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THE HEPATIC GLYCOGENOSES
814
vigorous treatment shows that all infections in children with M.S.U.D., however trivial, must be taken seriously. Treatment should be commenced early to provide sufficient calories and correct electrolyte imbalances, as well as to combat the infection. In particular, I would like to advocate the more widespread use of peritoneal dialysis in the crises of M.S.U.D., since it is our experience that this technique offers an effective and safe means of lowering plasma branched-chain-aminoacid levels and correcting the metabolic acidosis.2 I thank Dr. David Hull for his assistance in the of this report. Hospital for Sick Children, Great Ormond Street, London WC1N 3JH.
ROGER
preparation
J. HARRIS.
THE HEPATIC GLYCOGENOSES
SiR,—The following comment on low liver phosphorylactivity in hepatic glycogenosis may complement the report by Spencer-Peet et al. and your subsequent ase
4
editorial. The enzymatic cascade for activation of glycogen phosphorylase is shown in the accompanying figure. It indicates that low liver phosphorylase activity can result from different defects within the activating system; only one of these is the deficiency of phosphorylase enzyme itself. Liver phosphorylase deficiency (type-vi glycogenosis) has lately been demonstrated,5 but its diagnosis required a number of biochemical examinations in addition to the finding of low phosphorylase activity. Low activity of liver phosphorylase might also be expected if hepatic phosphorylase kinase was deficient (see figure). In 1966 this association was indeed reported
the deficiency of liver phosphorylase kinase (type-1g glycogenosis). However, X-linked inheritance of deficient muscle phosphorylase kinase has been well documented in mice.12 These animals had glycogenosis of muscle but not liver, whereas the patients with type-ix glycogenosis had glycogenosis of liver but not muscle, and their muscle phosphorylase kinase was normal. 6-8 Such different patterns of tissue involvement and inheritance might require attention if animal models are to be useful in the study of human diseases. Low activity of phosphorylase might also be expected if cyclic 3’5’-AMP-dependent kinase was deficient (figure). This association was reported in a girl with glycogenosis of liver and muscle,13 and was labelled type-x glycogenosis.14 Low activity of phosphorylase might occur because of faulty control over the extent of phosphorylase activation while all the enzymes of the activating system would be intact. This situation was observed in a patient with glycogenosis of liver and brain, 15 ,16 and was labelled type-vm glycogenosis.7 A similar patient has been reported by others." One might anticipate that the deficiency of adenyl cyclase could also result in low phosphorylase activity (figure). To our knowledge, deactivation of phosphorylase for this reason has not yet been reported. It is clear, however, that low activity of phosphorylase is but a symptom, equally observable in at least four different types of glycogenosis; and that the proper interpretation of this symptom depends on further biochemical examination of the affected tissue. Children’s Hospital Research Foundation, Department of Pediatrics, University of Cincinnati Medical College, Cincinnati, Ohio 45229, U.S.A.
GEORGE HUG.
EMERGENCY CHEMICAL PATHOLOGY SERVICE SIR,-Dr. Howorth and Mr. Walter (Sept. 18, p. 658)
deplore
Activation of glycogen phosphorylase.
girl with enlarged liver and hepatic glycogenosis,6 labelled type-ix glycogenosis.’ The initial patient with type-ix glycogenosis was a girl,6.7 as have been others described since. 8 In these patients, in
a
and
was
the defect did thus not seem inherited in X-linked fashion. Lately, X-linked inheritance has been postulated by others.9-11 Unfortunately, these latter studies did not include the assay of liver phosphorylase kinase; it is therefore difficult to evaluate their significance relative to 2. 3.
4. 5.
Sallan, S. E., Cottom, D. Lancet, 1969, ii, 1423. Spencer-Peet, J., Norman, M. E., Lake, B. P., McNamara, J., Patrick, A. D. Q. Jl Med. 1971, 40, 95. Lancet, 1971, i, 1339. Hug, G., Schubert, W. K. Biochem. biophys. Res. Commun. 1970,
41, 1178. 6. Hug, G., Schubert, W. K., Chuck, G. Science, 1966, 153, 1534. 7. Hug, G., Garancis, J. C., Schubert, W. K., Kaplan, S. Am. J. Dis. Child. 1966, 111, 457. 8. Hug, G., Schubert, W. K., Chuck, G. J. clin. Invest. 1969, 48, 704. 9. Huijing, F. Biochim. biophys. Acta, 1967, 148, 601. 10. Huijing, F., Fernandes, J. Am. J. hum. Genet. 1969, 21, 275. 11. Hug, G., Schubert, W. K., Chuck, G. J. clin. Invest. 1969, 48, 704.
a
scheme
which, by
all accounts,
now
provides
parts of central London with a more efficient emergency chemical pathology service than the area has ever had before; and they leave us wondering why. Some of their professed reasons-e.g., that it may be " in the patients’ best interest " (the most ominous phrase in medical oratory) to have emergency tests delayed until regular working hours or that the question has nothing to do with an uninterrupted 24-hour cover-cannot be taken seriously. It is true, of course, that many, perhaps most, patients would suffer no ill-effects from having their laboratory tests delayed: 90% of these tests could probably be scrapped without serious harm to anyone. But since we are committed to the extravagant notion-or, if not committed, dependent for our living-that it is worth doing 90 unnecessary tests for the sake of 9 which will calm the clinician and 1 which may directly benefit the patient, it is hard to see why the notion ceases to be valid between 5 P.M. and 9 A.M. It is also true that much work that is now done out of hours could be done in daylight if every large hospital were not cursed with a sprinkling of
housemen, registrars, and consultants who, to adapt Jowett’s phrase, devote the time they can spare from criticising the laboratory to the dereliction of their clinical duties. But it is in the patients’ interest that, having Lyon, J. B., Jr., Porter, J. Biochim. biophys. Acta, 1962, 58, 248. Hug, G., Schubert, W. K., Chuck, G. Biochem. biophys. Res. Commun. 1970, 40, 982. 14. Hug, G., Schubert, W. K., Chuck, G. J. clin. Invest. 1970, 49, 47a. 15. Hug, G., Schubert, W. K., Shwachman, H. J. Pediat. 1965, 67, 12. 13.
741. 16. Hug, G.,
Schubert, W. K., Chuck, G., Garancis, J. C. Am. J. Med.
1967, 42, 139. 17.
Resibois-Gregoire, A., Dourov, N. Acta neuropath. 1966, 6, 70.
vigorous treatment shows that all infections in children with M.S.U.D., however trivial, must be taken seriously. Treatment should be commenced early to provide sufficient calories and correct electrolyte imbalances, as well as to combat the infection. In particular, I would like to advocate the more widespread use of peritoneal dialysis in the crises of M.S.U.D., since it is our experience that this technique offers an effective and safe means of lowering plasma branched-chain-aminoacid levels and correcting the metabolic acidosis.2 I thank Dr. David Hull for his assistance in the of this report. Hospital for Sick Children, Great Ormond Street, London WC1N 3JH.
ROGER
preparation
J. HARRIS.
THE HEPATIC GLYCOGENOSES
SiR,—The following comment on low liver phosphorylactivity in hepatic glycogenosis may complement the report by Spencer-Peet et al. and your subsequent ase
4
editorial. The enzymatic cascade for activation of glycogen phosphorylase is shown in the accompanying figure. It indicates that low liver phosphorylase activity can result from different defects within the activating system; only one of these is the deficiency of phosphorylase enzyme itself. Liver phosphorylase deficiency (type-vi glycogenosis) has lately been demonstrated,5 but its diagnosis required a number of biochemical examinations in addition to the finding of low phosphorylase activity. Low activity of liver phosphorylase might also be expected if hepatic phosphorylase kinase was deficient (see figure). In 1966 this association was indeed reported
the deficiency of liver phosphorylase kinase (type-1g glycogenosis). However, X-linked inheritance of deficient muscle phosphorylase kinase has been well documented in mice.12 These animals had glycogenosis of muscle but not liver, whereas the patients with type-ix glycogenosis had glycogenosis of liver but not muscle, and their muscle phosphorylase kinase was normal. 6-8 Such different patterns of tissue involvement and inheritance might require attention if animal models are to be useful in the study of human diseases. Low activity of phosphorylase might also be expected if cyclic 3’5’-AMP-dependent kinase was deficient (figure). This association was reported in a girl with glycogenosis of liver and muscle,13 and was labelled type-x glycogenosis.14 Low activity of phosphorylase might occur because of faulty control over the extent of phosphorylase activation while all the enzymes of the activating system would be intact. This situation was observed in a patient with glycogenosis of liver and brain, 15 ,16 and was labelled type-vm glycogenosis.7 A similar patient has been reported by others." One might anticipate that the deficiency of adenyl cyclase could also result in low phosphorylase activity (figure). To our knowledge, deactivation of phosphorylase for this reason has not yet been reported. It is clear, however, that low activity of phosphorylase is but a symptom, equally observable in at least four different types of glycogenosis; and that the proper interpretation of this symptom depends on further biochemical examination of the affected tissue. Children’s Hospital Research Foundation, Department of Pediatrics, University of Cincinnati Medical College, Cincinnati, Ohio 45229, U.S.A.
GEORGE HUG.
EMERGENCY CHEMICAL PATHOLOGY SERVICE SIR,-Dr. Howorth and Mr. Walter (Sept. 18, p. 658)
deplore
Activation of glycogen phosphorylase.
girl with enlarged liver and hepatic glycogenosis,6 labelled type-ix glycogenosis.’ The initial patient with type-ix glycogenosis was a girl,6.7 as have been others described since. 8 In these patients, in
a
and
was
the defect did thus not seem inherited in X-linked fashion. Lately, X-linked inheritance has been postulated by others.9-11 Unfortunately, these latter studies did not include the assay of liver phosphorylase kinase; it is therefore difficult to evaluate their significance relative to 2. 3.
4. 5.
Sallan, S. E., Cottom, D. Lancet, 1969, ii, 1423. Spencer-Peet, J., Norman, M. E., Lake, B. P., McNamara, J., Patrick, A. D. Q. Jl Med. 1971, 40, 95. Lancet, 1971, i, 1339. Hug, G., Schubert, W. K. Biochem. biophys. Res. Commun. 1970,
41, 1178. 6. Hug, G., Schubert, W. K., Chuck, G. Science, 1966, 153, 1534. 7. Hug, G., Garancis, J. C., Schubert, W. K., Kaplan, S. Am. J. Dis. Child. 1966, 111, 457. 8. Hug, G., Schubert, W. K., Chuck, G. J. clin. Invest. 1969, 48, 704. 9. Huijing, F. Biochim. biophys. Acta, 1967, 148, 601. 10. Huijing, F., Fernandes, J. Am. J. hum. Genet. 1969, 21, 275. 11. Hug, G., Schubert, W. K., Chuck, G. J. clin. Invest. 1969, 48, 704.
a
scheme
which, by
all accounts,
now
provides
parts of central London with a more efficient emergency chemical pathology service than the area has ever had before; and they leave us wondering why. Some of their professed reasons-e.g., that it may be " in the patients’ best interest " (the most ominous phrase in medical oratory) to have emergency tests delayed until regular working hours or that the question has nothing to do with an uninterrupted 24-hour cover-cannot be taken seriously. It is true, of course, that many, perhaps most, patients would suffer no ill-effects from having their laboratory tests delayed: 90% of these tests could probably be scrapped without serious harm to anyone. But since we are committed to the extravagant notion-or, if not committed, dependent for our living-that it is worth doing 90 unnecessary tests for the sake of 9 which will calm the clinician and 1 which may directly benefit the patient, it is hard to see why the notion ceases to be valid between 5 P.M. and 9 A.M. It is also true that much work that is now done out of hours could be done in daylight if every large hospital were not cursed with a sprinkling of
housemen, registrars, and consultants who, to adapt Jowett’s phrase, devote the time they can spare from criticising the laboratory to the dereliction of their clinical duties. But it is in the patients’ interest that, having Lyon, J. B., Jr., Porter, J. Biochim. biophys. Acta, 1962, 58, 248. Hug, G., Schubert, W. K., Chuck, G. Biochem. biophys. Res. Commun. 1970, 40, 982. 14. Hug, G., Schubert, W. K., Chuck, G. J. clin. Invest. 1970, 49, 47a. 15. Hug, G., Schubert, W. K., Shwachman, H. J. Pediat. 1965, 67, 12. 13.
741. 16. Hug, G.,
Schubert, W. K., Chuck, G., Garancis, J. C. Am. J. Med.
1967, 42, 139. 17.
Resibois-Gregoire, A., Dourov, N. Acta neuropath. 1966, 6, 70.