereditary tyrosinaemia type i, and we think that this assay should be considered in any suspected case. Such measurements would assist in establishing the true incidence of this hereditary disorder in the UK. Bernhard Baron Memorial Research
Laboratory,
Queen Charlotte’s Hospital for Women, London W6 0XG
GRAHAM S. KING FINLAY MACKENZIE BRIAN R. PETTIT
1. Lindblad B, Lindstedt S, Steen G. On the enzymic defects in hereditary tyrosinaemia. Proc Natl Acad Sci (USA) 1977; 74: 464-45 2. Berger R, Smit GPA, Stoker de Vries SA, Duran M, Kettering D, Wadman SK. Deficiency of fumarylacetoacetase in a patient with hereditary tyrosinaemia Clin Chim Acta 1981; 114: 37-44 3. Christensen E, Brock Jacobsen B, Gregersen N, Hjeds H, Pedersen JB, Brandt N, Backmark UB. Urinary excretion of succinylacetone and deltaaminolaevulinic acid in patients with hereditary tyrosinaemia. Clin Chim Acta 1981; 116: 331-41 4. Goldsmith LA. Tyrosinemia and related disorders. In: Stanbury JB, et al, eds. The metabolic basis of inherited disease, 5th ed. New York: McGraw-Hill, 1983 Chap 13. 5. Grenier A, Lescault A, Laberge C, Gagné R, Mamer O. Detection of succinylacetone and the use of its measurement in mass screening for hereditary tyrosinaemia. Clin Chim Acta 1982; 123: 93-99. 6. Gagné R, Lescault A, Grenier A, Laberge C, Melancon SB, Dallaire L Prenatal diagnosis of tyrosinaemia: Measurement of succinylacetone in amniotic fluid. Prenatal Diagnosis 1982; 2: 185-88.
With long-term
theophylline,
or by exaggerating these differences. Primrose’s data are inconclusive because the mean curve of the nocturnal plasma concentrations was highly influenced by data from one of the three patients. Such pharmacokinetic studies should take food intake into account: this factor was controlled in our trial but not in Primrose’s pilot study, and this might explain the differences. We agree with Primrose that more data on nocturnal plasma theophylline concentrations are needed, especially for slowrelease theophylline preparations.
by smoothing out
Department of Biopharmaceutics and Clinical Pharmacokinetics, Laboratory for Drug Analysis, 9400 AC Assen, Netherlands
Laboratory investigations were: haemoglobin of 8 - 5 g/dl, white blood cells 2508 8 x 109/1, platelets 368 x 109/1, prothrombin time more than 200 s, and kaolin partial thromboplastin time 178 s. She was resuscitated with packed cell blood transfusion and fresh frozen plasma. Vitamin K 1 mg was given. Repeat coagulation studies were normal and the baby has since progressed well. Over the last 2 years, we have seen several other, milder cases of haemorrhagic disease of the newborn presenting with bruising, oozing from the cord, or passage of blood in the stool, all in breast fed babies, all of whom responded to vitamin KI. Over 85% of babies born in our district are breast fed. The severity of the above case illustrates the importance of recognising the condition promptly and of reconsidering the use of prophylactic vitamin KI. ’
St John’s
Hospital, Chelmsford, Essex CM2 9BG
GAIL C. BRIDGMAN
NEONATAL AND PRENATAL DIAGNOSIS OF HEREDITARY TYROSINAEMIA
SIR,-Lindblad and co-workers,l
in
1977,
were
the first
to
indicate the
JAN H. G. JONKMAN WIM J. V. VAN DER BOON
VITAMIN D BY MOUTH
SiR,-Dr Fraser (April 30, p 971) concludes that "The oral route of supplying vitamin D is ineffective, unnatural, and potentially dangerous". K. T. Koshy, in a 1982 review (J Pharm Sci 71: 137-51), concludes that "dietary vitamin Dis efficiently as a means
mobilised to 25 (OH) D3" and thus is an effective source. As to whether dietary vitamin D is natural, surely it makes more sense to question the "naturalness" of wearing clothes and living in temperate/sub-Arctic zones. Large sections of the UK population do not get enough ultraviolet to satisfy the needs of their bodies for vitamin D and its metabolites. The tragedy of rickets in immigrant communities, and the incidence of femoral neck fractures demonstrate this. As a natural source of vitamin D 33 codliver oil contains a high enough vitamin D3 level to be active (10-20 pig per dose), is acceptable as a food to most vegetarians, and yet is not likely to be taken in doses capable of producing toxicity, a daily dose estimated by Koshy as 2500 J.lg. Indeed the efficacy of codliver oil as an antirachitic agent has recently been acknowledged by the chief medical officer at the Department of Health.1I Seven Seas Health Care Ltd, Marfleet, Kingston-upon-Hull, HU9 5NJ
R. D. RICE
probability of a deficiency of fumarylacetoacetase (EC 3.7.12) in hereditary tyrosinaemia type I. Since then there have been several reports of this deficiency and of the excretion of the accumulating succinylacetone in urine. 2,3Progress has been reviewed by Goldsmith.4 In regions where the incidence of the disorder justifies such an approach, mass to screening has been undertaken, based upon the measurement of succinylacetone in neonatal urine.Prenatal diagnosis has been based upon the measurement of succinylacetone in amniotic fluid.6 This is an important development for there is no effective treatment for hereditary tyrosinaemia. We have established a precise gas-chromatography/massspectrometric assay for succinylacetone, which is measured as its isoxazole-pentafluorobenzyl derivative, using- the homologue glutarylacetone as an internal standard. We have found less than 6 nmol/l of succinylacetone in the amniotic fluid from unaffected pregnancies. Amniotic fluid from pregnancies associated with hereditary tyrosinaemia type I have been reported to contain greater than 100 nmol/l.6 Urine samples from ten patients who were suspected of having hereditary tyrosinaemia have been examined; four had concentrations above 5 mmol/mol creatinine and the remaining six had less than 0 - 4 mmol/mol, a value consistent with those observed for non-pathological samples. Two prenatal tests, with our method, have been done for pregnancies at risk for the disease. The Quebec groupagreed to do their assay in parallel with us. Both laboratories obtained negative results and both mothers have subsequently delivered apparently normal, healthy children. The parents knew that the assays were
experimental. PROPHYLACTIC VITAMIN K AND HAEMORRHAGIC DISEASE OF THE NEWBORN
SiR,-Like Dr McNinch and colleagues (May 14, p 1089) we have been considering returning to a policy of giving vitamin K routinely after birth, following a recent admission to our special care baby unit. The baby had been born at 40 weeks weighing 2380 g. Delivery was uneventful and the baby cried immediately. Examination after birth and again before discharge was satisfactory, and she was allowed home on the tenth day fully breast fed. 3 days later her parents brought her to the special care baby unit with a 36 h history of oozing blood from the umbilicus. She had been seen by a health visitor on the previous day and by a doctor on the morning of admission, but no investigations were requested or treatment given, apart from cord powder. The umbilical oozing of blood had continued all day, and on the night of admission the bleeding had become heavy. On arrival in the unit, she was shocked and pale with continuous bleeding from the cord but no bruising or bleeding from any other site. She had tachypnoea (64/min) and tachycardia (180/min). 1 Rickets and osteomalacia
(Rep Health Soc Subj no 19).
London: HMSO, 1980.
The measurement of succinylacetone in neonatal urine is of value in the differential diagnosis of hereditary tyrosinaemia type i, and we think that this assay should be considered in any suspected case. Such measurements would assist in establishing the true incidence of this hereditary disorder in the UK. Bernhard Baron Memorial Research
Laboratory,
Queen Charlotte’s Hospital for Women, London W6 0XG
GRAHAM S. KING FINLAY MACKENZIE BRIAN R. PETTIT
1. Lindblad B, Lindstedt S, Steen G. On the enzymic defects in hereditary tyrosinaemia. Proc Natl Acad Sci (USA) 1977; 74: 464-45 2. Berger R, Smit GPA, Stoker de Vries SA, Duran M, Kettering D, Wadman SK. Deficiency of fumarylacetoacetase in a patient with hereditary tyrosinaemia Clin Chim Acta 1981; 114: 37-44 3. Christensen E, Brock Jacobsen B, Gregersen N, Hjeds H, Pedersen JB, Brandt N, Backmark UB. Urinary excretion of succinylacetone and deltaaminolaevulinic acid in patients with hereditary tyrosinaemia. Clin Chim Acta 1981; 116: 331-41 4. Goldsmith LA. Tyrosinemia and related disorders. In: Stanbury JB, et al, eds. The metabolic basis of inherited disease, 5th ed. New York: McGraw-Hill, 1983 Chap 13. 5. Grenier A, Lescault A, Laberge C, Gagné R, Mamer O. Detection of succinylacetone and the use of its measurement in mass screening for hereditary tyrosinaemia. Clin Chim Acta 1982; 123: 93-99. 6. Gagné R, Lescault A, Grenier A, Laberge C, Melancon SB, Dallaire L Prenatal diagnosis of tyrosinaemia: Measurement of succinylacetone in amniotic fluid. Prenatal Diagnosis 1982; 2: 185-88.